Intravenous fate of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes

The objective of this study was to assess the in vivo fate of poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-based polyplexes after intravenous administration into mice. Circulation kinetics and tissue distribution in terms of plasmid localization and transfection efficiency were assessed. To gain more insight into the observed biodistribution and gene expression profile, the interaction of pDMAEMA-based polyplexes with blood components (erythrocytes and albumin) was investigated in vitro. In the case of i.v. injection of positively charged polyplexes at a dose of 30 microg DNA most of the radioactivity was found in the lungs and the liver 60 min after injection. In the case of pDMAEMA/DNA polyplexes with a negative charge, uptake occurred mainly by the liver. Administration of positively charged complexes at a 30 microg DNA dose resulted in reporter gene expression primarily in the lungs. Injection of negatively charged complexes and naked plasmid did not result in luciferase expression in any of the organs examined. In vitro turbidity experiments showed the induction of a charge dependent aggregation process upon addition of albumin to the polyplexes pointing out to the involvement of aggregate formation in the dominant lung uptake of the positively charged polyplexes. Also, incubations of polyplexes after pre-incubation with a physiological concentration of albumin with washed erythrocytes confirmed that polyplexes induce the formation of extremely large structures. This paper underlines the need for the design of systems with reduced interaction with blood components to promote the delivery of DNA to target tissues outside the lungs.     

Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain

Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal pain that is thought to be a disorder of central pain sensitization. A number of neurotransmitters in the ascending and descending pain pathways have been implicated in FM including glutamate and GABA. Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the conversion of glutamate to GABA and decreased expression or activity of this enzyme could result in an imbalance of excitatory and inhibitory neurotransmission in the ascending and descending pain pathways. Specifically, the expression and activity of the predominant isoform of GAD (GAD65) is influenced by several factors that are associated with FM such as female sex, poor diet, obesity, sedentary lifestyle, and stress. We hypothesize that decreased GAD expression and/or activity plays a role in the development and exacerbation of FM leading to impairments in the three common domains of FM symptomatology: increased pain (hyperalgesia and allodynia), disrupted sleep, and disturbances in mood (anxiety and depression). There are several lines of evidence that appear to support a role of GAD in FM. First, the defining symptom of FM is pain and GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia. Second, GAD has been implicated in disorders of muscle stiffness and rigidity and morning stiffness is a common symptom of FM. Third, stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity. Fourth, FM is associated with poor sleep, specifically disrupted non-rapid eye movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated with the activation of GAD-containing neurons in the preoptic hypothalamus. Fifth, FM is more commonly diagnosed in women than men and the activity of GAD is reduced by low levels of its cofactor pyroxidine, which is less well-absorbed by women and can be further lowered by diet, tobacco, and alcohol intake. Sixth, FM patients tend to be overweight or obese and caloric restriction and exercise have been shown to increase GAD expression and activity. These six general lines of evidence suggest that GAD expression and/or activity might underlie the pathophysiology of FM. If this hypothesis is supported by future empirical studies, our understanding of the etiology of FM could be greatly improved. Moreover, behavioral and pharmacological therapies that modulate or mimic the effects of GAD might hold promise for the treatment of this debilitating and poorly understood disorder.     

Shoulder dislocation in a very-low-birth-weight infant: case report and review of the literature

Shoulder dislocation in a preterm infant is very rare. We report a case of a preterm infant, with gestational age of 25 2/7 weeks and birth weight of 910 g, with anterior shoulder dislocation after breech delivery. The infant was successfully treated with closed reduction. In general, long-term outcome of shoulder dislocation in these infants is good. However, prompt recognition and treatment of the dislocated shoulder are essential to maintain normal shoulder girdle function and to prevent functional disability.     

The use of minimal fluoroscopy for cardiac electrophysiology procedures: A meta‐analysis and review of the literature

BackgroundConventional catheter ablation involves prolonged exposure to ionizing radiation, potentially leading to detrimental health effects. Minimal fluoroscopy (MF) represents a safer alternative, which should be explored. Data on the safety and efficacy of this technique are limited.HypothesisOur hypothesis is that MF is of equal efficacy and safety to conventional catheter ablation with the use of fluoroscopy by performing a meta‐analysis of both randomized controlled trials (RCTs) and real‐world registry studies.MethodsPubmed and Embase were searched from their inception to July 2020 for RCTs, cohort and observational studies that assessed the outcomes of catheter ablation using a MF technique versus the conventional approach.ResultsFifteen studies involving 3795 patients were included in this meta‐analysis. There was a significant reduction in fluoroscopy and procedural time with no difference in acute success (odds ratio [OR]:0.74, 95% CI: 0.50–1.10, p = .14), long‐term success (OR:0.92, 95% CI: 0.65–1.31, p = .38), arrhythmia recurrence (OR:1.24, 95% CI: 0.75–2.06, p = .97) or rate of complications. (OR:0.83, 95% CI: 0.46–1.48, p = .65). Additionally sub‐group analysis for those undergoing catheter ablation for atrial fibrillation (AF) did not demonstrate a difference in success or complication rates (OR:0.86, 95% CI: 0.30–2.42, p = .77). Multivariate meta‐regression did not identify the presence of moderator variables.ConclusionThis updated meta‐analysis demonstrated an overall reduction in procedural and fluoroscopy time for those undergoing a minimal fluoroscopic approach. There was no significant difference in either acute or chronic success rates or complications between a MF approach and conventional approach for the management of all arrhythmias including those undergoing catheter ablation for AF.     

