Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy

A randomized clinical trial comparing hydrocolloid, phenytoin and simple dressings for the treatment of pressure ulcers [ISRCTN33429693]

BACKGROUND: Pressure sores are important and common complications of spinal cord injury. Many preventive and therapeutic approaches have been tried and new trials are evolving. One relatively recent method is application of a hydrocolloid dressing (HD). In this study we compared the therapeutic effects of HD on pressure ulcer healing with two other topical applications, phenytoin cream (PC) and simple dressing (SD). METHODS: Ninety-one stage I and stage II pressure ulcers of 83 paraplegic male victims of the Iran-Iraq war were randomly allocated to three treatment groups. Mean age and weight of the participants were 36.64 ± 6.04 years and 61.12 ± 5.08 kg, respectively. All the patients were managed in long term care units or in their homes for 8 weeks by a team of general practitioners and nurses, and the ulcer status was recorded as "Complete healing", "Partial healing", "Without improvement" and "Worsening". RESULTS: Complete healing of ulcers, regardless of location and stage, was better in the HD group than the PC [23/31(74.19%) vs 12/30(40%); difference: 34.19%, 95% CI = 10.85–57.52, (P < 0.01)] or the SD [23/31(74.19%) vs 8/30(26.66%); difference: 47.53%, 95% CI = 25.45–69.61, (P < 0.005)] groups. Complete healing of stage I ulcers in the HD group [11/13(85%)] was better than in the SD [5/11(45%); difference: 40%, 95% CI = 4.7–75.22, (P < 0.05)] or PC [2/9 (22%); difference: 63%, 95% CI = 29.69–96.3, (P < 0.005)] groups. Complete healing of stage II ulcer in the HD group [12/18 (67%)] was better than in the SD group [3/19(16%); difference: 51%, 95% CI = 23.73–78.26, (P < 0.005)], but not significantly different from the PC group [10/21 (48%); difference: 19%, 95% CI = -11.47–49.47, (P > 0.05)]. We performed a second analysis considering only one ulcer per patient (i.e. 83 ulcers in 83 patients). This "per patient" analysis showed that complete ulcer healing in the HD group was better than in the PC [20/28(71.4%) vs 11/28 (39.3%); difference: 32.1%, 95% CI = 7.4–56.7, (P < 0.01)] or SD [20/28(71.4%) vs 8/27 (29.6%); difference: 41.8%, 95% CI = 17.7–65.8, (P < 0.005)] groups. CONCLUSION: We deduced that HD is the most effective method investigated for treating stage I and II pressure ulcers in young paraplegic men

Socioeconomic status, urbanicity and risk behaviors in Mexican youth: an analysis of three cross-sectional surveys

<p>Abstract</p> <p>Background</p> <p>The relationship between urbanicity and adolescent health is a critical issue for which little empirical evidence has been reported. Although an association has been suggested, a dichotomous rural versus urban comparison may not succeed in identifying differences between adolescent contexts. This study aims to assess the influence of locality size on risk behaviors in a national sample of young Mexicans living in low-income households, while considering the moderating effect of socioeconomic status (SES).</p> <p>Methods</p> <p>This is a secondary analysis of three national surveys of low-income households in Mexico in different settings: rural, semi-urban and urban areas. We analyzed risk behaviors in 15-21-year-olds and their potential relation to urbanicity. The risk behaviors explored were: tobacco and alcohol consumption, sexual initiation and condom use. The adolescents' localities of residence were classified according to the number of inhabitants in each locality. We used a logistical model to identify an association between locality size and risk behaviors, including an interaction term with SES.</p> <p>Results</p> <p>The final sample included 17,974 adolescents from 704 localities in Mexico. Locality size was associated with tobacco and alcohol consumption, showing a similar effect throughout all SES levels: the larger the size of the locality, the lower the risk of consuming tobacco or alcohol compared with rural settings. The effect of locality size on sexual behavior was more complex. The odds of adolescent condom use were higher in larger localities only among adolescents in the lowest SES levels. We found no statically significant association between locality size and sexual initiation.</p> <p>Conclusions</p> <p>The results suggest that in this sample of adolescents from low-income areas in Mexico, risk behaviors are related to locality size (number of inhabitants). Furthermore, for condom use, this relation is moderated by SES. Such heterogeneity suggests the need for more detailed analyses of both the effects of urbanicity on behavior, and the responses--which are also heterogeneous--required to address this situation.</p

Suppression of Her2/neu expression through ILK inhibition is regulated by a pathway involving TWIST and YB-1

