Immunologic Heterogeneity in 2 Cartilage-Hair Hypoplasia Patients With a Distinct Clinical Course.

BACKGROUND AND OBJECTIVE: Cartilage-hair hypoplasia (CHH) syndrome is a rare autosomal recessive syndrome associated with skeletal dysplasia, varying degrees of combined immunodeficiency (CID), short stature, hair hypoplasia, macrocytic anemia, increased risk of malignancies, and Hirschsprung disease. To provide clinical and immunological insights obtained from 2 unrelated patients who displayed clinical characteristics of CHH. METHODS: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency underwent an immunological and genetic work-up using flow cytometry, next-generation sequencing (NGS) of the immune repertoire, and Sanger sequencing to identify the underlying defects. RESULTS: Patient 1 presented with low birth weight and skeletal dysplasia. Newborn screening was suggestive of T-cell immunodeficiency, as T-cell receptor excision circle levels were undetectable. Both the T-cell receptor (TCR) Vß and TCR-g (TRG) repertoires were restricted, with evidence of clonal expansion. Genetic analysis identified compound heterozygous RMRP variants inherited from both parents. Patient 2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive, and hepatomegaly. The polyclonal pattern of the TCRß repertoire was normal, with only slight overexpression of TCR-ßV20 and restricted expression of Vßs. TRG expressed a normal diverse repertoire, similar to that of the healthy control sample. Genetic analysis identified biallelic novel regulatory variants in RMRP. Both parents are carriers of this mutation. CONCLUSION: Our findings demonstrate how the immunological work-up, supported by genetic findings, can dramatically change treatment and future outcome in patients with the same clinical syndrome.

Concurrent validity of the short-form Family Impact Scale (FIS-8) in 4-year-old US children.

BACKGROUND: US data on the validity and reliability of the short-form Family Impact Scale (FIS-8; a scale for measuring the impact of a child's oral condition on his/her family) are lacking. METHODS: Cross-sectional analysis of data on four-year-old US children taking part in a multi-center cohort study. For child-caregiver dyads recruited at child age 12 months, the impact of the child's oral condition on the family was assessed at age 48 months using the FIS-8, with a subsample of 422 caregivers (from 686 who were approached). Internal consistency reliability was assessed using Cronbach's α, with concurrent validity assessed against a global family impact item ("How much are your family's daily lives affected by your child's teeth, lips, jaws or mouth?") and a global oral health item ("How would you describe the health of your child's teeth and mouth?"). RESULTS: Cronbach's alpha was 0.83. Although gradients in mean scores across ordinal response categories of the global family impact item were inconsistent, there were marked, consistent gradients across the ordinal categories of the global item on the child's oral health, with scores highest for those rating their child's oral health as 'Poor'. CONCLUSIONS: While the findings provide some evidence for the utility of the FIS in a US child sample, the study's replication in samples of preschoolers with greater disease experience would be useful.

[Factors associated with intrahospital mortality in older patients with COVID-19 in Belgium : The COVID-AgeBru study]. / Face à la COVID-19. Mortalité intra-hospitalière chez les patients âgés de plus de 70 ans avec COVID-19 dans un hôpital universitaire en Belgique :l'étude COVID-AgeBru.