The macrophage CD163 surface glycoprotein is an erythroblast adhesion receptor

Erythropoiesis occurs in erythroblastic islands, where developing erythroblasts closely interact with macrophages. The adhesion molecules that govern macrophage-erythroblast contact have only been partially defined. Our previous work has implicated the rat ED2 antigen, which is highly expressed on the surface of macrophages in erythroblastic islands, in erythroblast binding. In particular, the monoclonal antibody ED2 was found to inhibit erythroblast binding to bone marrow macrophages. Here, we identify the ED2 antigen as the rat CD163 surface glycoprotein, a member of the group B scavenger receptor cysteine-rich (SRCR) family that has previously been shown to function as a receptor for hemoglobin-haptoglobin (Hb-Hp) complexes and is believed to contribute to the clearance of free hemoglobin. CD163 transfectants and recombinant protein containing the extracellular domain of CD163 supported the adhesion of erythroblastic cells. Furthermore, we identified a 13-amino acid motif (CD163p2) corresponding to a putative interaction site within the second scavenger receptor domain of CD163 that could mediate erythroblast binding. Finally, CD163p2 promoted erythroid expansion in vitro, suggesting that it enhanced erythroid proliferation and/or survival, but did not affect differentiation. These findings identify CD163 on macrophages as an adhesion receptor for erythroblasts in erythroblastic islands, and suggest a regulatory role for CD163 during erythropoiesis.     

The relation between HbA1c and hypoglycemia revisited; a secondary analysis from an intervention trial in patients with type 1 diabetes and impaired awareness of hypoglycemia

Aims

We aimed to re-assess the previously shown but recently disputed association between HbA1c and severe hypoglycemia.

Cancer of the pancreas and drinking water: a population-based case-control study in Washington County, Maryland.

A case-control study was done to assess a potential association between drinking water and pancreatic cancer in Washington County, Maryland. Cases of pancreatic cancer occurring from 1975 through 1989 were identified from the cancer registry. Controls were selected from the private 1975 census of Washington County. There were 101 cases and 206 controls. Chlorinated municipal water was used as a source of drinking water by 79% of cases and 63% of controls, yielding a significant odds ratio of 2.2. Adjustment for age and smoking had almost no effect on the risk, although both age and smoking were independently associated with an increased risk of pancreatic cancer. Although these findings must be interpreted with caution because of limitations in exposure assessment, these results have implications for the prevention of pancreatic cancer because chlorination of water is so widely practiced.     

The system of care and services for frail older persons in Canada and Quebec

Since the early 70s, Canada has had a public health care system that guarantees all Canadians universal access to hospital and medical services free of charge. The same values and principles have governed the organization of health and social services in Quebec, including long-term care and services. Over time, changes have occurred within the Quebec system in order to adapt services to new realities more effectively; such changes involve a diversification of services oriented towards helping individuals remain in the community, and services provided close to clients' own environments. Mechanisms have also been established to improve clinical assessment of clients' needs, in order to make service orientation and admission to residential facilities more systematic. Nonetheless, reform is required in order to respond to certain trends related to client needs, i.e., greater needs due to the significant increase in the number of older persons, but also needs that differ from those of a younger population, for whom the system was designed. The new Quebec policy on services for frail older persons advocates a different concept of organization of services for this population group and presupposes major changes in the ways in which services are delivered.     

Behavioral problems and tobacco use among adolescents in Chile.

OBJECTIVE: To examine the association between behavioral problems and tobacco smoking among adolescent students in Chile. METHODS: Data were drawn from a study that included questionnaire surveys of 46 907 school-attending adolescents in all 13 of the administrative regions of Chile. Assessments were based on an adapted, Spanish-language version of the Drug Use Screening Inventory. The conditional form of the logistic regression model was used for analysis, with matching of students on individual schools, and with further statistical adjustments for sex, age, and selected risk factors. RESULTS: The prevalence of tobacco smoking among the adolescents was very high across all of Chile, with a level between 56% and 65% in each of the 13 regions. The estimated odds of tobacco use in youths at the highest level of behavioral problems was about twice that for youths at the lowest levels, both before and after controlling for sex, age, lack of participation in recreational activities, level of irritability, and levels of problems with school, family attention, and mental health. CONCLUSIONS: These findings help to complement and complete the evidence of prior studies on tobacco smoking among adolescents with behavior problems, including recent research on Central American youths. Although the magnitude of observed associations in Chile was not as great as that for the associations found in Central America, both the strength of these associations and their statistical significance were observed throughout Chile. This is the first study in Chile on potentially causal relationships such as these.