Search

Although a growing number of studies have sought to understand what motivates the initiation of prescription stimulant misuse and diversion among college students, there has been a lack of studies focused on what motivates behavior cessation. We aimed to explore what motivates prescription stimulant misuse and diversion cessation, from the perspective of college students with a history of having initiated and then discontinued these behaviors. We conducted face-to-face interviews with students who had a history of misuse, diversion, or both, and who had intentionally, either for the short-term or long-term, ceased these behaviors. We audio-recorded, transcribed, and analyzed interviews inductively using a thematic analysis approach. Of the six themes we identified, four applied to both misuse and diversion, while two applied to diversion only. Engaging in related behavior change, seasonality of the behaviors, changes in personal needs, and negative and/or null experiences with the behaviors were themes for both misuse and diversion cessation. Themes that emerged solely for diversion cessation included: moral and legal concerns and not wanting to be perceived as a drug dealer. The information shared by students with first-hand misuse and diversion cessation experience has the potential to guide interventions designed to address prescription stimulant misuse on college campuses., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To evaluate outcomes with expectant management of preterm prelabor rupture of membranes (PROM) until 35 weeks versus immediate delivery at ≥34 weeks., Study Design: This was a multicenter retrospective cohort study of singletons with preterm PROM at >20 weeks from 2011 through 2017. Groups were defined as expectant management until 35 weeks versus immediate delivery at ≥34 weeks. Primary outcome was composite neonatal morbidity: need for respiratory support, culture positive neonatal sepsis, or antibiotic administration for >72 hours. Univariate and general estimating equation models were used with p  < 0.05 considered significant., Results: A total of 280 mother-infant dyads were included. There was no difference in composite neonatal outcome in pregnancies managed with expectant management compared with immediate delivery (43.4 vs. 37.5%; p  = 0.32). Those with expectant management had shorter length of neonatal intensive care unit (NICU) admission but higher rates of neonatal antibiotics for > 72 hours, endometritis, and histological chorioamnionitis. There were no cases of fetal demise, neonatal death, or maternal sepsis, and only three cases of neonatal sepsis., Conclusion: There is no difference in composite neonatal morbidity in pregnancies with preterm PROM managed with expectant management until 35 weeks as compared with immediate delivery at 34 weeks. Expectant management is associated with a decreased length of NICU admission but increased short-term infectious morbidity., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Unlabelled: Brain edema in acute liver failure (ALF) remains lethal. The role of vasogenic mechanisms of brain edema has not been explored. We previously demonstrated that matrix metalloproteinase-9 (MMP-9) contributes to the pathogenesis of brain edema. Here, we show that MMP-9 mediates disruptions in tight junction (TJ) proteins in vitro and in brains of mice with ALF. We transfected murine brain endothelial cells (ECs) with MMP-9 complementary DNA (cDNA) using pc DNA3.1 (+)/Myc-His A expression vector. Tissue inhibitor of matrix metalloproteinases (TIMP-1) cDNA transfection or GM6001 was used to inhibit MMP-9. ALF was induced in mice with azoxymethane. Endogenous overexpression of MMP-9 in brain ECs resulted in significant degradation of the TJ proteins occludin and claudin-5. The alterations in TJ proteins correlated with increased permeability to fluorescein isothiocyanate-dextran molecules. The degradation of TJ proteins and the increased permeability were reversed by TIMP-1 and GM6001. Similar results were found when MMP-9 was exogenously added to brain ECs. We also found that TJ protein degradation was reversed with GM6001 in the brains of mice with ALF., Conclusion: TJ proteins are significantly perturbed in brains of mice with ALF. These data corroborate the important role of MMP-9 in the vasogenic mechanism of brain edema in ALF.

