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Objective To assess the effects of two sizes of silicone endotracheal tubes with internal diameter 26 mm (ETT26) and 30 mm (ETT30) inflated to minimum occlusive volume on tracheal and laryngeal mucosa of adult horses anesthetized for 2 hours with isoflurane. Study design Prospective, randomized, blinded, crossover experimental study. Animals A total of eight healthy adult mares. Methods Upper airway endoscopy and ultrasound measurements of internal tracheal diameter were performed the day before anesthesia. Horses were anesthetized and orotracheally intubated with ETT26 or ETT30. Ease of intubation was scored. The cuff was inflated in 10 mL increments to produce a seal. Final volume of air used and intracuff (IC) pressure (measured by pressure transducer) were recorded. At the end of anesthesia, a manometer was used to measure IC pressure and these measurements compared against measurements from the pressure transducer. Laryngeal and tracheal mucosa were assessed via endoscopy and assigned a score 0–3 before anesthesia, and at 2 and 24 hours following extubation. Results Data are from seven horses because one horse with laryngeal hemiplegia was excluded. Mean tracheal ultrasound measurement was 3.5 ± 0.4 cm. No significant differences were noted between endotracheal tube sizes for intubation score, IC pressures, inflation volumes or tracheal or laryngeal injury scores at any time point. IC pressure measured by manometer was slightly higher than that by transducer (+1.0 ± 2.8 mmHg). Conclusions and clinical relevance Results identified no clear advantage of one endotracheal tube size over the other in the population of horses studied, when endotracheal intubation is properly applied and IC pressure is carefully monitored. However, given that ETT26 was associated with the highest observed IC pressures and the only observed incidents of tracheal circumferential erythema, the larger ETT30 may be the better choice in most cases where tracheal size is sufficient.

Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers.We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540.From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52-1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53-1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57-1·04]).In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting.COALITION COVID-19 Brazil and EMS.

The postconcussion syndrome following mild traumatic brain injuries (mTBI) has been regarded as a mostly benign syndrome that typically resolves in the immediate months following injury. However, in some individuals, symptoms become chronic and persistent. This has been a striking feature of the mostly blast-related mTBIs that have been seen in veterans returning from the recent conflicts in Iraq and Afghanistan. In these veterans a chronic syndrome with features of both the postconcussion syndrome and post-traumatic stress disorder has been prominent. Animal modeling of blast-related TBI has developed rapidly over the last decade leading to advances in the understanding of blast pathophysiology. However, most studies have focused on acute to subacute effects of blast on the nervous system and have typically studied higher intensity blast exposures with energies more comparable to that involved in human moderate to severe TBI. Fewer animal studies have addressed the chronic effects of lower level blast exposures that are more comparable to those involved in human mTBI or subclinical blast. Here we describe a rat model of repetitive low-level blast exposure that induces a variety of anxiety and PTSD-related behavioral traits including exaggerated fear responses that were present when animals were tested between 28 and 35 weeks after the last blast exposure. These animals provide a model to study the chronic and persistent behavioral effects of blast including the relationship of PTSD to mTBI in dual diagnosis veterans.

Despite advanced development of geopolymers, reliable methods to define their technological features are scarce. The objective of this paper is to evaluate the influence of synthesis parameters (water/binder ratio, alkaline activator type and concentration) on the temporal rheological behavior of metakaolin-based geopolymers. Oscillatory tests were conducted in rheometer with a parallel-plates system, where different rheological parameter were measured (storage/loss modulus, linear viscoelastic interval, loss factor, transition point, among others). The rheological behavior was assessed over time. From the results was identified the time period when pastes in fresh state can be handled and which synthesis conditions improve the workability.

