Adverse childhood experiences and early initiation of substance use: A survival analysis.

OBJECTIVE: Early adversity, such as adverse childhood experiences (ACEs), is a risk factor for the development of substance use disorder (SUD). ACEs are associated with earlier initiation of substance use. This study examined the relationship between ACEs and age of initiation of substance use using survival analysis. It is hypothesized that individuals with higher ACEs will have an earlier age of initiation. METHOD: Participants were recruited from the University of Kentucky's Laboratory for Human Behavioral Pharmacology. Participants were 18 years or older, English speaking, and actively engaged in substance use. Participants were not in substance abuse treatment nor were they seeking treatment. ACE scores were calculated, and age of substance use initiation was recorded. A Cox proportional hazard model was used to examine the effect of ACE score on age of substance use initiation. RESULTS: A total of 107 participants completed the study. An average number of 2.3 ACEs (SD = 2.2) were endorsed with 24% of participants reporting 4 or more ACEs. Higher ACE scores were associated with cigarette smoking and non-medical prescription opioid use onset ( hazard ratio (HR) = 1.14, 95% CI=1.02-1.28, p = 0.02, and HR=1.19, 95% CI = 1.04-1.37, p = 0.01, respectively. CONCLUSIONS: A significant association was found between higher ACE scores and earlier initiation of cigarette and non-medical prescription opioid use, consistent with prior research. Primary prevention of ACEs, screening for ACEs during childhood, and interventions for ACEs if detected, may help to reduce the risk of substance use/SUD in adulthood.

A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission.

Retinitis pigmentosa (RP) defines a group of hereditary progressive rod-cone degenerations that exhibit a common phenotype caused by variants in over 70 genes. While most variants in the dehydrodolichyl diphosphate synthase (DHDDS) gene result in syndromic abnormalities, some variants cause non-syndromic RP (RP59). DHDDS encodes one subunit of the enzyme cis-prenyltransferase (CPT), which is required for the synthesis of dolichol (Dol), that is a necessary protein glycosylation cofactor. We previously reported the creation and initial characterization of a knock-in (KI) mouse model harboring the most prevalent RP59-associated DHDDS variant (K42E) to understand how defects in DHDDS lead to retina-specific pathology. This model exhibited no profound retinal degeneration, nor protein N-glycosylation defects. Here, we report that the Dol isoprenylogue species in retina, liver, and brain of the K42E mouse model are statistically shorter than in the corresponding tissues of age-matched controls, as reported in blood and urine of RP59 patients. Retinal transcriptome analysis demonstrated elevation of many genes encoding proteins involved in synaptogenesis and synaptic function. Quantitative retinal cell layer thickness measurements demonstrated a significant reduction in the inner nuclear layer (INL) and total retinal thickness (TRT) beginning at postnatal (PN) ∼2 months, progressively increasing to PN 18-mo. Histological analysis revealed cell loss in the INL, outer plexiform layer (OPL) disruption, and ectopic localization of outer nuclear layer (ONL) nuclei into the OPL of K42E mutant retinas, relative to controls. Electroretinograms (ERGs) of mutant mice exhibited reduced b-wave amplitudes beginning at PN 1-mo, progressively declining through PN 18-mo, without appreciable a-wave attenuation, relative to controls. Our results suggest that the underlying cause of DHDDS K42E variant driven RP59 retinal pathology is defective synaptic transmission from outer to inner retina.

Vertebrate Animal Models of RP59: Current Status and Future Prospects.

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for the synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing "knowledge gaps" in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset or to dampen the severity or progression of RP59.

Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59.

