pinecone/core-2020-05-10-deduplication huggingface dataset:
Ulinastatin did not reduce mortality in elderly multiple organ failure patients: a retrospective observational study in a single center ICU

AimOur aim was to evaluate the effect of ulinastatin on 28‐day mortality in patients who developed multiple organ failure (MOF) related to their acute illness and were admitted to the intensive care unit (ICU).MethodsWe carried out a retrospective observational study of MOF patients in a general ICU of a tertiary care hospital in Japan from January 2009 to December 2012. The primary outcome was 28‐day all‐cause mortality. Secondary outcomes were ventilator‐free days, ICU‐free days, and vasopressor‐free days at day 28. We investigated the association between ulinastatin treatment and outcomes using multivariable regression analysis.ResultsA total of 212 MOF patients were included, 79 (37%) of whom received ulinastatin. The median age was 70 years (interquartile range, 60–77) and median APACHE II score was 25 (interquartile range, 19–29). Overall 28‐day mortality was 20%. There were no significant differences between the ulinastatin group and the control group in age, gender, or APACHE II score. The ulinastatin group had higher prevalence of sepsis (44% versus 22%, P = 0.001). Multivariable logistic regression analysis showed that ulinastatin was not associated with 28‐day mortality (odds ratio = 1.22; 95% confidence interval, 0.54–2.79). Moreover, ulinastatin did not reduce the mortality in patients with sepsis (odds ratio = 1.92; 95% confidence interval, 0.52–7.13). However, ICU‐free days and ventilator‐free days was significantly fewer in the ulinastatin group than control group.ConclusionsIn this retrospective observational study, ulinastatin was not associated with mortality in elderly patients with established MOF, although it might be related to patient\u27s utility
Development of the Japanese version of the Preschool Confusion Assessment Method for the ICU

AimDelirium is associated with various negative clinical outcomes, such as decline in cognitive ability, increased length of hospital stay, and higher mortality. For these reasons, early diagnosis of delirium is critical. Unfortunately, there are no reliable diagnostic criteria or tool of delirium for infants and preschool‐aged children in Japan.The aim of the present study was to translate a new delirium assessment tool, the Preschool Confusion Assessment Method for the Intensive Care Unit (psCAM‐ICU), for accurately diagnosing clinically ill infants and preschool‐aged children, from English to Japanese.MethodsThe translation was undertaken with the internationally established back‐translation method. The translation was repeated blindly and independently by eight medical researchers and clinicians from multiple disciplines. Any discrepancy evident from the translated works was discussed and resolved.ResultsWe report the successful development of the Japanese version of psCAM‐ICU. However, before its full application, this diagnostic tool requires further testing and study, most notably for its validation and reliability.ConclusionA Japanese version of the psCAM‐ICU was developed
Development of the Japanese version of the Cornell Assessment of Pediatric Delirium

AimDelirium is associated with various negative clinical outcomes, such as decline in cognitive ability, increased length of hospital stay, and higher mortality. For these reasons, early diagnosis of delirium is critical. Unfortunately, there are no reliable diagnostic criteria or tool of delirium for infants and preschool‐aged children in Japan. The aim of the present study was to translate a new delirium assessment tool, the Preschool Confusion Assessment Method for the Intensive Care Unit (psCAM‐ICU), for accurately diagnosing clinically ill infants and preschool‐aged children, from English to Japanese.MethodsThe translation was undertaken with the internationally established back‐translation method. The translation was repeated blindly and independently by eight medical researchers and clinicians from multiple disciplines. Any discrepancy evident from the translated works was discussed and resolved.ResultsWe report the successful development of the Japanese version of psCAM‐ICU. However, before its full application, this diagnostic tool requires further testing and study, most notably for its validation and reliability.ConclusionA Japanese version of the psCAM‐ICU was developed
Anterior temporal laterality in primary progressive aphasia shifts to the right