High-resolution sequence stratigraphy (HRSS) is a data-driven methodology that refers to the stratigraphic refinement achieved below seismic resolution. HRSS follows the standard sequence stratigraphy methodology and nomenclature, which are well established for the shallow marine to downstream reaches of the fluvial systems. Still, nomenclature must be flexible to some extent when applied to lacustrine carbonate settings. A high-resolution stratigraphic sequence is a cycle of change in stacking patterns of facies, facies associations, architectural elements, or depositional systems bound by the recurrence of the same sequence stratigraphic surface in the rock record that is observed below the resolution of a third-order sequence. Criteria that allow its identification include: I) typical internal Transgressive Regressive (T-R) pattern; II) vertical recurrence of the signature of stacking patterns at each considered hierarchy; III) trends (non-random distribution) of the vertical arrangement of stacking patterns that determine high-frequency sequences as the basis for defining and building the systems tracts of immediately higher-order sequences; IV) mappability of the stacking patterns and their respective bounding stratigraphic surfaces at each considered hierarchy. Reservoir zonation and characterisation is an essential application of HRSS in the petroleum industry. HRSS highlights the reservoir spatial distribution and heterogeneities, which are the stratigraphical essence of 3D geological and fluid flow models. Such models must be sufficiently robust to forecast production performance, to guide reservoir management, to optimise production, and to increase the ultimate recovery factor. In greenfields, HRSS identifies the best reservoirs for production. In brownfields, it guides an increase in production that marks a new phase of rejuvenation. HRSS rationalises and optimises hydrocarbon production and hence is an indispensable methodology for reservoir geology.

Background The diagnosis and treatment of disseminated intravascular coagulation (DIC) remain extremely controversial. Purpose The Italian Society for Thrombosis and Haemostasis commissioned a project to develop clinical practice guidelines for the diagnosis and treatment of DIC. Methods Key questions about the diagnosis and treatment of DIC were formulated by a multidisciplinary working group consisting of experts in clinical medicine and research. After a systematic review and discussion of the literature, recommendations were formulated and graded according to the supporting evidence. In the absence of evidence, evidence of low quality, or contradictory evidence, a formal consensus method was used to issue clinical recommendations. Results and Conclusions In suspected DIC, we suggest the use of the diagnostic scores ISTH (grade C), JMHW (grade C) or JAAM (grade D) over stand alone tests. The cornerstone of the management of DIC remains the treatment of the underlying triggering disease. We do not suggest the use of antithrombin (grade D), dermatan sulphate (grade D), gabexate (grade D), recombinant factor VIIa (grade D), activated protein C (grade D), thrombomodulin (grade B). The use of unfractionated heparin or low-molecular-weight heparin is not suggested except for thromboembombolic prophylaxis in patients a high risk who do not have active bleeding (grade D). In patients with severe sepsis/septic shock and DIC we suggest the use of human recombinant activated protein C (grade D). In patients with DIC and active bleeding we suggest the use of transfusion therapy (platelets, plasma, cryoprecipitate) (grade D).

Use of various induction regimens, of novel immunosuppressive agents, and of newer prophylactic strategies continues to change the pattern of infections among solid organ transplant (SOT) recipients. Although invasive fungal infections (IFIs) occur at a lower incidence than bacterial and viral infections in this population, they remain a major cause of morbidity and mortality worldwide. In March 2008, a panel of Italian experts on fungal infections and organ transplantation convened in Castel Gandolfo (Rome) to develop consensus guidelines for the diagnosis, prevention, and treatment of IFIs among SOT recipients. We discussed the definitions, microbiological and radiological diagnoses, prophylaxis, empirical treatment, and therapy of established disease. Throughout the consensus document, recommendations as clinical guidelines were rated according to the standard scoring system of the Infectious Diseases Society of America and the United Stated Public Health Service.

Introduction Four-corner fusion was described in 1984 by HK Watson for the treatment of SLAC wrist. This intervention has undergone few changes since that description, but the debate on the fixation method is still not resolved. Hypothesis Dorsal locking plates provide better stability, short immobilization and a quicker return to daily activities than traditional fixation methods such as staples. Materials and methods Thirty-one fusions using the Medartis Aptus Four-Corner Fusion ® plate at a mean 13.1 months’ follow-up and 35 using staples at a mean 80.4 months’ follow-up were reviewed in a clinical and radiographic retrospective comparative study. Results Results were comparable between the two groups in terms of range of motion (flexion-extension arc of 67.3° for plates and 60.6° for staples), force (29.6 and 28 kg.F), pain and disability (PRWE 34.8/150 and 40.9; QuickDASH 19.83/100 and 30). Mean time off work was significantly shorter in the plate group (4.5 vs. 7.9 months). There were no non-unions in the plate group, versus 2 in the staples group. Dorsal impingement implicating hardware was also less frequent in the plate group (2 vs. 11). Discussion The dorsal locking plate did not improve final results in four-corner fusion in terms of range of motion, force, pain or function compared to staples. However, it provided stable fixation, allowing a shorter immobilization and a quicker return to work. Although the initial cost is higher, it could allow significant savings on postoperative costs, shifting the technical debate into the field of public health. Level of evidence Level IV, retrospective study.

