Study of the possible link of 25-hydroxyvitamin D with Epstein-Barr virus and human herpesvirus 6 in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Although the causes of multiple sclerosis (MS) remain partially unknown, environmental and genetic factors are thought to play a role in its aetiopathogenesis. Hypovitaminosis D, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) infections have been described as possible MS triggers. Our aim was to analyse the possible link between 25-hydroxyvitamin D [25(OH)D] and viruses in patients with MS. METHODS: We included 482 patients with MS in a 2-year study. Serum samples were collected to analyse 25(OH)D levels and, according to sample availability, antibody titres against EBV and HHV-6 by enzyme-linked immunosorbent assay. DNA was extracted from blood in order to analyse EBV and HHV-6 viral load by quantitative real-time polymerase chain reaction and to genotype MS-related single nucleotide polymorphisms (rs3135388, rs2248359 and rs12368653) when possible. RESULTS: The 25(OH)D levels were significantly higher in the first semester of the year than in the second. Carriers of the risk allele rs2248359-C showed lower 25(OH)D levels than non-carriers. For EBV, viral load was significantly higher when 25(OH)D levels were low, demonstrating an inverse correlation between 25(OH)D levels and EBV load. CONCLUSIONS: The 25(OH)D levels could be involved in the regulation of EBV replication/reactivation in patients with MS.

Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) cases have arisen amongst multiple sclerosis patients treated with natalizumab. Our objective was to gain a better understanding of the mechanisms that underlie the John Cunningham virus (JCV) infection which causes PML. METHODS: A study was made of (i) the quarterly JCV DNA levels in peripheral blood mononuclear cells (PBMCs), serum and urine samples in 100 multiple sclerosis patients during their natalizumab treatment (3-39 months), (ii) the association between human leukocyte antigen (HLA) class II and the previous viral detection and (iii) the identification of the JCV variants in those patients suspected of having PML. RESULTS: (i) JCV DNA in PBMCs and/or serum was detected in 23% of our cohort. Patients with an intermittent JCV excretion in urine had a significant increase of the viral load and prevalence in this compartment during natalizumab treatment. (ii) The frequency of the DRB1*07/DQA1*02:01/DQB1*02:02 haplotype tended to be higher in patients with detectable versus undetectable JCV DNA in PBMCs (P(corrected) = 0.108). (iii) The variants in PBMCs and serum of the non-PML patient matched the archetype. In the patient with non-fatal PML, the archetype and the same neurotropic variant in PBMCs, serum and cerebrospinal fluid was identified at the time PML was diagnosed, whereas in the patient with a worse PML prognosis, four neurotropic variants in the three previous compartments were found by the PML diagnosis. CONCLUSIONS: The detection of the neurotropic variant in blood during natalizumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symptoms of PML and mutates quickly.

Toll-like receptor-9 in Spanish multiple sclerosis patients: an association with the gender.

BACKGROUND AND PURPOSE: Toll-like receptor-9 (TLR9) is a potent inducer of innate immune system triggered by infection with viruses, some of them previously related to multiple sclerosis (MS). The aim of this study was to analyze the possible association of two TLR9 single nucleotide polymorphisms (SNPs; rs352162 and rs187084) with susceptibility to MS. METHODS: Two independent cohorts of MS patients and controls were included: 574 clinically definite relapsing-remitting MS patients (367 females) and 807 healthy controls (418 females) for the first cohort; and 366 relapsing-remitting MS patients (238 females) and 224 healthy controls (160 females) for the second cohort. Genotyping was performed by TaqMan assays. RESULTS: The AT haplotype was found to be significantly higher in women than in men (P = 0.013 and P = 0.044). CONCLUSIONS: Here two possible genetic markers are proposed that could be also associated with the differences observed in the clinical course of MS in both genders. Further studies with larger cohorts should be performed to confirm these results.

Gene expression signatures and molecular markers associated with clinical outcome in locally advanced head and neck carcinoma.