OBJECTIVE: We aimed at assessing the association between demographical and clinical data and the intrahospital mortality in older patients with COVID-19 in Belgium. METHODS: Descriptive, retrospective study of consecutive patients admitted to Brugmann university hospital, Brussels (Belgium) due to COVID-19 (Mars-September-2020). INCLUSION CRITERIA: Patients aged ≥ 70 years admitted to acute care with a positive PCR-RT test, or a highly indicative computed tomography scan. EXCLUSION CRITERIA: Patients transferred to another institution during hospitalization. OUTCOME MEASURE: All-cause intrahospital mortality. Demographic, clinical data, presence of comordibidties and comprehensive geriatric assessment were collected. Adjusted and unadjusted logistic regression were performed. RESULTS: From the 226 eligible patients, 160 (82.7 ± 6.5-year-old; 57.5 % females) met inclusion criteria, from which 67 (42 %) died during hospital stay. The adjusted logistic regression showed an association between intrahospital mortality and increasing age [OR = 1.09 per every year increase (95 % CI 1.02-1.16); p <0.001], type 2 diabetes [OR = 2.75 ( 1.17-6.46); p = 0.021], and acute respiratory distress syndrome (ARDS) [OR = 8.67 ( 3.48-21.61); p < 0.01]. CONCLUSIONS: A higher positive association between intrahospital mortality and increasing age, type 2 diabetes, and ARDS was found. The prognosis value of the comprehensive geriatric assessment in older people with COVID-19 in Belgium requires further studies.

INTRODUCTION: Les études sur l'impact de la pandémie en Belgique sont rares. L'objectif est d'évaluer l'association de l'âge et des comorbidités à la mortalité intra-hospitalière de toutes causes chez les patients âgés ? 70 ans avec COVID-19 dans un hôpital universitaire à Bruxelles, Belgique. Méthodes : Etude rétrospective descriptive des patients admis au CHU Brugmann pour cause de maladie COVID-19 (mars-septembre 2020). Critères d'inclusion : âge ≥ 70 ans admis avec PCR-RT positif ou haute probabilité d'infection au CT-scan thoracique. Critères d'exclusion : transfert dans un autre hôpital. Critère de jugement : toute cause de mortalité intra-hospitalière. Variables collectées : démographiques, cliniques et gériatriques [Katz, Lawton, MMSE, MNA, MNA-SF]. Une régression logistique non ajustée et ajustée a été réalisée. Résultats : Parmi les 226 patients éligibles, 160 (82,7 ± 6,5 ans; 57,5 % femmes) ont rempli les critères d'inclusion. Au total, 67 (42 %) sont décédés durant l'hospitalisation. La régression logistique a montré une association augmentée entre la mortalité et l'âge [odds ratio ou OR = 1,09/année en plus (IC 95 % 1,02-1,16) ; p< 0,001], le diabète de type 2 [OR = 2,75 (1,17-6,46); p = 0,021], l'ARDS [OR = 8,67 (3,48-21,61); p < 0,01]. CONCLUSION: L'âge, le diabète de type 2 et le syndrome de détresse respiratoire aiguë (ARDS) sont associés à une augmentation de la mortalité chez les patients âgés hospitalisés avec COVID-19 en Belgique.

Potential tick vectors for Theileria equi in Israel.

Theileria equi Mehlhorn and Schein, 1998 (Piroplasmida: Babesiidae) is an important tick-borne pathogen of horses that is highly endemic in many parts of the world, including Israel. The present study evaluated the potential roles of five hard tick species [Hyalomma excavatum Koch, 1844; Hyalomma marginatum Koch, 1844; Rhipicephalus turanicus Pomerantsev 1936; Rhipicephalus annulatus Say, 1821; Haemaphysalis parva (Neumann, 1897) (all: Ixodida: Ixodidae)], previously found to infest horses in Israel, in acting as vectors for piroplasmosis. For this, DNA was extracted from whole ticks and, when possible, from the salivary glands in each species (n = 10-59). Polymerase chain reaction amplification and sequencing of the 18S rRNA gene were used to detect T. equi in 48 of the 127 ticks (37.8%) and in 21 of the 90 extracted salivary glands (23.3%) in all five species. All but two sequences were classified as T. equi genotype A; the remaining two were classified as genotype D. The findings of this study point to Ha. parva and R. annulatus as potential novel vectors of T. equi, and suggest that parasite genotype selection occurs within the tick vector.

[Social inequalities in oral health and early childhood caries: How can they be effectively prevented? A scoping review of disease predictors]. / Inégalités sociales de santé orale et caries précoces de l'enfant : comment prévenir efficacement ? Une revue de portée des prédicteurs de la maladie.