In aphasia due to stroke, language-related activity shifts not only to undamaged cortex within the dominant hemisphere but also toward right-sided areas homotopical to the left-sided lesion. We examined whether a rightward shift takes place in primary progressive aphasia (PPA). Nineteen PPA patients participated, 19 healthy subjects and 14 patients with amnestic mild cognitive impairment who served as controls. Subjects underwent neuropsychological assessment, structural magnetic resonance imaging (MRI), and a functional MRI with a factorial design: words versus pictures and associative-semantic versus visuoperceptual task. Measures of neuropsychological performance were entered as regressors into a multiple linear regression analysis, with response amplitude during the associative-semantic versus control conditions as outcome variable. Language competence correlated negatively with responses in the right anterior temporal cortex and positively with volume and responses in the left-sided homotope. In normal subjects, anterior temporal activation was more extensive to the left than the right (laterality index [LI], +0.64; standard error [SE], 0.11). Laterality was inverted in PPA with word comprehension deficit (LI, - 0.34; SE, 0.19), with an intermediate pattern in PPA without comprehension deficit (LI, +0.23; SE, 0.14). The rightward laterality shift previously reported in aphasic stroke extends to PPA, in particular, when comprehension is deficient.status: publishe
Methylthioadenosine reverses brain autoimmune disease

OBJECTIVE:
To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis.
METHODS:
We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot.
RESULTS:
We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10).
INTERPRETATION:
MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases
A Second Major Histocompatibility Complex Susceptibility Locus for Multiple Sclerosis

Objective: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. Methods: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects. Results: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 × 10−5). Interpretation: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene
Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain.

MMNPInternational audienceOBJECTIVE: Botulinum toxin type A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone, possibly by acting on neurogenic inflammation. Such a mechanism may be involved in peripheral neuropathic pain. METHODS: A possible direct analgesic effect of BTX-A pain processing was investigated in 29 patients with focal painful neuropathies and mechanical allodynia using a randomized, double-blind, placebo-controlled design. Patients received a one-time intradermal administration of BTX-A (20-190 units) into the painful area. Outcome measures, evaluated at baseline, then at 4, 12, and 24 weeks, included average spontaneous pain intensity, quantified testing of thermal and mechanical perception and pain, allodynia to brushing (area, intensity), neuropathic symptoms, clinical global impression, and quality of life. RESULTS: BTX-A treatment, relative to placebo, was associated with persistent effects on spontaneous pain intensity from 2 weeks after the injection to 14 weeks. These effects correlated with the preservation of thermal sensation at baseline (p < 0.05). BTX also improved allodynia to brush and decreased pain thresholds to cold, without affecting perception thresholds. There were sustained improvements in the proportion of responders (number needed to treat for 50% pain relief: 3.03 at 12 weeks), neuropathic symptoms, and general activity. Most patients reported pain during the injections, but there were no further local or systemic side effects. INTERPRETATION: These results indicate for the first time that BTX-A may induce direct analgesic effects in patients with chronic neuropathic pain independent of its effects on muscle tone and suggest novel indications for BTX-A in analgesia
Depletion of the neural precursor cell pool by glucocorticoids

OBJECTIVE:
Glucocorticoids (GCs) are indicated for a number of conditions in obstetrics and perinatal medicine; however, the neurodevelopmental and long-term neurological consequences of early-life GC exposure are still largely unknown. Preclinical studies have demonstrated that GCs have a major influence on hippocampal cell turnover by inhibiting neurogenesis and stimulating apoptosis of mature neurons. Here we examined the fate of the limited pool of neural progenitor cells (NPCs) after GC administration during neonatal development; the impact of this treatment on hippocampal structure was also studied.
METHODS:
Phenotype-specific genetic and antigenic markers were used to identify cultured NPCs at various developmental stages; the survival of these cells was monitored after exposure to the synthetic glucocorticoid dexamethasone (DEX). In addition, the effects of neonatal DEX treatment on the neurogenic potential of the rat hippocampus were examined by monitoring the incorporation of bromodeoxyuridine and expression of Ki67 antigen at various postnatal ages.
RESULTS:
Multipotent nestin-expressing NPCs and Talpha1-tubulin-expressing immature neurons succumb to GC-induced apoptosis in primary hippocampal cultures. Neonatal GC treatment results in marked apoptosis among the proliferating population of cells in the dentate gyrus, depletes the NPC pool, and leads to significant and sustained reductions in the volume of the dentate gyrus.
INTERPRETATION:
Both NPCs and immature neurons in the hippocampus are sensitive to the proapoptotic actions of GCs. Depletion of the limited NPC pool during early life retards hippocampal growth, thus allowing predictions about the potential neurological and psychiatric consequences of neonatal GC exposure.S. Yu, Y Wu, and J Lu were supported by fellowships from the Max Planck Society. This study was partly supported by grants from the German Academic Exchange Service (to O.F.X.A. and N.S.) and the Portuguese Rectors' Conference, a grant from Gulbenkian Foundation (JG 0495 to N.S.), and an Integrated Project grant from the European Commission (Contract No. LSHM-CT-2005-01852 to O.F.X.A.)
Postischemic treatment of neonatal cerebral ischemia should target autophagy.