The purpose of this study was to identify molecular markers associated with tumor recurrence and survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). We studied the expression profile of 63 pre-treatment tumor biopsies obtained from locally advanced HNSCCs treated with standard treatments. Cluster analysis identified three tumor subtypes associated with significant differences in local recurrence-free survival (LRFS) (P<0.001), progression free-survival (PFS) (P<0.009) and overall survival (OS) (P<0.004). Tumor subtype 1, associated with short LRFS, PFS and OS, showed features of epithelial-mesenchymal transition and undifferentiation. It also overexpressed genes involved in cell adhesion, NF-κB and integrin signalling. Tumor subtype 3, associated with longer LRFS, PFS and OS, showed a high degree of differentiation and overexpressed genes located in chromosomal regions 19q13 and 1q21. Tumor subtype 2, which had an intermediate clinical outcome between subtype 1 and subtype 3, overexpressed genes involved in branching morphogenesis. Finally, we validated the association between gene cluster classification and patient survival using Gene Set Enrichment Analysis and two HNSCC data sets obtained from two independent patient cohorts. In conclusion, we generated a gene prognostic signature associated with survival in locally advanced patients using the expression profile of the pre-treatment tumor biopsy. Independent prospective studies would be necessary to assess if the proposed survival signature could help to guide clinical management of HNSCC.

[Continuous paravertebral analgesia versus intravenous analgesia in minimally invasive cardiac surgery by mini-thoracotomy]. / Analgesia paravertebral continua frente a analgesia intravenosa en cirugía cardiaca mínimamente invasiva por minitoracotomía.

OBJECTIVES: Minimal access cardiac surgery via minithoracotomy aims faster recovery and shorter hospital length of stay. Pain control is essential in order to achieve this goal. A study was conducted to assess the quality of post-operative analgesia and complications related to the analgesia techniques after cardiac surgery by minithoracotomy. MATERIAL AND METHODS: A descriptive, observational and retrospective study was conducted on the patients subjected to minimal access cardiac surgery in our centre between the years 2009 to 2011. The patients were divided into two groups according to the type of analgesia received: analgesia through a paravertebral catheter, with an infusion of local anaesthetics (PVB group), and intravenous analgesia with opioids (IOA group). The aim of the study was to compare the analgesic quality and the complications associated to the analgesic technique, extubation time, post-surgical complications, and length of hospital stay between both techniques. RESULTS: A total of 37 patients underwent to a modified minimally invasive Heart-Port access cardiac surgery. Fifteen patients received analgesia through a paravertebral block and the other 22 IV analgesia with opioids. Data are shown as means and standard deviation (SD). Mean tracheal extubation time less than 4 hours was observed in 60% of the patients in the PVB group, compared to 22% in the IOA group (P<.05). Length of stay in ICU for the PVB group was 1.2 (0.7) days compared to 2.2 (0.7) days in the IOA group (P<.05). Mean hospital stay was 4.8 (1.2) days for the PVB group, and 5.6 (2.8) for the IOA group (P>.05. No complications associated to the continuous paravertebral block were observed. DISCUSSION: PVB analgesia is an acceptable safe technique in cardiac surgery via thoracotomy which enables early extubation with optimal pain control when compared with IV analgesia with opioids.

Neuro-otological symptoms in patients with migraine.

INTRODUCTION: Neurootological symptoms are common in patients with migraine, and have been reported to be associated with diverse conditions. PATIENTS AND METHODS: A total of 70 patients with a diagnosis of episodic migraine, with or without aura, attending our Migraine Unit were selected. The specific variables studied were the diagnosis of instability, psycho-physiological dizziness, presyncopal symptoms, benign paroxysmal positional vertigo (BPPV), migraine associated recurrent vertigo (MARV), and Meniere's disease. RESULTS: A total of 44.3% of cases had orthostatism or syncope, 15.7% with instability (possibly due to bilateral vestibular hypofunction), 14.2% with MARV and 8.6% with BPPV. The presence of BPPV was observed in older patients (40 years), whilst MARV was a condition seen in younger ones (35 years). These findings are of interest and remind us that benign paroxysmal vertigo is a childhood condition and age is a risk for BPPV. CONCLUSIONS: Migraine patients often present with neuro-otological symptoms that can be classified as inter-episodic and episodic symptoms, and specific and non-specific migraine symptoms. This approach is of obvious pathophysiological interest, given that MARV and the possible vestibular hypofunction of migraine patients are symptoms that share physiological aspects with migraine, while the orthostatism symptoms and BPPV are non-specific and are seen to be associated with other conditions.

[Late-onset postpartum sepsis with septic shock and heart dysfunction]. / Sepsis puerperal tardía con shock séptico y disfunción cardiaca.

We report a case of late-onset postpartum sepsis from endometritis due to group A streptococci (GAS) in a 37-year-old white woman. The patient developed septic shock, with mitral regurgitation and cardiac dysfunction. Early treatment with broad-spectrum antibiotics and hemodynamic support was essential for a favorable outcome. Because of the resurgence of virulent strains of GAS that can cause fatal infections, these pathogens should be included in the differential diagnosis of postpartum infections in the mother. Although cardiac dysfunction is rare in association with GAS infection, it should be ruled out by echocardiography when the condition of a patient with sepsis does not improve.