BACKGROUND: Early childhood caries represent a major public health problem. In addition to their individual impact, the massive social inequalities in oral health that are at the roots and result from the disease have largely underestimated consequences for the child, his family and the community. In response to the question of "how and where to act?", this scoping review identifies the individual characteristics associated with the disease on which it would be possible to act, using appropriate prevention strategies. METHODS: This scoping review is aimed at describing and analyzing available data in the literature on the different factors associated with early childhood caries. RESULTS: The predictors of early childhood caries are represented by mediating (knowledge, attitudes and parents' oral health practices) and moderating (psychosocial parameters, parental health literacy and alcohol consumption) factors. Twenty-eight articles fulfilled the selection criteria, twenty of which studied mediators related to early childhood caries, and fourteen of which dealt with moderators. The lower the parents' level of knowledge and literacy in oral health, the higher a child's dmft index. Additional studies are needed to assess the role of psychosocial parameters. CONCLUSION: Parents' knowledge and oral health literacy are the key predictors to be preferentially targeted in view of reducing social inequalities in health through actions undertaken on a local scale. The prevention of early childhood caries necessitates a combination of generic and targeted interventions.

[Lack of medical or dental care: Impact on health expenditures for people with chronic disease]. / L'effet du non-recours aux soins médicaux et dentaires sur les dépenses de santé des personnes ayant une maladie chronique.

BACKGROUND: People with chronic disease often have dental (especially periodontal) disorders. Nevertheless, people with chronic disease seek dental care less often than others. We wanted to know if there is a relationship between the consumption of medical care and the consumption of dental care, and if so if the relationship is especially strong for people with chronic disease. METHODS: We conducted a longitudinal study that combined two data-sets: consumption data from the French National Health Insurance Fund and health and socioeconomic welfare data collected with a dedicated national survey. We studied healthcare expenditure and analyzed the association between healthcare consumption, health status and healthcare expenditure over a four-year period (2010-2013). RESULTS: People who did not seek medical or dental care in 2010 exhibited irregular consumer behavior thereafter. This pattern was particularly evident among those with chronic disease whose healthcare expenditures did not stabilize during the study period compared with the rest of the study population. Among people who did not seek medical care in 2010, variation in average dental care expenditure was 91% in people with chronic disease versus 42% for those without chronic disease. Lack of medical care during the first year of the study was also associated with greater expenditure-delay in people with chronic disease (77%) compared with 15% in people without chronic disease. CONCLUSION: The lack of medical or dental care in 2010 for people with chronic disease did not lead to an increase in medical and dental consumption in the following years. The catch-up delay was longer than four years. This highlights a problem of monitoring and identifies a marginalized population within the healthcare system.

[Children's consultations for dental emergency. Retrospective study in Île-de-France]. / Consultations pour urgence bucco-dentaire chez les enfants : étude rétrospective en Île-de-France.

BACKGROUND: In France, the children oral health status has improved but the use of care remains insufficient. The complexity of the acts, the access to care difficulties and the programs of prevention and care for children lack of knowledge contribute to late care and often, in emergency. This study aims to describe the young patients' characteristics consulting in dental emergency and analyse the modalities of recourse. METHODS: A retrospective study was conducted on medical records. An extraction of data was carried out concerning all children under the age of 16, admitted to the Dental Emergency Functional Unit of the Pitié-Salpêtrière Hospital Group in 2015. Several variables of interest were analysed: socio-demographic characteristics, the time of the visit and the diagnostic category (tooth pathologies, facial trauma, infections, periodontal diseases and other emergencies). Descriptive and bivariate analyses were conducted. RESULTS: On the 62,500 dental emergency consultations in 2015, 5359 were for patients under 16 years of age (8%). Data were available for 5044 children. Among these, children aged 6 to 11 accounted most of consultations (43.9%). There were more boys (57.2%). The most frequent emergency diagnoses were related to a tooth pathology (42.9%) and traumatic event (38.4%). Consultations were more held on the evening schedule on weekdays and the day on weekends. Patients aged 0 to 5 years consulted more at night (P<10-3) and were, proportionally, the most affected by traumatic events (39.2%). Children aged 6 to 11 and 12 to 16 years consulted more often during the day (P<10-3), for emergencies related to a carious event (43.9% and 43.6%). Patients residing in Seine-Saint-Denis accounted for 22.6% of total visits and those living in Paris accounted for 20.8%. CONCLUSION: A large proportion of children presenting for dental emergencies, have most of the time, only the need for usual care. An offer of dental care, adapted to the territory needs, is necessary for the children dental health management. Preventive measures from an early age and early recourse would be favourable.

