Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels. METHODS: We studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals. RESULTS: Of the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P < 0.05), the immune-related CD86 (8.5 fold-change, P = 0.002) emerged among the up regulated genes (N = 409). Several genes encoding HOX transcription factors and histones potentially regulated by blood flow, were overexpressed. Smooth muscle contraction and cell adhesion processes emerged among down regulated genes (N = 515), including the neuronal cell adhesion L1CAM as top scorer (5 fold-change, P = 5 × 10- 4). Repeated measurements in jugular/peripheral plasma and overtime in peripheral plasma showed conserved individual plasma patterns for immune-inflammatory (CCL13, CCL18) and adhesion (NCAM1, VAP1, SELL) proteins, despite significant variations overtime (SELL P < 0.0001). Both age and MS disease phenotypes were determinants of VAP1 plasma levels. Data supported cerebral related-mechanisms regulating ANGPT1 levels, which were remarkably lower in jugular plasma and correlated in repeated assays but not between jugular/peripheral compartments. CONCLUSIONS: This study provides for the first time expression patterns of the IJV wall, suggesting signatures of altered vascular mRNA profiles in MS disease also independently from CCSVI. The combined transcriptome-protein analysis provides intriguing links between IJV wall transcript alteration and plasma protein expression, thus highlighting proteins of interest for MS pathophysiology.

Individual and group treatment for patients with acquired brain injury in comprehensive rehabilitation.

PRIMARY OBJECTIVE: The aim of this study was to investigate the hypothesis that group rehabilitation is more effective than individual treatments and provides an improvement in clinical outcomes similar to that achieved by individual treatments alone. RESEARCH DESIGN: Two groups of patients were placed in different rehabilitation settings treated using the same rehabilitation approach. One received only individual treatments and the second group received a combination of both individual and group treatments. The independent variables were measured both pre- and post-treatment and compared between the two groups. METHODS AND PROCEDURES: Seventy-four patients treated with a comprehensive rehabilitation approach were divided into two groups: (a) individual treatment only and, (b) combined treatments (both individual and group). The outcome scales were LCF (Rancho Los Amigos Level of Cognitive Functioning), DRS (Disability Rating Scale) and FIM™ (Functional Independence Measure). RESULTS: The whole sample had obtained statistically significant improvements in all of the outcome scales: LCF (χ(2) = 45.26; p < 0.001), DRS (z = -3.92; p < 0.001) and FIM (z = -4.9; p < 0.001). The comparison between groups did not reveal any pre-treatment difference. Analysis of post-treatment, however, showed a greater improvement in the FIM scale for those in combined individual and group treatment (z = -0.2544, p = 0.01). CONCLUSIONS: Group rehabilitation integrated with individual treatments is more effective than individual treatments alone in improving independence measured by the FIM™ scale. Both groups had obtained statistically significant clinical improvements, the improvement in the FIM™ scale was significantly better in the combined treatment group.

Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours.

AIM: Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance. METHODS: Forty-seven patients received GEM 1000-1250mgm(-2) i.v. over 30min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA. RESULTS: Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration-time curve from time 0 to infinity (AUC(0,∞)) (r(2) = 0.77). CONCLUSIONS: Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.

Expression profiles of the internal jugular and saphenous veins: Focus on hemostasis genes.

INTRODUCTION: Venous bed specificity could contribute to differential vulnerability to thrombus formation, and is potentially reflected in mRNA profiles. MATERIALS AND METHODS: Microarray-based transcriptome analysis in wall and valve specimens from internal jugular (IJV) and saphenous (SV) veins collected during IJV surgical reconstruction in patients with impaired brain outflow. Multiplex antigenic assay in paired jugular and peripheral plasma samples. RESULTS: Most of the top differentially expressed transcripts have been previously associated with both vascular and neurological disorders. Large expression differences of HOX genes, organ patterning regulators, pinpointed the vein positional identity. The "complement and coagulation cascade" emerged among enriched pathways. In IJV, upregulation of genes for coagulation inhibitors (TFPI, PROS1), activated protein C pathway receptors (THBD, PROCR), fibrinolysis activators (PLAT, PLAUR), and downregulation of the fibrinolysis inhibitor (SERPINE1) and of contact/amplification pathway genes (F11, F12), would be compatible with a thromboprotective profile in respect to SV. Further, in SV valve the prothrombinase complex genes (F5, F2) were up-regulated and the VWF showed the highest expression. Differential expression of several VWF regulators (ABO, ST3GAL4, SCARA5, CLEC4M) was also observed. Among other differentially expressed hemostasis-related genes, heparanase (HPSE)/heparanase inhibitor (HPSE2) were up-/down-regulated in IJV, which might support procoagulant features and disease conditions. The jugular plasma levels of several proteins, encoded by differentially expressed genes, were lower and highly correlated with peripheral levels. CONCLUSIONS: The IJV and SV rely on differential expression of many hemostasis and hemostasis-related genes to balance local hemostasis, potentially related to differences in vulnerability to thrombosis.