The role of connectivity on COVID-19 preventive approaches.

Preventive and modelling approaches to address the COVID-19 pandemic have been primarily based on the age or occupation, and often disregard the importance of heterogeneity in population contact structure and individual connectivity. To address this gap, we developed models based on Erdos-Rényi and a power law degree distribution that first incorporate the role of heterogeneity and connectivity and then can be expanded to make assumptions about demographic characteristics. Results demonstrate that variations in the number of connections of individuals within a population modify the impact of public health interventions such as lockdown or vaccination approaches. We conclude that the most effective strategy will vary depending on the underlying contact structure of individuals within a population and on timing of the interventions.

Discovery of an unmelted h-chondrite inclusion in an iron meteorite.

The link between H chondrites and silicate inclusions in group IIE iron meteorites has long been suspected, but direct evidence for a common parentage has remained elusive. The discovery of an unmelted chondritic inclusion in the Techado iron meteorite sheds light on the genetic relation between these two groups, providing clues on the origin of chondritic materials as inclusions in iron meteorites. It is proposed that the complex IIE iron meteorite breccias formed by collisions with several different bodies, followed by deep burial of metal and silicate fragments in the asteroidal megaregolith.

Metal complexes of a novel heterocyclic benzimidazole ligand formed by rearrangement-cyclization of the corresponding Schiff base. Electrosynthesis, structural characterization and antimicrobial activity.

The electrochemical oxidation of anodic metals (M = cobalt, nickel, copper, zinc and cadmium) in a solution of the ligand 1H-anthra[1,2-d]imidazol-6,11-dione-2-[2-hydroxyphenyl] [H2L] afforded homoleptic [ML] compounds. The addition to the electrochemical cell of coligands (L') such as 2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen) allowed the synthesis, in one step, of heteroleptic [MLL'] compounds. The crystal structures of H2L (1), [CoL(MeOH)]2 (2), [CoL(phen)]2 (3), [NiL(bpy)]2 (4), [CuL(bpy)] (5), [CuL(phen)] (6) and [CdL(bpy)]2 (7) have been determined by X-ray diffraction techniques. The crystal structures of 2, 3, 4 and 7 consist of dimeric species in which both metallic atoms are connected through two phenolate bridges in a penta-coordinated (2) or hexa-coordinated (3, 4 and 7) environment. Copper compounds 5 and 6 are monomeric species with the metal in a pentacoordinated [N4O] environment. In all the compounds, the main interactions responsible for the crystal packing are classic (N-HO, O-HN and O-HO) and non-classic (C-HO and C-HN) hydrogen bond interactions, and π interactions (π-π-stacking and C-Hπ). All compounds were also characterized by microanalysis, IR spectroscopy, FAB mass spectrometry and 1H NMR spectroscopy. Magnetic susceptibility data were measured for 2-4 over the temperature range 2-300 K, and their analysis has revealed the occurrence of intramolecular antiferromagnetic coupling for 2 (J = -2 cm-1) and ferromagnetic coupling for 3 (J = 7.8 cm-1) and 4 (J = 2.8 cm-1) [J being the isotropic magnetic coupling parameter]. The nature of the magnetic coupling in 2-4 is correlated with the magnitude of the M-Ophenolate-M angle between the phenolate bridge and the metallic centers [M(ii) = Co, Ni]. The in vitro antimicrobial properties of the novel ligand and its metal complexes were detected against Gram positive and Gram negative bacteria and fungi. [NiL(bpy)]2 and all tested Cd(ii) complexes were the most active compounds, showing the highest inhibitory effect against bacilli (MIC 1.5-3 µg mL-1) and Sarcina, Streptococci and Haemophilus influenzae bacterial strains (MIC 12-50 µg mL-1), while almost no antifungal properties were observed.

[Prevention of respiratory risks]. / Prevención de riesgos respiratorios.

A need for oxygen is determined by the base pathology a patient suffers which produces immobilization, due to being bedridden and due to the problems which began due to an organic insufficiency associated with muscular weakness, a failure in the respiratory system, insufficient sputum, and cardiovascular alterations. This article deals with those alterations which cause a need to provide oxygen to a patient and its prevention in bedridden patients.

Mouse models in oncogenesis and cancer therapy.

Animal models have been critical in the study of the molecular mechanisms of cancer and in the development of new antitumor agents; nevertheless, there is still much room for improvement. The relevance of each particular model depends on how close it replicates the histology, physiological effects, biochemical pathways and metastatic pattern observed in the same human tumor type. Metastases are especially important because they are the main determinants of the clinical course of the disease and patient survival, and are the target of systemic therapy. The generation of clinically relevant models using the mouse requires their humanization, since differences exist in transformation and oncogenesis between human and mouse. Although genetically modified (GM) mice have been instrumental in understanding the molecular mechanisms involved in tumor initiation, they have been less successful in replicating advanced cancer. Moreover, a particular genetic alteration frequently leads to different tumor types in human and mouse and to lower metastastatic rates in GM mice than in humans. These findings question the capacity of current GM mouse carcinoma models to predict clinical response to therapy. On the other hand, orthotopic (ORT) xenografts of human tumors, or tumor cell lines, in nude mice reproduce the histology and metastatic pattern of most human tumors at advanced stage. Using ex vivo genetic manipulation of human tumor cells, ORT models can be used to molecularly dissect the metastatic process and to evaluate in vivo tumor response to therapy, using non-invasive procedures. Nevertheless, this approach is not useful in the study of the initial stages of tumorigenesis or the contribution of the immune system in this process. Despite ORT models are more promising than the most commonly used subcutaneous xenografts in preclinical drug development, their capacity to predict clinical response to antitumor agents remains to be studied. Humanizing mouse models of cancer will most likely require the combined use of currently available methodologies.

K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression.

The position of the point mutation in the c-K-ras gene appears associated with different degrees of aggressiveness in human colorectal tumors. In addition, colon tumors carrying K-ras codon 12 mutations associate with lower levels of apoptosis than tumors lacking this mutation. To test the hypothesis of a distinct transforming capacity of different K-ras forms in an in vitro system, we generated stable transfectants of NIH3T3 cells expressing a plasmid containing K-ras mutated at codon 12 (K12) or at codon 13 (K13), or overexpressing the K-ras proto-oncogene (Kwt-oe). We evaluated changes in morphology, proliferative capacity, contact inhibition, and predisposition to apoptosis and anchorage-independent growth in K12, K13, and Kwt-oe transformants. In addition, we studied alterations in expression and/or activation of proteins that participate in signal transduction downstream of Ras or are involved in the regulation of apoptosis and cell-cell (E-cadherin and beta-catenin) and cell-substrate (focal adhesion kinase) interactions. We observed that K13 or Kwt-oe transformants died synchronically 24-48 h after reaching confluency. Their death was apoptotic. In contrast, K12 grew, forming bigger colonies with higher cell densities; and before reaching confluency, spontaneously formed spheroids and showed no sign of apoptosis. The enhanced resistance to apoptosis, loss of contact inhibition, and predisposition to anchorage-independent growth in the K12 transformants were associated with higher AKT/protein kinase B activation, bcl-2, E-cadherin, beta-catenin, and focal adhesion kinase overexpression, and RhoA underexpression, whereas the increased sensitivity of K13 or Kwt-oe transformants to apoptosis was associated with increased activation of the c-Jun-NH2-terminal kinase 1 pathway. All transformants showed a similar overactivation of mitogen-activated protein kinases and levels of bax expression similar to the endogenous level. Therefore, in our in vitro model, the localization of the mutation in the K-ras gene predisposes to a different level of aggressiveness in the transforming phenotype. K12 may increase aggressiveness not by altering proliferative pathways, but by the differential regulation of K-Ras downstream pathways that lead to inhibition of apoptosis, enhanced loss of contact inhibition, and increased predisposition to anchorage-independent growth. These results offer a molecular explanation for the increased aggressiveness of the tumors with K-ras codon 12 mutations observed in the clinical setting.

[Posterior reversible encephalopathy syndrome after neurosurgery: A literature review]. / Síndrome de encefalopatía posterior reversible en el postoperatorio de neurocirugía. Revisión de la literatura.

Posterior reversible encephalopathy syndrome is a clinical-radiological characterized by decreased level of consciousness, seizures, and visual disturbances, as well as radiologically ras brain edema, predominantly in parieto-occipital white matter regions. There are many situations that can trigger the disorder, including the administration of immunosuppressants, chemotherapy agents, hypertensive disorders, and sepsis. The case is described of a patient diagnosed with stage IV prostate adenocarcinoma, receiving chemotherapy, andundergoing a posterior reversible encephalopathy syndrome after surgery for resection of brain metastasis.

Multicausal etiology of anemia among women of reproductive age in Vietnam.

BACKGROUND/OBJECTIVES: Anemia is a significant public health concern, especially among women and young children. An improved understanding of the complex etiology of anemia is crucial for developing appropriate prevention strategies. This paper examines the determinants of anemia in a large sample of Vietnamese women of reproductive age (WRA). METHODS: We included baseline data from 4986 WRA participating in a randomized controlled trial (PRECONCEPT). Hemoglobin (Hb) concentrations were measured with Hemocue. Plasma ferritin (Fe), retinol binding protein (RBP) and markers of inflammation were assessed using the ELISA technique. We used multivariate logistic regression to describe associations with anemia and structural equation modeling (SEM) to characterize direct and indirect pathways influencing Hb concentrations. RESULTS: Prevalence of anemia, iron deficiency (Fe <12 µg/l), insufficient iron stores (Fe<30 µg/l) and iron deficiency anemia was 19.7, 3.5, 14.4 and 1.9%, respectively. Ferritin concentration (0.29 per log-mg/dl), being an ethnic minority (-0.24 compared with Kinh), number of children (-0.17) and socioeconomic status (0.09) were directly associated with Hb concentration (P<0.05). Similarly, RBP was directly (0.27 per mg/dl) associated with Hb and also indirectly (0.09 mg/dl) with ferritin. Hookworm infection was indirectly associated with Hb (-0.11) through RBP and ferritin. CONCLUSION: These findings illustrate the complex etiology of anemia and provide a useful framework for designing, targeting and evaluating appropriate strategies for the prevention and control of anemia. Contrary to expectations, iron deficiency accounted for a very small proportion of anemia in Northern Vietnam.

Motor excitability measurements: the influence of gender, body mass index, age and temperature in healthy controls.

STUDY AIMS: The technique of threshold tracking to test axonal excitability gives information about nodal and internodal ion channel function. We aimed to investigate variability of the motor excitability measurements in healthy controls, taking into account age, gender, body mass index (BMI) and small changes in skin temperature. MATERIALS AND METHODS: We examined the left median nerve of 47 healthy controls using the automated threshold-tacking program, QTRAC. Statistical multiple regression analysis was applied to test relationship between nerve excitability measurements and subject variables. RESULTS: Comparisons between genders did not find any significant difference (P>0.2 for all comparisons). Multiple regression analysis showed that motor amplitude decreases with age and temperature, stimulus-response slope decreases with age and BMI, and that accommodation half-time decrease with age and temperature. CONCLUSION: The changes related to demographic features on TRONDE protocol parameters are small and less important than in conventional nerve conduction studies. Nonetheless, our results underscore the relevance of careful temperature control, and indicate that interpretation of stimulus-response slope and accommodation half-time should take into account age and BMI. In contrast, gender is not of major relevance to axonal threshold findings in motor nerves.

Analysis of cubic and orthorhombic C3A hydration in presence of gypsum and lime.

Field emission scanning electron microscopy (FE-SEM) and X-ray diffraction (XRD) have been used to study the microstructural changes and phase development that take place during the hydration of cubic (pure) and orthorhombic (Na-doped) tricalcium aluminate (C3A) and gypsum in the absence and presence of lime. The results demonstrate that important differences occur in the hydration of each C3A polymorph and gypsum when no lime is added; orthorhombic C3A reacts faster with gypsum than the cubic phase, forming longer ettringite needles; however, the presence of lime slows down the formation of ettringite in the orthorhombic sample. Additional rheometric tests showed the possible effects on the setting time in these cementitious mixes.

[Osmophobia analysis in primary headache]. / Análisis de la osmofobia en las cefaleas primarias.

INTRODUCTION: Osmophobia is often reported by migraine patients. This study evaluates osmophobia in connection with the diagnosis of episodic migraine with or without aura, chronic migraine and episodic and chronic tension-type headache. METHODS: We recruited from our Headache Unit 68 patients (59 female, 9 male; age 37+/-14.7 years), of whom 24 were migraine without aura (MoA), 11 migraine with aura (MA), 10 chronic migraine (CM) and 23 TTH (episodic-TTH). Patients with two or more forms of primary headache were excluded. RESULTS: Among migraine patients, 54% with MoA and 0% with MA, 40 %CM reported osmophobia during the attacks; none of the 23 TTH patients suffered this symptom. The crisis frequency was MoA and osmophobia 2.15 crisis per month; MoA without osmophobia 3,14. MC with osmophobia 22; MC without osmophobia 21.7. CONCLUSIONS: Osmophobia and taste abnormalities were demonstrated to be very specific in diagnosing migraine, but very insensitive. Osmophobia frequency does not depend on migraine frequency. Osmophobia seems to be more frequent in females than in males. The lack of osmophobia in MA patients could be explained by a different pathophysiological mechanism between MA and MoA.