New-generation azaindole-adamantyl-derived synthetic cannabinoids

Purpose

This work reports the synthesis and pharmacological and analytical data for a new series of recently identified azaindole-adamantyl-derived synthetic cannabinoids (SCs).

Methods

Each SC was synthesised using an efficient and divergent synthesis, and assessed by electron ionisation mass spectrometry (EIMS). The cannabimimetic activity of each compound was conducted using a fluorometric imaging plate reader (FLIPR) assay.

Results

The described EIMS method and retention time by gas chromatography were able to effectively differentiate each of the analogues regardless of the bicyclic core. For the first time in these SC structures, the bicyclic ring system was shown to have an impact on the cannabimimetic activities in the fluorometric assay of membrane potential. Analogues ranged from moderately potent at both CB₁ and CB₂ (e.g., AP4AIC EC₅₀?=?160 nM and EC₅₀?=?64 nM, respectively) to not active at either cannabinoid receptor (AP4AICA, AP5AICA, and APIC).

Conclusions

Further investigation into receptor selectivity surrounding these bicyclic cores could prove useful for future therapeutic applications.

     

Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization

Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.     

Dynamic development of the pancreas from birth to adulthood

After birth the endocrine pancreas continues its development, a complex process that involves both the maturation of islet cells and a marked expansion of their numbers. New beta cells are formed both by duplication of pre-existing cells and by new differentiation (neogenesis) across the first postnatal weeks, with the result of beta cells of different stages of maturation even after weaning. Improving our understanding of this period of beta cell expansion could provide valuable therapeutic insights.     

Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice

Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-beta (A beta) deposits, and neurofibrillary lesions, which consist of intracellular aggregates of hyperphosphorylated tau protein. To study the in vivo induction of tau pathology, dilute brain extracts from aged A beta-depositing APP23 transgenic mice were intracerebrally infused in young B6/P301L tau transgenic mice. Six months after the infusion, tau pathology was induced in the injected hippocampus but also in brain regions well beyond the injection sites such as the entorhinal cortex and amygdala, areas with neuronal projection to the injection site. No or only modest tau induction was observed when brain extracts from aged nontransgenic control mice and aged tau-depositing B6/P301L transgenic mice were infused. To further study A beta-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although A beta deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high A beta plaque load. The present results suggest that both extract-derived A beta species and deposited fibrillary A beta can induce the formation of tau neurofibrillary pathology. The observation that infused A beta can trigger the tau pathology in the absence of A beta deposits provides an explanation for the discrepancy between the neuroanatomical location of A beta deposits and the development and spreading of tau lesions in Alzheimer's disease brain.     

Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density

Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a −0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (−4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Post-intubation tracheal rupture: poor healing of the tracheal wall

Purpose

To describe tracheal rupture after orotracheal intubation assisted by a tracheal tube introducer.

Clinical features

A 73-yr-old morbidly obese female patient with a history of hypertension underwent a total knee replacement. There were no anticipated signs of difficult intubation. Orotracheal intubation was attempted twice by direct laryngoscopy, and a Boussignac bougie was used as a tube exchanger for the second attempt. Seven hours after tracheal extubation, the patient became dyspneic and showed a large subcutaneous emphysema. A chest x-ray and computerized tomography scan revealed rupture of the posterior tracheal wall. The distal part of the injury was 26.5 cm from the patient’s teeth and 0.5 cm from the carina (i.e., beyond the normal location of the tracheal tube tip) and extended to the origin of the right main bronchus, where the tip of the Boussignac bougie was probably pushed. Formation of an endotracheal sac occurred during the first two weeks after intubation, accompanied by dyspnea and alveolar hypoventilation, but symptoms resolved favourably with conservative management.

Conclusion

The tracheal rupture was attributed to airway manipulations, and the distal location of the lesion suggests that the cause was the Boussignac bougie rather than the tracheal tube. Long-term healing of the injury was satisfactory, although the patient continued to complain of dyspnea one year after the rupture.     

Socio-economic impact of endovenous thermal ablation techniques

Varicose veins are common and cause extensive morbidity; however, the value of treatment is under-appreciated. Many procedures allow the treatment of varicose veins with minimal cost and extensive literature supporting differing minimally invasive approaches. In this article, we investigate the current literature regarding treatment options, clinical outcome and the cost-benefit economics associated with varicose vein treatment. The practice of defining clinical outcome with quality of life (QOL) assessment is explained to provide valid concepts of treatment success beyond occlusion rates.     

Assessment and Management of Hypertension in Patients on Dialysis

Hypertension is common, difficult to diagnose, and poorly controlled among patients with ESRD. However, controversy surrounds the diagnosis and treatment of hypertension. Here, we describe the diagnosis, epidemiology, and management of hypertension in dialysis patients, and examine the data sparking debate over appropriate methods for diagnosing and treating hypertension. Furthermore, we consider the issues uniquely related to hypertension in pediatric dialysis patients. Future clinical trials designed to clarify the controversial results discussed here should lead to the implementation of diagnostic and therapeutic techniques that improve long-term cardiovascular outcomes in patients with ESRD.     

Differences in Access to HIV Services and Risky Sexual Behaviors Among Malawian Women at Social Venues Who Do and Do Not Engage in Sex Work

AIDS and Behavior - In the high HIV-burden country of Malawi, female sex workers (FSW) are one of the populations most profoundly affected by HIV. The Malawi Priorities for Local AIDS Control...