Systematic reanalysis of genomic data improves quality of variant interpretation.

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

Fluoride Use in Health Care Settings: Association with Children's Caries Risk.

Expanded partnership with the medical community is an important strategy for reducing dental caries disparities. The purpose of this study was to assess the relationship between fluoride (F) "in office" (drops/tablets and/or varnish), as prescribed or applied by a health care professional by age 1 y, and 1) caries development and 2) presence of other caries risk factors or mediators (e.g., socioeconomic status). Child-primary caregiver (PCG) pairs ( N = 1,325) were recruited in Indiana, Iowa, and North Carolina as part of a longitudinal cohort study to validate a caries risk tool for primary health care settings. PCGs completed a caries risk questionnaire, while children received caries examinations per the criteria of the International Caries Detection and Assessment System at ages 1, 2.5, and 4 y. Baseline responses regarding children's history of F in office were tested for association with other caries risk variables and caries experience at ages 2.5 and 4 y via generalized estimating equation models applied to logistic regression. The sample was 48% female, and many children (61%) were Medicaid enrolled. The prevalence of cavitated caries lesions increased from 7% at age 2.5 y to 25% by age 4 y. Children who received F in office were likely deemed at higher caries risk and indeed were significantly ( P < 0.01) more likely to develop cavitated caries lesions by ages 2.5 and 4 y, even after F application (odds ratios: 3.5 and 2.3, respectively). Factors significantly associated with receiving F included the following: child being Medicaid enrolled, not having an employed adult in the household, child and PCG often consuming sugary drinks and snacks, and PCG having recent caries experience. Increased F in office from a health care provider by age 1 y was associated with known caries risk factors. Most (69%) children had never been to the dentist, suggesting that risk factors could be alerting medical providers and/or parents, thereby affecting in-office F recommendations. Differences among states could also be related to state-specific F-varnish reimbursement policies (ClinicalTrials.gov NCT01707797).

In vivo modeling of neuronal function, axonal impairment and connectivity in neurodegenerative and neuropsychiatric disorders using induced pluripotent stem cells.

Modeling neurological diseases using human embryonic or patient-derived induced pluripotent stem cells (iPSCs) improves the understanding of molecular and cellular changes underlying these diseases and can lead to new, potentially personalized therapies. Changes in expression of axon guidance cues and altered cytoskeletal maintenance have been implicated in neurodegenerative and neuropsychiatric disorders. To date, most of the iPSC patient-derived cellular dysfunction and phenotypic studies have been performed in vitro. To study the intrinsic axonal impairments and neuronal connectivity deficits in human disease iPSC-derived neurons we propose to graft these cells into the physiological three-dimensional multi-structural environment of the central nervous system of rodent models to obtain relevant in vivo data. Such human iPSC in vivo chimeric models can allow for neuronal maturation, capture neuropathological phenotypes of axonal and connectivity impairments, and serve as target engagement and drug validation studies using human cells, thus highly relevant for advancement of the drug development process in the late pre-clinical stages.

[Pseudotumor cerebri due to taking minocycline]. / Pseudotumeur cérébrale due à la prise de minocycline.

