Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

Tetramethylenedisulfotetramine (TETS) is a potent convulsant that is considered a chemical threat agent. We characterized TETS as an activator of spontaneous Ca²⁺ oscillations and electrical burst discharges in mouse hippocampal neuronal cultures at 13-17 days in vitro using FLIPR Fluo-4 fluorescence measurements and extracellular microelectrode array recording. Acute exposure to TETS (≥ 2 µM) reversibly altered the pattern of spontaneous neuronal discharges, producing clustered burst firing and an overall increase in discharge frequency. TETS also dramatically affected Ca²⁺ dynamics causing an immediate but transient elevation of neuronal intracellular Ca²⁺ followed by decreased frequency of Ca²⁺ oscillations but greater peak amplitude. The effect on Ca²⁺ dynamics was similar to that elicited by picrotoxin and bicuculline, supporting the view that TETS acts by inhibiting type A gamma-aminobutyric acid (GABA(A)) receptor function. The effect of TETS on Ca²⁺ dynamics requires activation of N-methyl-D-aspartic acid (NMDA) receptors, because the changes induced by TETS were prevented by MK-801 block of NMDA receptors, but not nifedipine block of L-type Ca²⁺ channels. Pretreatment with the GABA(A) receptor-positive modulators diazepam and allopregnanolone partially mitigated TETS-induced changes in Ca²⁺ dynamics. Moreover, low, minimally effective concentrations of diazepam (0.1 µM) and allopregnanolone (0.1 µM), when administered together, were highly effective in suppressing TETS-induced alterations in Ca²⁺ dynamics, suggesting that the combination of positive modulators of synaptic and extrasynaptic GABA(A) receptors may have therapeutic potential. These rapid throughput in vitro assays may assist in the identification of single agents or combinations that have utility in the treatment of TETS intoxication

Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013.

ObjectiveTo examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM).Research design and methodsUsing claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1) age- and sex-standardized proportion of patients who filled each class of agents; 2) age-, sex-, race-, and region-standardized proportion with hemoglobin A1c (HbA1c) <6%, 6 to <7%, 7 to <8%, 8 to <9%, ≥9%; and 3) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18-44, 45-64, 65-74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more).ResultsFrom 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P < 0.001). The proportion of patients with HbA1c <7% declined (from 56.4 to 54.2%; P < 0.001) and with HbA1c ≥9% increased (9.9 to 12.2%; P < 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P < 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36).ConclusionsDuring the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged

Trivial, Strongly Minimal Theories Are Model Complete After Naming Constants

We prove that if M is any model of a trivial, strongly minimal theory, then the elementary diagram Th(MM) is a model complete LM-theory. We conclude that all countable models of a trivial, strongly minimal theory with at least one computable model are 0 -decidable, and that the spectrum of computable models of any trivial, strongly minimal theory is Σ05

Iterative Design and Usability Testing of the iMHere System for Managing Chronic Conditions and Disability

A novel mobile health platform, Interactive Mobile Health and Rehabilitation (iMHere), is being developed to support wellness and self-management among people with chronic disabilities. The iMHere system currently includes a smartphone app with six modules for use by persons with disabilities and a web portal for use by medical and rehabilitation professionals or other support personnel. Our initial clinical research applying use of this system provides insight into the feasibility of employing iMHere in the development of self-management skills in young adults (ages 18-40 years) with spina bifida (Dicianno, Fairman, McCue, Parmanto, Yih, et al., 2015). This article is focused on describing the iterative design of the iMHere system including usability testing of both the app modules and clinician portal. Our pilot population of persons with spina bifida fostered the creation of a system appropriate for people with a wide variety of functional abilities and needs. As a result, the system is appropriate for use by persons with various disabilities and chronic conditions, not only spina bifida. In addition, the diversity of professionals and support personnel involved in the care of persons with spina bifida (SB) also enabled the design and implementation of the iMHere system to meet the needs of an interdisciplinary team of providers who treat various conditions. The iMHere system has the potential to foster communication and collaboration among members of an interdisciplinary healthcare team, including individuals with chronic conditions and disabilities, for client-centered approach to support self-management skills.

Epigenetic Variation May Compensate for Decreased Genetic Variation with Introductions: A Case Study Using House Sparrows (Passer domesticus) on Two Continents

Epigenetic mechanisms impact several phenotypic traits and may be important for ecology and evolution. The introduced house sparrow (Passer domesticus) exhibits extensive phenotypic variation among and within populations. We screened methylation in populations from Kenya and Florida to determine if methylation varied among populations, varied with introduction history (Kenyan invasion <50 years old, Florida invasion ~150 years old), and could potentially compensate for decrease genetic variation with introductions. While recent literature has speculated on the importance of epigenetic effects for biological invasions, this is the first such study among wild vertebrates. Methylation was more frequent in Nairobi, and outlier loci suggest that populations may be differentiated. Methylation diversity was similar between populations, in spite of known lower genetic diversity in Nairobi, which suggests that epigenetic variation may compensate for decreased genetic diversity as a source of phenotypic variation during introduction. Our results suggest that methylation differences may be common among house sparrows, but research is needed to discern whether methylation impacts phenotypic variation

Association and disparities of food insecurity and child abuse: Analysis of the National Survey of Children’s Health

Background: Child abuse is a major public health issue and is a significant risk factor for compromised development, health morbidities, and the development of mental and behavioral disorders in children. Many factors contribute to child abuse, especially family stressors. Food insecurity, a significant family stressor, likely increases the rate of child abuse while also contributing directly and indirectly to the consequences on child development and lifespan. Given the adverse effects of child abuse and food insecurity, investigating their relationship is crucial to developing mitigation strategies.Purpose: Our primary objective was to assess the relationship between child abuse and food insecurity using data from the National Survey of Children’s Health (NSCH). Given that these disproportionately affect children of different demographic groups, our study aims to identify associations amongst varying demographic factors.Methods: We conducted an observational study assessing the National Survey of Children’s Health (2016-2021) to investigate the relationship between food security and child abuse. Using survey weights provided by the NSCH, we determined population estimates and rates of children experiencing food insecurity and child abuse. We then constructed logistic regression models to assess associations, via odds ratio, between food security groups and whether the child experienced child abuse. Finally, we constructed logistic regression models, via odds ratios, to assess food security and child abuse by demographic factors.Results: While rates of food security were similar across age groups, households with lower income had higher rates of marginal or low food security, as well as homes with Black, Indigenous, multi-racial, and Hispanic children. Compared to those with high food security, the odds of children with marginal or low food security were significantly more likely to experience child abuse (AORs: 2.36, 95% CI: 2.17-2.57 and 5.24, 95% CI: 4.59-6.00, respectively). Compared to White children with high food security, Indigenous, Black, and White children were significantly more likely to experience child abuse as household food security decreased.Conclusion: Child abuse and food insecurity have a significant association, including overlapping contributory factors and disparities. Efforts to improve food insecurity through policy, community food banks, and school-based programs may secondarily reduce child abuse. To address racial/ethnic disparities, the expansion of culturally-competent, evidence-based programs to reduce food insecurity should be established, which may also reduce risk factors for child abuse

Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors

Anti-microRNA (miRNA) oligonucleotides (AMOs) with 2\u27-O-Methyl (2\u27OMe) residues are commonly used to study miRNA function and can achieve high potency, with low cytotoxicity. Not withstanding this, we demonstrate the sequence-dependent capacity of 2\u27OMe AMOs to inhibit Toll-like receptor (TLR) 7 and 8 sensing of immunostimulatory RNA, independent of their miRNA-targeting function. Through a screen of 29 AMOs targeting common miRNAs, we found a subset of sequences highly inhibitory to TLR7 sensing in mouse macrophages. Interspecies conservation of this inhibitory activity was confirmed on TLR7/8 activity in human peripheral blood mononuclear cells. Significantly, we identified a core motif governing the inhibitory activity of these AMOs, which is present in more than 50 AMOs targeted to human miRNAs in miRBaseV20. DNA/locked nucleic acids (LNA) AMOs synthesized with a phosphorothioate backbone also inhibited TLR7 sensing in a sequence-dependent manner, demonstrating that the off-target effects of AMOs are not restricted to 2\u27OMe modification. Taken together, our work establishes the potential for off-target effects of AMOs on TLR7/8 function, which should be taken into account in their therapeutic development and in vivo application