Resume Introduction L’arthrodese des 4 os a ete decrite en 1984 par H.K. Watson pour le traitement de l’arthrose du poignet de type SLAC. Cette intervention n’a subi que peu de modifications depuis cette description, mais le debat portant sur le procede de fixation n’est toujours pas resolu. Hypothese L’utilisation d’une plaque verrouillee dorsale accorde une meilleure stabilite, permettant une immobilisation courte et une reprise plus rapide des activites par rapport aux modes de fixation traditionnels comme les agrafes. Materiels et methodes Trente et un arthrodeses par plaque Medartis Aptus Four-Corner Fusion® au recul moyen de 13,1 mois et 35 arthrodeses par agrafes au recul moyen de 80,4 mois ont ete revues dans le cadre d’une etude retrospective comparative clinique et radiographique. Resultats Les resultats etaient comparables entre les 2 groupes en termes d’amplitudes articulaires (arc de flexion-extension de 67,3° pour la plaque contre 60,6° pour les agrafes), de force (29,6 kg.F vs. 28 kg.F), de douleur et d’incapacite (PRWE a 34,8/150 vs. 40,9 ; QuickDASH a 19,83/100 vs. 30). La duree moyenne d’arret de travail etait significativement plus faible dans le groupe « plaques » (4,5 mois vs. 7,9 mois). Aucune pseudarthrodese n’a ete constatee avec la plaque verrouillee contre 2 dans le groupe « agrafes ». Les conflits dorsaux lies au materiel etaient egalement moins nombreux dans le groupe « plaques » (2 vs. 11). Discussion L’utilisation de la plaque verrouillee dorsale dans l’arthrodese des 4 os ne semble pas ameliorer les resultats finaux en termes d’amplitudes articulaires, force, douleur et fonction par rapport aux agrafes. Elle confere cependant une stabilite de fixation autorisant une immobilisation plus courte et une reprise plus rapide des activites professionnelles. Meme si le cout initial est eleve, ces plaques pourraient permettre une economie importante sur les couts postoperatoires, le debat se deplacant alors dans un champ de sante publique. Niveau de preuve Niveau 4, etude retrospective.

Introduction/Background The assessment and rehabilitation of aphasia through a neurolinguistic approach is well known, so as its functional impairments to communicate, and its psycho-social consequences. We make the hypothesis that severe aphasia might leads gradually to a decrease of communication among inpatients whose needs are supplied by the institution. We propose to evaluate a new tool, the Communication Independence Measurement (CIM) scale, built like the Functional Impairment Measurement (FIM) scale. Material and method The CIM scale was used among aphasic's inpatients in a neurorehabilitation center, at baseline (M0) and 3 months (M3), by 4 different professionals (2 speech therapists and 2 nurses or carers). Four subdomains were evaluated, from 1 to 7 (motivation to communicate, expression, understanding, interaction). Psychometric properties and correlation to the Boston Diagnostic Aphasia Examination (BDAE) severity grade were analysed. Results Fifty-five patients (mean age 48 ± 11.8 years old, sex ratio 0.83) were consequently included, at 0.91 ± 1.49 months from stroke. Seventeen of them were evaluated at M3. Inter-rater validity was good, with no statistically difference between the 4 examiners at M0 (Kruskal–Wallis test P = 0.77) and at M3 (Kruskal–Wallis test P = 0.96). CIM was highly correlated to BDAE at M0 [intraclass correction (ICC) = 0.60–0.69] and at M3 (ICC = 0.82–0.85). We founded that patients who obtained a score less than the cut-off value of 35 had a bad daily communication. Conclusion The CIM scale seems to be a reliable tool to measure communication in aphasics in rehabilitation center. It might help identifying and thus helping patients with a negative prognosis of communication early during post-stroke rehabilitation time.

Objective To evaluate the ability of the BioFire FilmArray Blood Culture Identification (BCID) panel to rapidly detect pathogens producing late-onset ventilator-associated pneumonia (VAP), a severe infection often produced by Gram-negative bacteria. These microorganisms are frequently multidrug resistant and typically require broad-spectrum empiric treatment. Methods In the context of an international multicentre clinical trial (MagicBullet), respiratory samples were collected at the time of suspicion of VAP from 165 patients in 32 participating hospitals in Spain, Greece and Italy. Microorganisms were identified using the BCID panel and compared with results obtained by conventional microbiologic techniques. Results Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae were the most commonly identified species, representing 54.7% (70/128) of microorganisms. The BCID panel showed high global specificity (98.1%; 95% confidence interval, 96–100) and negative predictive values (96.6%) and a global sensitivity and positive predictive value of 78.6% (95% confidence interval, 70–88) and 87.3%, respectively, for these microorganisms. Importantly, the BCID panel provided results in only 1 hour directly from respiratory samples with minimal sample processing times. Conclusions The BCID panel may have clinical utility in rapidly ruling out microorganisms causing VAP, specifically multidrug-resistant Gram-negative species. This could facilitate the optimization of empiric treatment.

Summary Introduction Children affected by obstetric brachial plexus palsy have an internal rotation contracture of the shoulder and a deformed glenohumeral joint. In 2003, Pearl proposed doing an arthroscopic release of the shoulder to restore external rotation and allow the glenohumeral joint to remodel. The goal of the current study was to evaluate the active and passive shoulder external rotation range of motion and glenohumeral joint remodelling in children treated with arthroscopic-directed release. Materials and methods Between 2004 and 2010, 18 children with passive external rotation under 10° were treated with shoulder arthroscopy to release the anterior capsule and ligaments and perform a subscapularis tenotomy; no tendon transfer was performed. The average age was 4 years, 2 months. Nine children had an injury at C5C6, four had an injury at C5C6C7 and five had a complete injury. The average follow-up was 4.5 years. The clinical evaluation consisted of active and passive external rotation (ER) with elbow at the side, active internal rotation, and the modified Mallet score. One child who required an external rotation osteotomy of the proximal humerus was excluded from the clinical outcomes. An MRI was performed on both shoulders to assess glenoid retroversion, glenoid type, degree of posterior subluxation (measured by the percentage of humeral head anterior to the middle glenoid fossa) and humeral head hypoplasia. Results At the latest follow-up, passive ER was 58° on average and active ER was 42°. Eleven children had regained more than 30° of active ER. The average internal rotation had decreased after the release. The MRI assessment showed that the glenohumeral joint had remodelled in 66% of cases; the glenoid type had improved, the glenoid retroversion had diminished and the humeral head was recentred. Humeral head hypoplasia was found in 28% of cases. Discussion and conclusion Arthroscopic release of the shoulder results in more external rotation and allows for glenohumeral joint remodelling. Tendon transfer is not always necessary to restore active external rotation. Level of evidence Level IV – Retrospective study.

INTRODUÇÃO: A intervenção coronária percutânea (ICP) primária é a mais eficaz técnica de reperfusão no infarto agudo do miocárdio (IAM) e seu sucesso depende de múltiplos fatores. Este estudo teve como objetivo avaliar o perfil e comparar os resultados hospitalares da ICP primária entre os pacientes do Sistema Único de Saúde (SUS) e da saúde suplementar (SS). MÉTODOS: Entre 2006 e 2010, 493 pacientes foram submetidos a ICP primária, sendo 220 tratados pelo SUS e 273, pela SS. A técnica e a escolha do material ficaram a cargo dos operadores. RESULTADOS: O grupo SUS tinha maior número de pacientes Killip > I. Doença coronária multiarterial, fluxo coronário pré-procedimento TIMI 0/1 e presença de colaterais para o vaso tratado não diferiram entre os grupos. O grupo SS utilizou mais cateteres de aspiração de trombos (10% vs. 20,8%; P < 0,01) e inibidores da glicoproteína IIb/IIIa (24,1% vs. 36,6%; P < 0,01). Não houve diferença em relação ao tempo porta-balão (62,3 minutos vs. 64,2 minutos; P = 0,91). Para os pacientes encaminhados de outros hospitais, no entanto, o tempo de transferência foi maior no SUS (400,8 minutos vs. 262,4 minutos; P < 0,01). O sucesso da ICP e a ocorrência de eventos cardiovasculares e cerebrovasculares maiores (ECCAM) não diferiram entre os grupos (6,3% vs. 6,2%; P = 0,1). Idade, Killip III/IV e tempo de transferência foram as variáveis que melhor explicaram a ocorrência de ECCAM. CONCLUSÕES: As diferenças nos perfis clínico, angiográfico e do procedimento dos pacientes submetidos a ICP primária, atendidos pelo SUS e pela SS, não tiveram impacto nos ECCAM. O tempo de transferência, entretanto, elevado nos dois grupos e maior no grupo SUS, mostrou ser preditor independente de eventos adversos. BACKGROUND: Primary percutaneous coronary intervention (PCI) is the most effective reperfusion technique in acute myocardial infarction (AMI) and its success rate depends on many factors. This study aimed to assess the profile and to compare in-hospital outcomes of primary PCI among patients from the Public Healthcare System (PuHS) versus those from the Private Healthcare System (PrHS). METHODS: From 2006 to 2010, 493 patients were submitted to primary PCI, of which 220 were treated by the PuHS and 273 by the PrHS. Procedure technique and materials were left to the operator's discretion. RESULTS: The PuHS group had a larger number of Killip > 1 patients. Multivessel coronary disease, pre-procedure coronary flow TIMI 0/1 and the presence of collaterals for the treated vessel did not differ between groups. The PrHS group used more thromboaspiration catheters (10% vs. 20.8%; P < 0.01) and glycoprotein IIb/IIIa inhibitors (24.1% vs. 36.6%; P < 0.01). There was no difference for door-to-balloon times (62.3 minutes vs. 64.2 minutes; P = 0.91). For patients referred from other hospitals, however, transportation times were higher for PuHS patients (400.8 minutes vs. 262.4 minutes; P < 0.01). PCI success rates and the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) did not differ between groups (6.3% vs. 6.2%; P = 0.1). Age, Killip III/IV and transportation time were the variables that best explained the occurrence of MACCE. CONCLUSIONS: Differences in the clinical, angiographic and procedure profile of patients undergoing primary PCI treated by the PuHS and the PrHS did not have an impact on MACCE. Transportation times, however, high in both groups and higher in the PuHS group, proved to be an independent predictor of adverse events.

INTRODUÇÃO: Estudos prévios demonstram que há diferenças entre homens e mulheres em relação aos resultados clínicos pós-intervenção coronária percutânea (ICP). Buscamos avaliar as diferenças entre os gêneros na apresentação tanto clínica como angiográfica e nos resultados hospitalares de pacientes submetidos a ICP contemporânea. MÉTODOS: No período de 2002 a 2009, 6.067 pacientes consecutivos foram submetidos a ICP, dos quais 2.021 (33,3%) eram do sexo feminino. A técnica e a escolha do material durante o procedimento ficaram a cargo dos operadores. RESULTADOS: O sexo feminino mostrou ser mais idoso e com maior ocorrência de fatores de risco para aterosclerose, à exceção do tabagismo. Prevaleceu nas mulheres o quadro clínico de síndrome coronária aguda sem supradesnivelamento do segmento ST. As mulheres apresentaram maior prevalência de doença uniarterial e menor prevalência de lesões B2/C, trombos, lesões em bifurcações, e disfunção ventricular moderada a grave. Os pacientes foram tratados predominantemente com stents não-farmacológicos e não foram observadas diferenças quanto ao diâmetro e à extensão dos stents. Não foram observadas diferenças na incidência hospitalar de eventos cardíacos e cerebrovasculares adversos maiores (1,5% vs. 1,4%; P = 0,76), óbito (0,9% vs. 0,6%; P = 0,15), acidente vascular cerebral (0,05% vs. 0,05%; P > 0,99), infarto agudo do miocárdio (0,7% vs. 1,1%; P = 0,16) e cirurgia de revascularização miocárdica de emergência (0,1% vs. 0; P = 0,62). Diabetes, coronariopatia multiarterial, lesões tipo B2/C e oclusões totais foram as variáveis que melhor explicaram a ocorrência de eventos hospitalares. CONCLUSÕES: As mulheres, que representam um terço dos pacientes submetidos a ICP em nosso serviço, têm perfil clínico mais grave, mas menor complexidade anatômica que os homens. Neste estudo, o sexo feminino não foi preditor de eventos clínicos adversos hospitalares. BACKGROUND: Prior studies have shown there are differences in the clinical outcomes of percutaneous coronary intervention (PCI) between men and women. We tried to assess gender differences in clinical and angiographic presentation as well as in the in-hospital outcomes of patients undergoing contemporary PCI. METHODS: From 2002 to 2009, 6,067 consecutive patients were submitted to PCI, of these, 2,021 (33.3%) were women. The interventional strategy, including the type of stent implanted, was conducted at the operators discretion. RESULTS: The female gender was older and had a greater incidence of risk factors for atherosclerosis, except for smoking. Acute coronary syndrome without ST segment elevation was the most prevalent presentation in women. Women had a higher number of single vessel lesions and a lower prevalence of B2/C lesions, thrombi, bifurcation lesions and moderate to severe ventricular dysfunction. Patients were predominantly treated with bare metal stents and no differences were observed for the diameter and length of the stents. No differences were observed for the in-hospital incidence of major adverse cardiac and cerebrovascular events (1.5% vs. 1.4%; P = 0.76), death (0.9% vs. 0.6%; P = 0.15), stroke (0.05% vs. 0.05%; P > 0.99), acute myocardial infarction (0.7% vs. 1.1%; P = 0.16) and emergency myocardial revascularization surgery (0.1% vs. 0; P = 0.62). Diabetes, multivessel coronary artery disease, B2/C type lesions and total occlusions were the variables that best explained the occurrence of in-hospital events. CONCLUSIONS: Women correspond to one third of the patients undergoing PCI at our service and have a more severe clinical profile, but lower anatomic complexity than men. In our study, the female gender was not a predictor of in-hospital adverse clinical events.

Background SLC25A12 , a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate production. Methods We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies. Results Slc25a12 -knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In postnatal day 13 to 14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cell-autonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/ N -acetylaspartate and/or alterations in the dihydronicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide + ratio, resulting in myelin defects. Conclusions Our data implicate AGC1 activity in myelination and in neuronal structure and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development, contributing to increased autism susceptibility.

Mutations in the presenilin 1 (PS1) gene are the most commonly recognized cause of familial Alzheimer's disease (FAD). Besides senile plaques, neurofibrillary tangles, and neuronal loss, Alzheimer's disease (AD) is also accompanied by vascular pathology. Here we describe an age-related vascular pathology in two lines of PS1 FAD-mutant transgenic mice that mimics many features of the vascular pathology seen in AD. The pathology was especially prominent in the microvasculature whose vessels became thinned and irregular with the appearance of many abnormally looped vessels as well as string vessels. Stereologic assessments revealed a reduction of the microvasculature in the hippocampus that was accompanied by hippocampal atrophy. The vascular changes were not congophilic. Yet, despite the lack of congophilia, penetrating vessels at the cortical surface were often abnormal morphologically and microhemorrhages sometimes occurred. Altered immunostaining of blood vessels with basement membrane-associated antigens was an early feature of the microangiopathy and was associated with thickening of the vascular basal laminae and endothelial cell alterations that were visible ultrastructurally. Interestingly, although the FAD-mutant transgene was expressed in neurons in both lines of mice, there was no detectable expression in vascular endothelial cells or glial cells. These studies thus have implications for the role of neuronal to vascular signaling in the pathogenesis of the vascular pathology associated with AD.

Acute liver failure (ALF) is defined as a severe, sudden liver dysfunction that induces encephalopathy and coagulopathy (prothrombin time [PT/INR] > 1.5) within 26 weeks of the onset of symptoms (usually jaundice) in patients without previous liver disease. Quantitative and qualitative platelet dysfunction, reduced synthesis of clotting factors, increased consumption of factors (mainly II, V, VII, X), reduced clearance of both activated factors, and/or factor inhibitor complexes are among the most important proposed pathogenetic factors. A possible role might be also played by the diminished degradation of anticoagulants. Plasminogen activator inhibitor 1 (PAI-1) is increased, shifting the balance toward hypofibrinolysis, despite the elevated levels of tissue plasminogen activator (tPA). Although changes in coagulation parameters provide crucial information for the management of the patient with ALF, the optimal management of the hemostatic defects is far from being defined. Because spontaneous bleeding occurs rarely during ALF, measures to improve the bleeding diathesis (fresh frozen plasma, cryoprecipitate, platelet transfusion) are recommended only in patients with clinically significant bleeding or before placement of invasive devices. Antifibrinolytic drugs are used in some cases, but often empirically. The role of rFVIIa, even if promising, is still under debate.