CSF lactate dehydrogenase activity in patients with Creutzfeldt-Jakob disease exceeds that in other dementias

The diagnosis of Creutzfeldt- Jakob disease (CJD) is still made by exclusion of other dementias. We now evaluated lactate dehydrogenase (LDH) in the cerebrospinal fluid (CSF) as a possible additional diagnostic tool. CSF LDH levels of patients with CJD ( n = 26) were compared with those in other dementias ( n = 28). LDH isoenzymes were determined in a subset ( n = 9). Total LDH and isoenzyme LDH-1 were significantly higher, whereas the fractions of LDH-2 and LDH-3 were significantly lower in CJD patients. We conclude that in addition to established CSF parameters, LDH and its isoenzymes might serve as a further help to discriminate between CJD and other dementias. Copyright (C) 2004 S. Karger AG, Basel

Plasmatic Dimethylarginines in Dogs With Myxomatous Mitral Valve Disease

Plasmatic dimethylarginines, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are considered biomarkers of endothelial and renal dysfunction, respectively, in humans. We hypothesize that plasmatic concentration of dimethylarginines in dogs with myxomatous mitral valve disease (MMVD) is influenced by heart disease stage. Eighty-five client-owned dogs with MMVD, including 39, 19, and 27 dogs in ACVIM stages B1, B2, and C+D, respectively, and a control group of 11 clinically healthy dogs were enrolled. A prospective, multicentric, case-control study was performed. Each dog underwent a complete clinical examination, arterial blood pressure measurement, thoracic radiography, six-lead standard electrocardiogram, transthoracic echocardiography, CBC, biochemical profile, and urinalysis. Plasmatic concentration of dimethylarginines was determined through high-performance liquid chromatography coupled with tandem mass spectrometry. Median ADMA was significantly increased in dogs of group C+D (2.5 μmol/L [2.1–3.0]) compared to those of group B1 (1.8 μmol/L [1.6–2.3]; p < 0.001) and healthy dogs (1.9 μmol/L [1.7–2.3]; p = 0.02). Median SDMA was significantly increased in dogs of group C+D (0.7 μmol/L [0.5–0.9]) compared to those of groups B1 (0.4 μmol/L [0.3–0.5]; p < 0.001), B2 (0.4 μmol/L [0.3–0.6]; p < 0.01), and the control group (0.4 μmol/L [0.35–0.45]; p = 0.001). In the final multivariable analysis, ADMA and SDMA were significantly associated with left atrium to aorta ratio (p < 0.001), and creatinine (p < 0.001), respectively. Increased plasmatic concentrations of dimethylarginines suggest a possible role as biomarkers of disease severity in dogs with decompensated MMVD

Tau protein, A beta 42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies

The intra vitam diagnosis of dementia with Lewy bodies (DLB) is still based on clinical grounds. So far no technical investigations have been available to support this diagnosis. As for tau protein and beta-amyloid((1-42)) (Abeta42), promising results for the diagnosis of Alzheimer's disease ( AD) have been reported; we evaluated these markers and S-100B protein in cerebrospinal fluid (CSF), using a set of commercially available assays, of 71 patients with DLB, 67 patients with AD and 41 nondemented controls (NDC) for their differential diagnostic relevance. Patients with DLB showed significantly lower tau protein values compared to AD but with a high overlap of values. More prominent differences were observed in the comparison of DLB patients with all three clinical core features and AD patients. Abeta42 levels were decreased in the DLB and AD groups versus NDC, without significant subgroup differences. S-100B levels were not significantly different between the groups. Tau protein levels in CSF may contribute to the clinical distinction between DLB and AD, but the value of the markers is still limited especially due to mixed pathology. We conclude that more specific markers have to be established for the differentiation of these diseases. Copyright (C) 2005 S. Karger AG, Basel

Determination of pharmacological interactions of uliginosin B, a natural phloroglucinol derivative, with amitriptyline, clonidine and morphine by isobolographic analysis

AbstractUliginosin B is a natural phloroglucinol derivative, obtained from Hypericum species native to South America. Previous studies have shown that uliginosin B presents antidepressant-like and antinociceptive effects. Although its mechanism of action is still not completely elucidated, it is known that it involves the activation of monoaminergic neurotransmission. The aim of the current study was to further investigate the antinociceptive mechanism of action of uliginosin B by combining it with different drugs used for treating pain in clinical practice. The intraperitoneal administration of uliginosin B, morphine, amitriptyline and clonidine, alone or in mixture, produced a dose-dependent antinociceptive effect in the hot-plate assay in mice. The effect of the mixtures of drugs was studied using an adapted isobologram analysis at the effect level of 50% of the maximal effect observed. The analysis showed that the interactions between uliginosin B and morphine was synergistic, while the interactions between uliginosin B and amitriptyline or clonidine were additive. These findings point to uliginosin B as a potential adjuvant for pain pharmacotherapy, especially for opioid analgesia

A randomised controlled trial of oxygen therapy on growth and development of preterm infants

Background: Physiological studies have shown that many preterm infants and infants with chronic lung disease may suffer chronic hypoxaemia, which possibly leads to poor growth and development. Anecdotal reports indicate that there is a drive to increase the oxygen saturation target range to a higher level in these infants due primarily to perceived benefits derived from clinical experience and from uncontrolled observational studies of babies discharged on home oxygen. Objective The BOOST (Benefits Of Oxygen Saturation Targeting) trial is the first randomised trial to assess the long-term benefits and harms of two different oxygen saturation target ranges. Methods: BOOST was a multicentre, double blinded, randomised controlled trial that enrolled 358 infants born at less than 30 weeks� gestation who remained oxygen-dependent at 32 weeks postmenstrual age. They were randomly assigned to target either a functional oxygen saturation range of 91-94% (standard or control group) or 95-98% (higher or treatment group). The primary outcomes were growth and neurodevelopmental measures at 12 months corrected age. Secondary outcomes included length of hospital stay, retinopathy of prematurity, health service utilisation, parental stress, and infant temperament. Results: Prognostic baseline characteristics did not differ between the two groups. Mean birth weight and gestational age of enrolled infants was 917g and 26.5 weeks respectively. The rate of antenatal corticosteroid use was 83%

Antidepressant-like effect of Valeriana glechomifolia Meyer (Valerianaceae) in mice

AbstractThe antidepressant-like effect of a supercritical CO2 (SCCO2) Valeriana glechomifolia extract enriched in valepotriates was investigated in a mice tail suspension test (TST) and forced swimming test (FST). The SCCO2 extract decreased mice immobility in the FST (0.5–20mg/kg p.o.) and elicited a biphasic dose–response relationship in the TST (1–20mg/kg p.o.) with no alterations in locomotor activity and motor coordination (assessed in the open-field and rota-rod tests, respectively). The anti-immobility effect of the SCCO2 extract (5mg/kg, p.o.) was prevented by mice pre-treatment with yohimbine (1mg/kg, i.p., an α2 adrenoceptor antagonist), SCH 23390 (15μg/kg, s.c., D1 dopamine receptor antagonist) and sulpiride (50mg/kg, i.p., D2 dopamine receptor antagonist). However, mice pre-treatments with prazosin (1mg/kg, i.p., α1 adrenoceptor antagonist) and p-chlorophenilalanine methyl ester (4×100mg/kg/day, i.p., a serotonin synthesis inhibitor) were not able to block the anti-immobility effect of the SCCO2 extract. Administration (p.o.) of the SCCO2 extract (0.25mg/kg) and imipramine (10mg/kg), desipramine (5mg/kg) and bupropion (3mg/kg) at sub-effective doses significantly reduced mice immobility time in the FST. These data provide the first evidence of the antidepressant-like activity of V. glechomifolia valepotriates, which is due to an interaction with dopaminergic and noradrenergic neurotransmission

Loss of full length CtBP1 expression enhances the invasive potential of human melanoma

BACKGROUND: The C-terminal binding protein 1 (CtBP1) is a known co-repressor of gene transcription. We recently revealed that CtBP1 expression is lost in melanoma cells and melanoma inhibitory activity (MIA) expression is subsequently increased. The present study was performed to evaluate a more general role of CtBP1 in human melanoma and identify further CtBP1-regulated target genes. METHODS: Sequence analysis and expression profile of CtBP1 in melanoma cell lines were done by PCR. Boyden Chamber assays and co-immunoprecipitation were performed to investigate the functional role of CtBP1. Gene expression analysis and micro array data were used to define target genes. RESULTS: Interestingly, we detected an alternative splice product of CtBP1 with unknown function whose expression is induced at reduction of full length CtBP1. Overexpression of full length CtBP1 in melanoma cells had no effect on cell proliferation but did influence cell migration and invasiveness. To understand the effect of CtBP1 we identified putative LEF/TCF target genes found to be strongly expressed in melanoma using DNA microarray analysis. We focused on fourteen genes not previously associated with melanoma. Detailed analysis revealed that most of these were known to be involved in tumor metastasis. Eleven genes had expression profiles associated with melanoma cell invasiveness. CONCLUSION: In summary, this study revealed that reduction of CtBP1 expression is correlated with migratory, invasive potential of melanoma cells

Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin

Nuclear protein aggregation has been linked to genome instability and disease. The main source of aggregation-prone proteins in cells is defective ribosomal products (DRiPs), which are generated by translating ribosomes in the cytoplasm. Here, we report that DRiPs rapidly diffuse into the nucleus and accumulate in nucleoli and PML bodies, two membraneless organelles formed by liquid\u2013liquid phase separation. We show that nucleoli and PML bodies act as dynamic overflow compartments that recruit protein quality control factors and store DRiPs for later clearance. Whereas nucleoli serve as constitutive overflow compartments, PML bodies are stress-inducible overflow compartments for DRiPs. If DRiPs are not properly cleared by chaperones and proteasomes due to proteostasis impairment, nucleoli undergo amyloidogenesis and PML bodies solidify. Solid PML bodies immobilize 20S proteasomes and limit the recycling of free ubiquitin. Ubiquitin depletion, in turn, compromises the formation of DNA repair compartments at fragile chromosomal sites, ultimately threatening cell survival

Decellularized aortic conduits: could their cryopreservation affect post-implantation outcomes? A morpho-functional study on porcine homografts

Decellularized porcine aortic valve conduits (AVCs) implanted in a Vietnamese Pig (VP) experimental animal model were matched against decellularized and then cryopreserved AVCs to assess the effect of cryopreservation on graft hemodynamic performance and propensity to in vivo repopulation by host\u2019s cells. VPs (n = 12) underwent right ventricular outflow tract substitution using AVC allografts and were studied for 15-month follow-up. VPs were randomized into two groups, receiving AVCs treated with decellularization alone (D; n = 6) or decellularization/cryopreservation (DC; n = 6), respectively. Serial echocardiography was carried out to follow up hemodynamic function. All explanted AVCs were processed for light and electron microscopy. No signs of dilatation, progressive stenosis, regurgitation, and macroscopic calcification were echocardiographically observed in both D and DC groups. Explanted D grafts exhibited near-normal features, whereas the presence of calcification, inflammatory infiltrates, and disarray of elastic lamellae occurred in some DC grafts. In the unaltered regions of AVCs from both groups, almost complete re-endothelialization was observed for both valve cusps and aorta walls. In addition, side-by-side repopulation by recipient\u2019s fibroblasts, myofibroblasts, and smooth muscle cells was paralleled by ongoing tissue remodeling, as revealed by the ultrastructural identification of typical canals of collagen fibrillogenesis and elastogenesis-related features. Incipient neo-vascularization and re-innervation of medial and adventitial tunicae of grafted aortic walls were also detected for both D and DC groups. Cryopreservation did not affect post-implantation AVC hemodynamic behavior and was topically propensive to cell repopulation and tissue renewal, although graft deterioration including calcification was present in several areas. Thus, these preliminary data provide essential information on feasibility of decellularization and cryopreservation coupling in the perspective of treatment optimization and subsequent clinical trials using similarly treated human allografts as innovative heart valve substitutes