In a previous study it was found that the therapeutic effects of QLT0267, a small molecule inhibitor of integrin-linked kinase (ILK), were influenced by Her2/neu expression. To understand how inhibition or silencing of ILK influences Her2/neu expression, Her2/neu signaling was evaluated in six Her2/neu-positive breast cancer cell lines (LCC6Her2, MCF7Her2, SKBR3, BT474, JIMT-1 and KPL-4). Treatment with QLT0267 engendered suppression (32–87%) of total Her2/neu protein in these cells. Suppression of Her2/neu was also observed following small interfering RNA-mediated silencing of ILK expression. Time course studies suggest that ILK inhibition or silencing caused transient decreases in P-AKTser473, which were not temporally related to Her2/neu downregulation. Attenuation of ILK activity or expression was, however, associated with decreases in YB-1 (Y-box binding protein-1) protein and transcript levels. YB-1 is a known transcriptional regulator of Her2/neu expression, and in this study it is demonstrated that inhibition of ILK activity using QLT0267 decreased YB-1 promoter activity by 50.6%. ILK inhibition was associated with changes in YB-1 localization, as reflected by localization of cytoplasmic YB-1 into stress granules. ILK inhibition also suppressed TWIST (a regulator of YB-1 expression) protein expression. To confirm the role of ILK on YB-1 and TWIST, cells were engineered to overexpress ILK. This was associated with a fourfold increase in the level of YB-1 in the nucleus, and a 2- and 1.5-fold increase in TWIST and Her2/neu protein levels, respectively. Taken together, these data indicate that ILK regulates the expression of Her2/neu through TWIST and YB-1, lending support to the use of ILK inhibitors in the treatment of aggressive Her2/neu-positive tumors

Strontium substituted bioactive glasses for tissue engineered scaffolds: the importance of octacalcium phosphate

Porous bioactive glasses are attractive for use as bone scaffolds. There is increasing interest in strontium containing bone grafts, since strontium ions are known to up-regulate osteoblasts and down regulate osteoclasts. This paper investigates the influence of partial to full substitution of strontium for calcium on the dissolution and phase formation of a multicomponent high phosphate content bioactive glass. The glasses were synthesised by a high temperature melt quench route and ground to a powder of <38 microns. The dissolution of this powder and its ability to form apatite like phases after immersion in Tris buffer (pH 7.4) and simulated body fluid (SBF) was followed by inductively coupled plasma optical emission spectroscopy (ICP), Fourier transform infra red spectroscopy (FTIR), X-ray powder diffraction (XRD) and (31)P solid state nuclear magnetic resonance spectroscopy up to 42 days of immersion. ICP indicated that all three glasses dissolved at approximately the same rate. The all calcium (SP-0Sr-35Ca) glass showed evidence of apatite like phase formation in both Tris buffer and SBF, as demonstrated after 3 days by FTIR and XRD analysis of the precipitate that formed during the acellular dissolution bioactivity studies. The strontium substituted SP-17Sr-17Ca glass showed no clear evidence of apatite like phase formation in Tris, but evidence of an apatite like phase was observed after 7 days incubation in SBF. The SP-35Sr-0Ca glass formed a new crystalline phase termed “X Phase” in Tris buffer which FTIR indicated was a form of crystalline orthophosphate. The SP-35Sr-0Ca glass appeared to support apatite like phase formation in SBF by 28 days incubation. The results indicate that strontium substitution for calcium in high phosphate content bioactive glasses can retard apatite like phase formation. It is proposed that apatite formation with high phosphate bioactive glasses occurs via an octacalcium phosphate (OCP) precursor phase that subsequently transforms to apatite. The equivalent octa-strontium phosphate does not exist and consequently in the absence of calcium, apatite formation does not occur. The amount of strontium that can be substituted for calcium in OCP probably determines the amount of strontium in the final apatite phase and the speed with which it forms

Dental caries in primary and permanent teeth in children's worldwide, 1995 to 2019: a systematic review and meta-analysis

Background: Early childhood caries (ECC) is a type of dental caries in the teeth of infants and children that is represented as one of the most prevalent dental problems in this period. Various studies have reported different types of prevalence of dental caries in primary and permanent teeth in children worldwide. However, there has been no comprehensive study to summarize the results of these studies in general, so this study aimed to determine the prevalence of dental caries in primary and permanent teeth in children in different continents of the world during a systematic review and meta-analysis. Methods: In this review study, articles were extracted by searching in the national and international databases of SID, MagIran, IranMedex, IranDoc, Cochrane, Embase, ScienceDirect, Scopus, PubMed, and Web of Science (ISI) between 1995 and December 2019. Random effects model was used for analysis and heterogeneity of studies was evaluated by using the I2 index. Data were analyzed by using the Comprehensive Meta-Analysis (Version 2) software. Findings: In this study, a total of 164 articles (81 articles on the prevalence of dental caries in primary teeth and 83 articles on the prevalence of dental caries in permanent teeth) were entered the meta-analysis. The prevalence of dental caries in primary teeth in children in the world with a sample size of 80,405 was 46.2% (95% CI: 41.6–50.8%), and the prevalence of dental caries in permanent teeth in children in the world with a sample size of 1,454,871 was 53.8% (95% CI: 50–57.5%). Regarding the heterogeneity on the basis of meta-regression analysis, there was a significant difference in the prevalence of dental caries in primary and permanent teeth in children in different continents of the world. With increasing the sample size and the year of study, dental caries in primary teeth increased and in permanent teeth decreased. Conclusion: The results of this study showed that the prevalence of primary and permanent dental caries in children in the world was found to be high. Therefore, appropriate strategies should be implemented to improve the aforementioned situation and to troubleshoot and monitor at all levels by providing feedback to hospitals

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS