Developmental Defects of Enamel in Primary Teeth and Association with Early Life Course Events: A Study of 6--36 Month old Children in Manyara, Tanzania.

Children with low birth weight show an increased prevalence of developmental defects of enamel in the primary dentition that subsequently may predispose to early childhood caries (ECC).Focusing 6--36 months old, the purpose of this study was to assess the frequency of enamel defects in the primary dentition and identify influences of early life course factors; socio-demographics, birth weight, child's early illness episodes and mothers' perceived size of the child at birth, whilst controlling for more recent life course events in terms of current breastfeeding and oral hygiene. A cross-sectional study was conducted in the high fluoride area of Manyara, northern Tanzania including 1221 child-mother pairs who attended Reproductive and Child Health (RCH) clinics for immunization and/or growth monitoring. After the primary caregivers had completed face to face interviews at the health care facility, children underwent oral clinical examination whereby ECC and developmental defects of enamel were recorded using field criteria. All erupted teeth were examined and the enamel defects were assessed on buccal surfaces according to the modified DDE Index. The prevalence of enamel defects was 33.3%. Diffuse opacities were the most common defects identified (23.1%), followed by hypoplasia (7.6%) and demarcated opacities (5.0%). The most frequently affected teeth were the upper central incisors (29.0% - 30.5%), whereas lower central incisors (4.3% to 4.5%) were least frequently affected. Multiple logistic regression analysis, adjusting for confounding the factors revealed that having normal birth weight (equal or more than 2500 g) associated with lower odds of having enamel hypoplasia [OR 0.22 (95% CI 0.1-0.7)]. No statistically significant association occurred between birth weight and diffuse opacities, demarcated opacities or combined DDE. Children with the history of low birth weight were more likely than their normal birth weight counterparts to present with enamel hypoplasia. In view of the frequent occurrence of enamel defects and the fact that hypoplasia may constitute a risk factor for future ECC, enamel defects should be included as a dental health indicator in epidemiological studies of children in northern Tanzania

L-Glutamine therapy reduces endothelial adhesion of sickle red blood cells to human umbilical vein endothelial cells

BACKGROUND: We have previously demonstrated that therapy with orally administered L-glutamine improves nicotinamide adenosine dinucleotide (NAD) redox potential of sickle red blood cells (RBC). On further analysis of L-glutamine therapy for sickle cell anemia patients, the effect of L-glutamine on adhesion of sickle RBC to human umbilical vein endothelial cells (HUVEC) was examined. METHODS: The first part of the experiment was conducted with the blood samples of the 5 adult sickle cell anemia patients who had been on L-glutamine therapy for at least 4 weeks on a dosage of 30 grams per day compared to those of patient control group. In the second part of the experiment 6 patients with sickle cell anemia were studied longitudinally. Five of these patients were treated with oral L-glutamine 30 grams daily and one was observed without treatment as the control. t-test and paired t-test were used for determination of statistical significance in cross-sectional and longitudinal studies respectively. RESULTS: In the first study, the mean adhesion to endothelial cells with the autologous plasma incubated cells were 0.97 ± 0.45 for the treated group and 1.91 ± 0.53 for the nontreated group (p < 0.02). Similarly with lipopolysaccharide (LPS) incubated cells the mean adhesion to endothelial cells were 1.39 ± 0.33 for the treated group and 2.80 ± 0.47 for the untreated group (p < 0.001). With the longitudinal experiment, mean decrease in the adhesion to endothelial cells was 1.13 ± 0.21 (p < 0.001) for the 5 treated patients whereas the control patient had slight increase in the adhesion to endothelial cells. CONCLUSION: In these studies, oral L-glutamine administration consistently resulted in improvement of sickle RBC adhesion to HUVEC. These data suggest positive physiological effects of L-glutamine in sickle cell disease

Alexitimia y depresión en mayores que practican actividad física dirigida

Associations between alexithymia and depression and sociodemographic factors have been investigated in elderly population. Whether exercise plays a role as a protective factor against these conditions has yet to be determined. Thus, the aim of this study was to investigate alexithymia and depression and its association with physical activity in elderly people. Twenty-seven participants, 9 men and 18 women (aged 64 ± 5.1). Subjects were assigned to either a sedentary group or a physically active group. All participants filled in Yesavage Scale, Toronto Alexithymia Scale (TAS)-20 and SF-12. Data were analyzed using Student’s t-test andmultiple linear regression analyses. Results showed that physically active elderly people scored lower for alexithymia and depression than sedentary subjects. These findings suggest that physical activity may have a role in benefiting mental disorders.La relación entre la alexitimia y la depresión y los factores sociodemográficos ha sido estudiada en personas mayores. Sin embargo, el papel atenuador del ejercicio en estas afecciones aún debe ser determinado. En el presente estudio se mide el grado de alexitimia y depresión en adultos mayores, comparando una muestra sedentaria con una de practicantes de actividad física. Se utilizó un diseño descriptivo transversal con una muestra compuesta por 27 participantes, 9 hombres y 18 mujeres de más de 60 años (64±5.1 años), con objeto de medir el grado de alexitimia y depresión que presentaban en el momento de la recogida de datos. Los instrumentos utilizados fueron la escala de depresión de Yesavage, la Escala de Alexitimia de Toronto (TAS-20) y el Cuestionario de Salud SF-12. Los resultados mostraron que los practicantes de actividad física presentaban puntuaciones más bajas en alexitimia y depresión que los sujetos sedentarios, sin que éstas variables estuvieran relacionadas en función del género y la edad. A tenor de los resultados, el ejercicio pudiera jugar algún papel en la modulación de las alteraciones psicológicas.

Microparticle-mediated transfer of the viral receptors CAR and CD46, and the CFTR channel in a CHO cell model confers new functions to target cells

Cell microparticles (MPs) released in the extracellular milieu can embark plasma membrane and intracellular components which are specific of their cellular origin, and transfer them to target cells. The MP-mediated, cell-to-cell transfer of three human membrane glycoproteins of different degrees of complexity was investigated in the present study, using a CHO cell model system. We first tested the delivery of CAR and CD46, two monospanins which act as adenovirus receptors, to target CHO cells. CHO cells lack CAR and CD46, high affinity receptors for human adenovirus serotype 5 (HAdV5), and serotype 35 (HAdV35), respectively. We found that MPs derived from CHO cells (MP-donor cells) constitutively expressing CAR (MP-CAR) or CD46 (MP-CD46) were able to transfer CAR and CD46 to target CHO cells, and conferred selective permissiveness to HAdV5 and HAdV35. In addition, target CHO cells incubated with MP-CD46 acquired the CD46-associated function in complement regulation. We also explored the MP-mediated delivery of a dodecaspanin membrane glycoprotein, the CFTR to target CHO cells. CFTR functions as a chloride channel in human cells and is implicated in the genetic disease cystic fibrosis. Target CHO cells incubated with MPs produced by CHO cells constitutively expressing GFP-tagged CFTR (MP-GFP-CFTR) were found to gain a new cellular function, the chloride channel activity associated to CFTR. Time-course analysis of the appearance of GFP-CFTR in target cells suggested that MPs could achieve the delivery of CFTR to target cells via two mechanisms: the transfer of mature, membrane-inserted CFTR glycoprotein, and the transfer of CFTR-encoding mRNA. These results confirmed that cell-derived MPs represent a new class of promising therapeutic vehicles for the delivery of bioactive macromolecules, proteins or mRNAs, the latter exerting the desired therapeutic effect in target cells via de novo synthesis of their encoded proteins

A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses

Many contemporary studies have shown that astrocytes play a significant role in modulating both short and long form of synaptic plasticity. There are very few experimental models which elucidate the role of astrocyte over Long-term Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of astrocytes in induction of LTP at single hippocampal synapses. They suggested a purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA) Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic induction were not investigated. Here, in this article, we propose a mathematical model for astrocyte modulated LTP which successfully emulates the experimental findings of Perea & Araque (2007). Our study suggests the role of retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically modulated LTP.Comment: 51 pages, 15 figures, Journal of Computational Neuroscience (to appear

In Search of Cellular Immunophenotypes in the Blood of Children with Autism

Autism is a neurodevelopmental disorder characterized by impairments in social behavior, communication difficulties and the occurrence of repetitive or stereotyped behaviors. There has been substantial evidence for dysregulation of the immune system in autism.We evaluated differences in the number and phenotype of circulating blood cells in young children with autism (n = 70) compared with age-matched controls (n = 35). Children with a confirmed diagnosis of autism (4-6 years of age) were further subdivided into low (IQ<68, n = 35) or high functioning (IQ ≥ 68, n = 35) groups. Age- and gender-matched typically developing children constituted the control group. Six hundred and forty four primary and secondary variables, including cell counts and the abundance of cell surface antigens, were assessed using microvolume laser scanning cytometry.There were multiple differences in immune cell populations between the autism and control groups. The absolute number of B cells per volume of blood was over 20% higher for children with autism and the absolute number of NK cells was about 40% higher. Neither of these variables showed significant difference between the low and high functioning autism groups. While the absolute number of T cells was not different across groups, a number of cellular activation markers, including HLA-DR and CD26 on T cells, and CD38 on B cells, were significantly higher in the autism group compared to controls.These results support previous findings that immune dysfunction may occur in some children with autism. Further evaluation of the nature of the dysfunction and how it may play a role in the etiology of autism or in facets of autism neuropathology and/or behavior are needed

Impact of a Prohibitive Versus Restrictive Tobacco Policy on Liver Transplant Candidate Outcomes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150602/1/lt25497_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150602/2/lt25497.pd

Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND: Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. // METHODS: We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. // FINDINGS: The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST -14 IU/L [-91 to 64; p=0·728] and for ALT -8 IU/L [-49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [-804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study. // INTERPRETATION: Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis. //FUNDING: Horizon 20/20 European programme

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography–tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan–kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan–kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development

Adaptive and Innate Immune Responses in Autism: Rationale for Therapeutic Use of Intravenous Immunoglobulin

Autism is a complex polygenic neurodevelopmental disorder characterized by deficits in communication and social interactions as well as specific stereotypical behaviors. Both genetic and environmental factors appear to contribute to the pathogenesis of autism. Accumulating data including changes in immune responses, linkage to major histocompatibility complex antigens, and the presence of autoantibodies to neural tissues/antigens suggest that the immune system plays an important role in its pathogenesis. In this brief review, we discuss the data regarding changes in both innate and adaptive immunity in autism and the evidence in favor of the role of the immune system, especially of maternal autoantibodies in the pathogenesis of a subset of patients with autism. The rationale for possible therapeutic use of intravenous immunoglobulin is also discussed