Dehydrodolichyl diphosphate synthase (DHDDS) is required for protein N-glycosylation in eukaryotic cells. A K42E point mutation in the DHDDS gene causes an autosomal recessive form of retinitis pigmentosa (RP59), which has been classified as a congenital disease of glycosylation (CDG). We generated K42E Dhdds knock-in mice as a potential model for RP59. Mice heterozygous for the Dhdds K42E mutation were generated using CRISPR/Cas9 technology and crossed to generate DhddsK42E/K42E homozygous mice. Spectral domain-optical coherence tomography (SD-OCT) was performed to assess retinal structure, relative to age-matched wild type (WT) controls. Immunohistochemistry against glial fibrillary acidic protein (GFAP) and opsin (1D4 epitope) was performed on retinal frozen sections to monitor gliosis and opsin localization, respectively, while lectin cytochemistry, plus and minus PNGase-F treatment, was performed to assess protein glycosylation status. Retinas of DhddsK42E/K42E mice exhibited grossly normal histological organization from 1 to 12 months of age. Anti-GFAP immunoreactivity was markedly increased in DhddsK42E/K42E mice, relative to controls. However, opsin immunolocalization, ConA labeling and PNGase-F sensitivity were comparable in mutant and control retinas. Hence, retinas of DhddsK42E/K42E mice exhibited no overt signs of degeneration, yet were markedly gliotic, but without evidence of compromised protein N-glycosylation. These results challenge the notion of RP59 as a DHDDS loss-of-function CDG and highlight the need to investigate unexplored RP59 disease mechanisms.

Coagulation using organic carbonates opens up a sustainable route towards regenerated cellulose films.

Due to their biodegradability, biocompatibility and sustainable nature, regenerated cellulose (RC) films are of enormous relevance for green applications including medicinal, environmental and separation technologies. However, the processes used so far are very hazardous to the environment and health. Here, we disclose a simple, fast, environmentally friendly, nontoxic and cost-effective processing method for preparing RC films. High quality non-transparent and transparent RC films and powders can be produced by dissolution with tetrabutylphosphonium hydroxide [TBPH]/[TBP]+[OH]- followed by coagulation with organic carbonates. Investigations on the coagulation mechanism revealed an extremely fast reaction between the carbonates and the hydroxide ions. The high-quality powders and films were fully characterized with respect to structure, surface morphology, permeation and selectivity. This method represents a future-oriented green alternative to known industrial processes.

The Effect of Additives on the Viscosity and Dissolution of Cellulose in Tetrabutylphosphonium Hydroxide.

An electrolyte solution of tetrabutylphosphonium hydroxide (TBPH) in water can dissolve over 20 wt % of cellulose in minutes and therefore constitutes a promising alternative green solvent system compared to known imidazolium- or dimethylacetamide-based systems. Overcoming the disadvantage of the extremely high viscosity of TBPH/cellulose solutions can facilitate their use for various applications. In this study, the application of cosolvents for the reduction, and thus adjustability, of the viscosity is addressed. Even well-known antisolvents can be easily deployed, resulting in a dramatic drop in viscosity. High concentrations of cosolvents (excluding ethanol) are tolerated without precipitation of the dissolved cellulose. Furthermore, the effect of the cosolvents on the additional dissolution of cellulose is discussed. The amount of dissolved cellulose is quantified by 13 C NMR spectroscopy.

What happens after graduation? Outcomes, employment, and recommendations of recent junior/community college graduates with and without disabilities.

PURPOSE: The objective was to compare employment status of junior/community college graduates with and without disabilities. METHODS: We compared post-graduation outcomes of 182 graduates with and 1304 without disabilities from career/technical and pre-university programs from three junior/community colleges. Findings for graduates who had registered for disability related services from their school and those who had not were examined separately. Reported academic obstacles and facilitators were also compared. RESULTS: Few employment differences between graduates with and without disabilities were found. Two-thirds of career/technical graduates from both groups were employed, approximately 30% were studying, and less than 3% were either looking for work or "unavailable for work." Over 80% of pre-university graduates in both groups were continuing their studies; here, too, numbers of employed graduates (14% with and 13% without disabilities) were similar and very few in both groups (<2%) were either looking for work or "unavailable for work." Full versus part-time employment of these two groups was very similar and the same proportion of graduates with and without disabilities were working in jobs related to their studies. Only in "closely related" work did graduates without disabilities have the advantage. CONCLUSIONS: Employment prospects for junior/community college graduates with disabilities seem to be quite positive.