The cerebral pseudotumor (PTC) is defined by the increase in cerebrospinal fluid (CSF) pressure, a normal composition of the latter in the absence of identified intracranial structural abnormalities, in particular by neuroimaging. The pathophysiology of PTC is poorly understood although its diagnostic criteria are well established. Drugs such as minocycline, tetracycline and doxycycline have been repeatedly implicated as a causative factor in PTC. The prognosis of PTC related to minocycline, reported in the literature is quite variable. Some authors suggest a benign condition with spontaneous healing by stopping the antibiotic, while others report permanent loss of vision. A 12-year-old girl is admitted to the emergency room for progressively progressive pulsatile temporal headaches associated with diplopia. The patient reported the use of minocycline 50 mg / d for five months, prescribed by her attending physician as part of an acne treatment. PTC will be demonstrated by severe papillary edema and cerebral NMR will demonstrate an enlargement of the subarachnoid space around the optic nerves. After three lumbar punctures, the condition of the patient stabilized and there was a marked improvement in headache despite the persistence of bilateral papillary edema. This work describes a clinical case of PTC induced by the use of minocycline and reviews the physiopathology, the diagnosis and the management of this one.

La pseudotumeur cérébrale (PTC) est définie par l'augmentation de la pression du liquide céphalo- rachidien (LCR), une composition normale de ce dernier en l'absence d'anomalies structurelles intracrânienne identifiée, en particulier par neuro- imagerie. La physiopathologie de la PTC est mal comprise bien que ses critères de diagnostic soient bien établis. Les médicaments tels que la minocycline, la tétracycline et la doxycycline ont été mis à plusieurs reprises en cause comme un facteur causal dans la PTC. Le pronostic de PTC lié à la minocycline, rapporté dans la littérature est tout à fait variable. Certains auteurs suggèrent une affection bénigne avec une guérison spontanée par l'arrêt de l'antibiotique, tandis que d'autres signalent une perte de vision permanente. Une jeune fille de 12 ans est admise aux urgences pour des céphalées temporales pulsatiles apparues de manière progressive, associée à de la diplopie. La patiente rapporte la prise de minocycline 50 mg/j depuis cinq mois, prescrite par son médecin traitant dans le cadre d'un traitement contre l'acné. La PTC sera objectivée par un œdème papillaire sévère et la RMN cérébrale mettra en évidence un élargissement de l'espace sous-arachnoïdien autour des nerfs optiques. Après réalisation de trois ponctions lombaires de décharge, l'état de la patiente s'est stabilisé et on note une nette amélioration des céphalées malgré la persistance de l'œdème papillaire bilatéral. Ce travail décrit un cas clinique de PTC induite par la prise de minocycline et revoit la physiopathologie, le diagnostic et la prise en charge de celle-ci.

Glutamate Receptor Interacting Protein 1 Regulates CD4(+) CTLA-4 Expression and Transplant Rejection.

PDZ domains are common 80- to 90-amino-acid regions named after the first three proteins discovered to share these domains: postsynaptic density 95, discs large, and zonula occludens. PDZ domain-containing proteins typically interact with the C-terminus of membrane receptors. Glutamate receptor interacting protein 1 (GRIP1), a seven-PDZ domain protein scaffold, regulates glutamate receptor surface expression and trafficking in neurons. We have found that human and mouse T cells also express GRIP1. T cell-specific GRIP1(-/-) mice >11 weeks old had prolonged cardiac allograft survival. Compared with wild-type T cells, in vitro stimulated GRIP1(-/-) T cells had decreased expression of activation markers and increased apoptotic surface marker expression. Surface expression of the strong T cell inhibitory molecule cytotoxic T lymphocyte antigen-4 (CTLA-4) was increased on GRIP1(-/-) T cells from mice >11 weeks old. CTLA-4 increases with T cell stimulation and its surface expression on GRIP1(-/-) T cells remained high after stimulation was removed, indicating a possible internalization defect in GRIP1-deficient T cells. CTLA-4-blocking antibody treatment following heart transplantation led to complete rejection in T cell GRIP1(-/-) mice, indicating that increased CTLA-4 surface expression contributed to the extended graft survival. Our data indicate that GRIP1 regulates T cell activation by regulating CTLA-4 surface expression.