C6orf10 Low-Frequency and Rare Variants in Italian Multiple Sclerosis Patients.

In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value ≤ 5 × 10-6). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) ≤ 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 × 10-7 and p < 1 × 10-20). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3' region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS.

An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis.

Data with border-line statistical significance, copiously generated in genome-wide association studies of coronary artery disease (CAD), could include functionally relevant associations. We propose an integrated genomic and transcriptomic approach for unravelling new potential genetic signatures of atherosclerosis. Fifteen among 91 single nucleotide polymorphisms (SNPs) were first selected for association in a sex- and age-adjusted model by examining 510 patients with CAD and myocardial infarction and 388 subjects with normal coronary arteries (CAD-free) in the replication stages of a genome-wide association study. We investigated the expression of 71 genes proximal to the 15 tag-SNPs by two subsequent steps of microarray-based mRNA profiling, the former in vascular smooth muscle cell populations, isolated from non-atherosclerotic and atherosclerotic human carotid portions, and the latter in whole carotid specimens. BCL3 and PVRL2, contiguously located on chromosome 19, and ABCA1, extensively investigated before, were found to be differentially expressed. BCL3 and PVRL2 SNPs were genotyped within a second population of CAD patients (n=442) and compared with CAD-free subjects (n=393). The carriership of the BCL3 rs2965169 G allele was more represented among CAD patients and remained independently associated with CAD after adjustment for all the traditional cardiovascular risk factors (odds ratio=1.70 with 95% confidence interval 1.07-2.71), while the BCL3 rs8100239 A allele correlated with metabolic abnormalities. The up-regulation of BCL3 mRNA levels in atherosclerotic tissue samples was consistent with BCL3 protein expression, which was detected by immunostaining in the intima-media of atherosclerotic specimens, but not within non-atherosclerotic ones. Our integrated approach suggests a role for BCL3 in cardiovascular diseases.

Operating room fires: optimizing safety.

BACKGROUND: This prospective study was undertaken to determine the safest means of supplemental oxygen delivery for patients undergoing facial cosmetic surgery under conscious sedation. Two common methods of oxygen delivery were used in 20 patients: (1) a nasal cannula and (2) a red rubber nasopharyngeal tube through which the cut ends of the nasal cannula were passed into the posterior pharynx. METHODS: The project was carried out in two parts. In part one, each subject was placed supine and oxygen supplementation at 3 liters/minute was applied through the nasal cannula. The oxygen concentration at 24 different set locations around the patient's face was analyzed using the random access mass spectrometer unit, starting at the right and left alar rim and then at 2-cm intervals laterally, superiorly, and inferiorly. The procedure in part one was repeated with oxygen being delivered by passing the cut cannula end through a red rubber nasopharyngeal tube into the posterior pharynx. RESULTS: Statistical analysis has showed that in all sites at or above the nasal area, the difference between the nasal cannula and red rubber nasopharyngeal tube is significantly greater than 0, indicating that higher concentrations are observed with the nasal cannula than with the red rubber nasopharyngeal tube (p = 0.004). CONCLUSION: The authors' study demonstrates a significant reduction in oxygen concentration, to levels consistent with ambient air, even at points extremely close to the oxygen source, when the nasopharyngeal tube system was used.

Polidrâmnio agudo idiopático recorrente: relato de um caso / Recurrent idiopatic acute polydramnio: a case report

Neste trabalho os autores ressaltam a raridade do ocorrência de Polidrâmnio Agudo Idiopático Recorrente - PAIR, sendo que a incidência de polidrâmnio na populaçäo geral é de 0,4 a 1,5 por cento e destes 34 por cento säo idiopáticos, havendo apenas quatro casos de PAIR descritos na literatura. Para ilustrar tal fato, é relatado o caso de uma paciente de 28 anos de idade sem qualquer patologia, com duas gestaçöes diagnosticadas como polidrâmnio idiopático sem presença de malformaçöes fetais, acompanhada pelo serviço de ginecologia e Obstetrícia da Faculdade de Medicina da FUABC. Na segunda cesárea, foi encontrado uma tumoraçäo em tuba direita, cujo anatomo-patológico fora Endometriose, uma associaçäo inédita na literatura. É conhecida a relaçäo entre o polidrâmnio e as anomalias congênitas fetais, presentes em 1/5 dos casos, especialmente as do SNC e do tubo digestivo alto. Säo feitas mençöes de possíveis etiologias ainda näo confirmadas como: teoria imunológica dos receptores hormonais placentários e presença de antígenos de compatibilidade leucocítica, destacando-se os métodos de diagnóstico e tratamento mais recente