OBJECTIVE: To evaluate the contributions of autophagic, necrotic, and apoptotic cell death mechanisms after neonatal cerebral ischemia and hence define the most appropriate neuroprotective approach for postischemic therapy. METHODS: Rats were exposed to transient focal cerebral ischemia on postnatal day 12. Some rats were treated by postischemic administration of pan-caspase or autophagy inhibitors. The ischemic brain tissue was studied histologically, biochemically, and ultrastructurally for autophagic, apoptotic, and necrotic markers. RESULTS: Lysosomal and autophagic activities were increased in neurons in the ischemic area from 6 to 24 hours postinjury, as shown by immunohistochemistry against lysosomal-associated membrane protein 1 and cathepsin D, by acid phosphatase histochemistry, by increased expression of autophagosome-specific LC3-II and by punctate LC3 staining. Electron microscopy confirmed the presence of large autolysosomes and putative autophagosomes in neurons. The increases in lysosomal activity and autophagosome formation together demonstrate increased autophagy, which occurred mainly in the border of the lesion, suggesting its involvement in delayed cell death. We also provide evidence for necrosis near the center of the lesion and apoptotic-like cell death in its border, but in nonautophagic cells. Postischemic intracerebroventricular injections of autophagy inhibitor 3-methyladenine strongly reduced the lesion volume (by 46%) even when given &gt;4 hours after the beginning of the ischemia, whereas pan-caspase inhibitors, carbobenzoxy-valyl-alanyl-aspartyl(OMe)-fluoromethylketone and quinoline-val-asp(OMe)-Ch2-O-phenoxy, provided no protection. INTERPRETATION: The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia
Glutamate receptor-mediated ischemic injury of premyelinated central axons

This is the author’s submitted draft of the paper published as Annals of Neurology, 2009, 66 (5), pp. 682-693.  The definitive version is available at www3.interscience.wiley.com, Doi: 10.1002/ana.21767Objective: Ischemic injury of axons is a feature of periventricular leukomalacia, a pathological correlate of cerebral palsy. Recent evidence suggests that axons are damaged before they receive the first layer of compact myelin. Here we examine the cellular mechanisms underlying ischemic-type injury of premyelinated central axons.\ud
Methods: Two-thirds of axons in the postnatal day 10 (P10) rat optic nerve are small premyelinated axons (<0.4µm in diameter), and one-third have undergone radial expansion in preparation for glial contact and the onset of myelination. Compound action potential recording and quantitative electron microscopy were used to examine the effect of modeled ischemia (oxygen-glucose deprivation) upon these two axon populations. Glutamate receptor (GluR) expression was investigated using polymerase chain reaction (PCR) and immunostaining approaches at the confocal light and ultrastructural levels.\ud
Results: Oxygen-glucose deprivation produced action potential failure and focal breakdown of the axolemma of small premyelinated axons at sites of contact with oligodendrocyte processes, which were also disrupted. The resulting axon loss was Ca²+- dependent, Na+- and Cl¯-independent, and required activation of N-methyl-D-aspartic acid (NMDA) and non-NMDA GluRs.  NMDA receptor expression was localized to oligodendrocyte processes at sites of contact with premyelinated axons, in addition to expression within compact myelin. No periaxonal NMDA receptor expression was observed on oligodendrocyte processes ensheathing large premyelinated axons and no protective effect of GluR block was observed in these axons.\ud
Interpretation: NMDA receptor-mediated injury to oligodendrocyte processes navigating along small premyelinated axons precedes damage to the underlying axon, a phenomena that is lost following radial expansion and subsequent oligodendrocyte ensheathment.National Institutes of Neurological Disorders and Stroke; Grant Number: NS44875
High-intensity focused ultrasound for noninvasive functional neurosurgery

Transcranial magnetic resonance (MR)-guided high-intensity focused ultrasound (tcMRgHIFU) implies a novel, noninvasive treatment strategy for various brain diseases. Nine patients with chronic neuropathic pain were treated with selective medial thalamotomies. Precisely located thermal ablations of 4mm in diameter were produced at peak temperatures of 51 degrees C to 60 degrees C under continuous visual MR guidance and MR thermometry. The resulting lesions are clearly visible on follow-up MR imaging. All treatments were well tolerated, without side effects or neurological deficits. This is the first report on successful clinical application of tcMRgHIFU in functional brain disorders, portraying it as safe and reliable for noninvasive neurosurgical interventions
Loss of hypocretin (orexin) neurons with traumatic brain injury

Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson disease and other disorders. We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI. This observation highlights the often overlooked hypothalamic injury in TBI and provides new insights into the causes of chronic sleepiness in patients with TBI
Early onset collagen VI myopathies: Genetic and clinical correlations.

OBJECTIVE: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.
METHODS: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA.
RESULTS: ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation).
INTERPRETATION: This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials
Antiepileptic drugs interact with folate and vitamin B12 serum levels

OBJECTIVE: Antiepileptic drugs (AEDs) are important for the treatment of epilepsy, psychiatric diseases, and pain syndromes. Small studies have suggested that AED treatment reduces serum levels of folate and vitamin B12. METHODS: This prospective monocenter study aimed at testing the hypothesis that AED treatment is associated with folate and vitamin B12 serum levels in a large population. A total of 2730 AED-treated and 170 untreated patients with epilepsy and 200 healthy individuals were enrolled. RESULTS: Treatment with carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, or valproate was associated with lower mean serum folate levels or with a higher frequency of folate levels below the reference range in comparison with the entire group of patients, untreated patients, or controls. Treatment with phenobarbital, pregabalin, primidone, or topiramate was associated with lower vitamin B12 levels compared with the entire group of patients. Vitamin B12 serum levels were higher in patients treated with valproate compared with the entire group of patients, untreated patients, and healthy controls. Folate or vitamin B12 levels below the reference range were associated with higher mean corpuscular volume (MCV) and higher homocysteine plasma levels. Vitamin substitution for 3 months in 141 patients with folate or vitamin B12 levels below the reference range yielded normal vitamin levels in 95% of the supplemented patients and reduced MCV and homocysteine plasma levels. INTERPRETATION: Treatment with most of the commonly used AEDs is associated with reduced folate or vitamin B12 serum levels and is a risk factor for hyperhomocysteinemia. Oral substitution is effective to restore vitamin, MCV, and homocysteine levels. Ann Neurol 2011
Solvent exposures and parkinson disease risk in twins

Objective:  Several case reports have linked solvent exposure to Parkinson disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design.    Methods:  Ninety‐nine twin pairs discordant for PD ascertained from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort were interviewed regarding lifetime occupations and hobbies using detailed job task–specific questionnaires. Exposures to 6 specific solvents selected a priori were estimated by expert raters unaware of case status.    Results:  Ever exposure to trichloroethylene (TCE) was associated with significantly increased risk of PD (odds ratio [OR], 6.1; 95% confidence interval [CI] 1.2–33;  p  = 0.034), and exposure to perchloroethylene (PERC) and carbon tetrachloride (CCl 4 ) tended toward significance (respectively: OR, 10.5; 95% CI, 0.97–113;  p  = 0.053; OR, 2.3; 95% CI, 0.9–6.1;  p  = 0.088). Results were similar for estimates of exposure duration and cumulative lifetime exposure.    Interpretation:  Exposure to specific solvents may increase risk of PD. TCE is the most common organic contaminant in groundwater, and PERC and CCl 4  are also ubiquitous in the environment. Our findings require replication in other populations with well‐characterized exposures, but the potential public health implications are substantial. ANN NEUROL 201