The relationship between amyloid beta and cognitive dysfunction in mouse models of Alzheimer's disease has been evaluated predominantly with the spatial reference memory version of the water maze task. However, as Alzheimer's disease encompasses decline in multiple memory systems, it is important to also utilize non-spatial tasks to fully characterize the role of amyloid on behaviour in animal models. We used the TgCRND8 mouse model of Alzheimer's disease to evaluate the effect of amyloid on spatial reference memory, as well as on the non-spatial task of acquisition of conditioned taste aversion, and on the procedural task of swimming to a visible platform. We demonstrate that 8- to 12-month-old TgCRND8 mice are significantly impaired in all three tasks, and that the levels of soluble amyloid beta are significantly correlated with impairment in spatial reference memory, but not with impairment in conditioned taste aversion or swimming to a visible platform. Insoluble fractions of amyloid, which correspond closely to amyloid plaque burden in the brain, are not associated with any behavioural measure. Our study extends the characterization of the model to stages of advanced amyloid pathology and demonstrates that older TgCRND8 mice are impaired in multiple memory systems, including procedural tasks, which are spared at younger ages. The lack of association between amyloid plaques and memory decline supports clinical findings in Alzheimer's patients.

Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.

Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Hereditary mutations in the MAPT gene were shown to promote the formation of structurally distinct tau aggregates in patients that had a parkinsonian-like clinical presentation. Whether tau aggregates themselves or the soluble intermediate species that precede their aggregation are neurotoxic entities in these disorders has yet to be resolved; however, recent in vivo evidence supports the latter. We hypothesized that depletion of CHIP, a tau ubiquitin ligase, would lead to an increase in abnormal tau. Here, we show that deletion of CHIP in mice leads to the accumulation of non-aggregated, ubiquitin-negative, hyperphosphorylated tau species. CHIP-/- mice also have increased neuronal caspase-3 levels and activity, as well as caspase-cleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP-/- mice is insufficient to promote either argyrophilic or "pre-tangle" structures, despite marked phospho-tau accumulation throughout the brain. These observations are supported in post-developmental studies using RNA interference for CHIP (chn-1) in Caenorhabditis elegans and cell culture systems. Our results demonstrate that CHIP is a primary component in the ubiquitin-dependent degradation of tau. We also show that hyperphosphorylation and caspase-3 cleavage of tau both occur before aggregate formation. Based on these findings, we propose that polyubiquitination of tau by CHIP may facilitate the formation of insoluble filamentous tau lesions.

Neurofibrillary tangles (NFTs) are a characteristic neuropathological feature of Alzheimer's disease (AD), and molecular chaperones appear to be involved in the removal of disease-associated hyperphosphorylated tau, a primary component of NFTs. Here, novel HSP90 inhibitors were used to examine the impact of chaperone elevation on clearance of different tau species in transfected cells using a unique quantitative assay. The HSP90 inhibitors reduced levels of tau phosphorylated at proline-directed Ser/Thr sites (pS202/T205, pS396/S404) and conformationally altered (MC-1) tau species, an epitope that is immeasurable by standard Western blot techniques. The selective clearance of these phospho-tau species and MC-1 tau was mediated via the proteasome, while lysosomal-mediated tau degradation seems to lack specificity for certain tau species, suggesting a more general role in total tau removal. Interestingly, tau phosphorylated at S262/S356 within the tau microtubule binding domain was minimally affected by chaperone induction. Overall, our data show that chaperone induction results in the selective clearance of specific phospho-tau and conformationally altered tau species mediated by the proteasome; however, the apparent stability of pS262/S356 tau may also explain why MARK is able to regulate normal tau function yet still be linked to the initiation of pathogenic tau hyperphosphorylation in AD.

The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (Abeta) sequence and leads to Alzheimer's disease (AD). Arctic Abeta peptides more easily form Abeta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APPArcSwe) and transgenic mice with the Swedish mutation alone (tg-APPSwe). Intense intraneuronal Abeta-immunoreactive staining was present in young tg-APPArcSwe mice, but not in tg-APPSwe mice. Intracellular Abeta aggregates in tg-APPArcSwe were strongly stained by antibodies recognizing the N-terminus of Abeta, while those recognizing the C-terminus of Abeta stained weakly. The Abeta aggregates inside neurons increased with age and predated extracellular Abeta deposition in both tg-APPArcSwe and tg-APPSwe mice. Senile plaque deposition was markedly accelerated in tg-APPArcSwe mice, as compared to tg-APPSwe mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular Abeta aggregates in association with a rapid onset of senile plaque deposition.