White matter atlas of the human spinal cord with estimation of partial volume effect.

Template-based analysis has proven to be an efficient, objective and reproducible way of extracting relevant information from multi-parametric MRI data. Using common atlases, it is possible to quantify MRI metrics within specific regions without the need for manual segmentation. This method is therefore free from user-bias and amenable to group studies. While template-based analysis is common procedure for the brain, there is currently no atlas of the white matter (WM) spinal pathways. The goals of this study were: (i) to create an atlas of the white matter tracts compatible with the MNI-Poly-AMU template and (ii) to propose methods to quantify metrics within the atlas that account for partial volume effect. The WM atlas was generated by: (i) digitalizing an existing WM atlas from a well-known source (Gray's Anatomy), (ii) registering this atlas to the MNI-Poly-AMU template at the corresponding slice (C4 vertebral level), (iii) propagating the atlas throughout all slices of the template (C1 to T6) using regularized diffeomorphic transformations and (iv) computing partial volume values for each voxel and each tract. Several approaches were implemented and validated to quantify metrics within the atlas, including weighted-average and Gaussian mixture models. Proof-of-concept application was done in five subjects for quantifying magnetization transfer ratio (MTR) in each tract of the atlas. The resulting WM atlas showed consistent topological organization and smooth transitions along the rostro-caudal axis. The median MTR across tracts was 26.2. Significant differences were detected across tracts, vertebral levels and subjects, but not across laterality (right-left). Among the different tested approaches to extract metrics, the maximum a posteriori showed highest performance with respect to noise, inter-tract variability, tract size and partial volume effect. This new WM atlas of the human spinal cord overcomes the biases associated with manual delineation and partial volume effect. Combined with multi-parametric data, the atlas can be applied to study demyelination and degeneration in diseases such as multiple sclerosis and will facilitate the conduction of longitudinal and multi-center studies.

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.

GABA estimation in the brains of children on the autism spectrum: measurement precision and regional cortical variation.

(1)H magnetic resonance spectroscopy ((1)H MRS) and spectral editing methods, such as MEGA-PRESS, allow researchers to investigate metabolite and neurotransmitter concentrations in-vivo. Here we address the utilization of (1)H MRS for the investigation of GABA concentrations in the ASD brain, in three locations; motor, visual and auditory areas. An initial repeatability study (5 subjects, 5 repeated measures separated by ~5days on average) indicated no significant effect of reference metabolite choice on GABA quantitation (p>0.6). Coefficients of variation for GABA+/NAA, GABA+/Cr and GABA+/Glx were all of the order of 9-11%. Based on these findings, we investigated creatine-normalized GABA+ ratios (GABA+/Cr) in a group of (N=17) children with autism spectrum disorder (ASD) and (N=17) typically developing children (TD) for Motor, Auditory and Visual regions of interest (ROIs). Linear regression analysis of gray matter (GM) volume changes (known to occur with development) revealed a significant decrease of GM volume with Age for Motor (F(1,30)=17.92; p<0.001) and Visual F(1,16)=14.41; p<0.005 but not the Auditory ROI (p=0.55). Inspection of GABA+/Cr changes with Age revealed a marginally significant change for the Motor ROI only (F(1,30)=4.11; p=0.054). Subsequent analyses were thus conducted for each ROI separately using Age and GM volume as covariates. No group differences in GABA+/Cr were observed for the Visual ROI between TD vs. ASD children. However, the Motor and Auditory ROI showed significantly reduced GABA+/Cr in ASD (Motor p<0.05; Auditory p<0.01). The mean deficiency in GABA+/Cr from the Motor ROI was approximately 11% and Auditory ROI was approximately 22%. Our novel findings support the model of regional differences in GABA+/Cr in the ASD brain, primarily in Auditory and to a lesser extent Motor but not Visual areas.

In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline.

Omadacycline is the first intravenous and oral 9-aminomethylcycline in clinical development for use against multiple infectious diseases including acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). The comparative in vitro activity of omadacycline was determined against a broad panel of Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Lancefield groups A and B beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae (PRSP), and Haemophilus influenzae (H. influenzae). The omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci were 1.0 µg/ml, 0.25 µg/ml, and 0.5 µg/ml, respectively, and the omadacycline MIC90s for PRSP and H. influenzae were 0.25 µg/ml and 2.0 µg/ml, respectively. Omadacycline was active against organisms demonstrating the two major mechanisms of resistance, ribosomal protection and active tetracycline efflux. In vivo efficacy of omadacycline was demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibited efficacy against Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, including tet(M) and tet(K) efflux-containing strains and MRSA strains. The 50% effective doses (ED50s) for Streptococcus pneumoniae obtained ranged from 0.45 mg/kg to 3.39 mg/kg, the ED50s for Staphylococcus aureus obtained ranged from 0.30 mg/kg to 1.74 mg/kg, and the ED50 for Escherichia coli was 2.02 mg/kg. These results demonstrate potent in vivo efficacy including activity against strains containing common resistance determinants. Omadacycline demonstrated in vitro activity against a broad range of Gram-positive and select Gram-negative pathogens, including resistance determinant-containing strains, and this activity translated to potent efficacy in vivo.

Seasonal variation in basal metabolic rates among the Yakut (Sakha) of Northeastern Siberia.

OBJECTIVES: Previous research has shown that indigenous circumpolar populations have elevated basal metabolic rates (BMRs), yet few studies have explored whether metabolic rates increase during the winter. This study addresses this gap by examining seasonal variation in BMR and its associations with thyroid function and lifestyle factors among the Yakut (Sakha) of Siberia. METHODS: Anthropometric dimensions, BMR, and thyroid hormone levels (free triiodothyronine [fT3], free thyroxine [fT4], thyroid-stimulating hormone [TSH]) were measured on two occasions (July/August, 2009 and January 2011) on a sample of 94 Yakut (Sakha) adults (35 men, 59 women) from the rural village of Berdygestiakh, Sakha Republic, Russia. RESULTS: Seasonal changes in BMR varied by age. Younger Yakut adults (19-49 years) showed significant elevations in winter-time BMR of 6% (P < 0.05), whereas older individuals (≥50 years) showed modest declines (2%; n.s.). Both younger and older Yakut men and women showed increased respiratory quotients during the winter. FT3 and fT4 levels significantly declined during the winter in both younger and older Yakut men and women (P < 0.05). Lifestyle factors were significant predictors of BMR variation, particularly among older men and women. CONCLUSIONS: Among the Yakut, increased wintertime BMR was observed among younger but not older adults, whereas all adults showed sharp reductions in free thyroid hormone levels during the winter. Among men, greater participation in subsistence activities was associated with increased BMRs and greater fat oxidation. Among women, variation in food use had the strongest impact on metabolic function.

Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries.

Dental caries continues to be the most common chronic disease in children today. Despite the substantial involvement of genetics in the process of caries development, the specific genes contributing to dental caries remain largely unknown. We performed separate genome-wide association studies of smooth and pit-and-fissure tooth surface caries experience in the primary dentitions of self-reported white children in two samples from Iowa and rural Appalachia. In total, 1,006 children (ages 3-12 years) were included for smooth surface analysis, and 979 children (ages 4-14 years) for pit-and-fissure surface analysis. Associations were tested for more than 1.2 million single nucleotide polymorphisms, either genotyped or imputed. We detected genome-wide significant signals in KPNA4 (p value = 2.0E-9), and suggestive signals in ITGAL (p value = 2.1E-7) and PLUNC family genes (p value = 2.0E-6), thus nominating these novel loci as putative caries susceptibility genes. We also replicated associations observed in previous studies for MPPED2 (p value = 6.9E-6), AJAP1 (p value = 1.6E-6) and RPS6KA2 (p value = 7.3E-6). Replication of these associations in additional samples, as well as experimental studies to determine the biological functions of associated genetic variants, are warranted. Ultimately, efforts such as this may lead to a better understanding of caries etiology, and could eventually facilitate the development of new interventions and preventive measures.

Frequency of daily tooth brushing: predictors of change in 9- to 11-year old US children.

OBJECTIVE: To investigate whether an increase in daily tooth brushing frequency in children was predicted by either a) having a strong intention to brush twice a day or b) their parents receiving information about their new caries experience. BASIC RESEARCH DESIGN: Secondary data analyses were conducted on two waves of data from the Aban Aya Youth Project and the Iowa Fluoride Study. PARTICIPANTS: The Aban Aya study included 576 10- and 11-year olds from Chicago, Illinois. The Iowa Fluoride Study included a convenience sample of 709 babies born in Iowa. The present study includes those children at age 9. MAIN OUTCOME MEASURES: In both studies, reported daily tooth brushing frequency was assessed twice six months apart. RESULTS: In the Aban Aya data, compared with children with a weak intention at wave 1 to brush twice a day, children with a strong intention to brush twice a day were more likely to increase their brushing frequency by wave 2, OR 7.0, 95%CI 1.5,32.9. In the Iowa Fluoride Study, compared with children who did not have new caries at wave 1, children who had new caries experience were less likely to increase their brushing frequency by wave 2, OR 0.4, 95%CI 0.2,0.9. CONCLUSIONS: Strengthening intention to brush twice a day might increase children's brushing frequency. However, simply providing parents with information about new caries probably will not. Future studies should assess tooth brushing frequency, habit strength, intention, and situational cues at closely-spaced waves.

[Dental health and dental care according diabetic status; results from 2008 ESPS study]. / État de santé et suivi bucco-dentaire selon le statut diabétique : exploitation de l'enquête ESPS 2008.

BACKGROUND: Poorly controlled diabetes leads to serious complications including periodontal disease, oral disease leading to tooth loss. Diabetics benefit from care facilitated follow-up. Social inequalities are observed in oral health and diabetes. The objective of this study was to estimate the effect of the social factors on oral health and use of dental care for people with diabetes from the Health and Social Protection Survey 2008 (ESPS) and to compare it with that observed among non-diabetic people. METHODS: The ESPS is a representative survey of the French population. In 2008, data were derived from a self-administered health questionnaire given to all household members aged 16 or older. The scope of this study was restricted to persons aged 35 and over (12.082) having filled out their health survey (8961). Diabetes was defined from self-reports of disease or use of anti-diabetic medication. Oral health was estimated from perceived oral health and the number of missing teeth not replaced. Use of dental care was measured by self-report of a visit within the last two years. Socio-demographic and social coverage indicators were collected. RESULTS: The participation rate was 74.1% and prevalence of diabetes was 7.2% (648). People with diabetes had a poorer dental status (42.7% vs 26.5% - OR=1.22, 95% CI [1.01-1.47]), related to social characteristics. The effect of level of precariousness on dental health was equivalent in diabetic and non-diabetic populations. The use of dental care (73.4% of participants) was associated with social factors. Diabetics were less likely to consult dentists than non-diabetics (61.5% vs 74.4%), but this difference was not statistically significant (OR=0.86, 95%CI [0.72-1.04]). The effect of the level of precariousness on use of dental care was the same in both populations. CONCLUSION: This study raises the question of the impact of recommendations on monitoring dental health among diabetics especially for vulnerable populations despite better management and coverage.