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.     

Variability of Clinical and Pressure-Flow Study Variables After 6 Months of Watchful Waiting in Patients with Lower Urinary Tract Symptoms and Benign Prostatic Enlargement

Purpose

We quantified the physiological variability of clinical and pressure-flow study variables in patients with symptomatic benign prostatic enlargement.

Materials and Methods

Symptom scores were measured, and advanced urodynamic studies with pressure-flow analysis were performed in 178 patients before and 6 months after a period of watchful waiting.

Results

Patients without bladder outlet obstruction experienced significant symptomatic improvement. Symptoms in patients with obvious bladder outlet obstruction did not improve significantly. The reproducibility of mean pressure-flow variables was evident. However, there was an important intra-individual variability. Patients with obvious bladder outlet obstruction showed a significant decrease in detrusor pressure at maximal flow of 14 cm. water, a significant decrease in the urethral resistance factor of 7 cm. water and a significant decrease of 1 obstruction class on the linear passive urethral resistance relation nomogram, indicating less severe bladder outlet obstruction.

Conclusions

Mean differences among therapy groups must be regarded critically, especially when the differences are slight and possibly within physiological variability.     

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.     

Effects of transmembrane region variability on cell surface expression and allorecognition of HLA-DP3

The functional relevance of polymorphisms outside the peptide binding groove of HLA molecules is poorly understood. Here we have addressed this issue by studying HLA-DP3, a common antigen relevant for functional matching algorithms of unrelated hematopoietic stem cell transplantation (HSCT) encoded by two transmembrane (TM) region variants, DPB1^*03:01 and DPB1^*104:01. The two HLA-DP3 variants were found at a overall allelic frequency of 10.4% in 201 volunteer stem cell donors, at a ratio of 4.2:1. No significant differences were observed in cell surface expression levels of the two variants on B lymphoblastoid cell lines (BLCL), primary B cells or monocytes. Three different alloreactive T cell lines or clones showed similar levels of activation marker CD107a and/or CD137 upregulation in response to HLA-DP3 encoded by DPB1^*03:01 and DPB1^*104:01, either endogenously on BLCL or after lentiveral-vector mediated transfer into the same cellular background. These data provide, for the first time, direct evidence for a limited functional role of a TM region polymorphism on expression and allorecognition of HLA-DP3 and are compatible with the notion that the two variants can be considered as a single functional entity for unrelated stem cell donor selection.     

Cost-effectiveness of Surgery in Low- and Middle-income Countries: A Systematic Review

Background

There is increasing interest in provision of essential surgical care as part of public health policy in low- and middle-income countries (LMIC). Relatively simple interventions have been shown to prevent death and disability. We reviewed the published literature to examine the cost-effectiveness of simple surgical interventions which could be made available at any district hospital, and compared these to standard public health interventions.

Methods

PubMed and EMBASE were searched using single and combinations of the search terms “disability adjusted life year” (DALY), “quality adjusted life year,” “cost-effectiveness,” and “surgery.” Articles were included if they detailed the cost-effectiveness of a surgical intervention of relevance to a LMIC, which could be made available at any district hospital. Suitable articles with both cost and effectiveness data were identified and, where possible, data were extrapolated to enable comparison across studies.

Results

Twenty-seven articles met our inclusion criteria, representing 64 LMIC over 16 years of study. Interventions that were found to be cost-effective included cataract surgery (cost/DALY averted range US$5.06–$106.00), elective inguinal hernia repair (cost/DALY averted range US$12.88–$78.18), male circumcision (cost/DALY averted range US$7.38–$319.29), emergency cesarean section (cost/DALY averted range US$18–$3,462.00), and cleft lip and palate repair (cost/DALY averted range US$15.44–$96.04). A small district hospital with basic surgical services was also found to be highly cost-effective (cost/DALY averted 1 US$0.93), as were larger hospitals offering emergency and trauma surgery (cost/DALY averted US$32.78–$223.00). This compares favorably with other standard public health interventions, such as oral rehydration therapy (US$1,062.00), vitamin A supplementation (US$6.00–$12.00), breast feeding promotion (US$930.00), and highly active anti-retroviral therapy for HIV (US$922.00).

Conclusions

Simple surgical interventions that are life-saving and disability-preventing should be considered as part of public health policy in LMIC. We recommend an investment in surgical care and its integration with other public health measures at the district hospital level, rather than investment in single disease strategies.     

Trauma and traumatized populations in Israel: the Israel Journal of Psychiatry and Related Sciences, 1963-2002

In Europe and the U.S., awareness of interpersonal traumatization has disappeared and reappeared, seemingly connected to socio-historical conditions. The authors wanted to explore this phenomenon in Israel, a complex, multicultural, society that has yet to know peace. Content analysis of a professional journal, the Israel Journal of Psychiatry, was the method of choice. This journal has existed since the fifteenth year of Israel's existence and, because it is published in English, is in active dialogue with the rest of the world. Striking parallels were found between the timing and focus on traumas in the published articles and the socio-cultural context.     

A randomized study comparing epirubicin in a 4-weekly versus a weekly intravenous regimen in patients with metastatic,hormone resistant,prostatic carcinoma: effects on health related quality of life

The treatment of hormone resistant prostate cancer) with epirubicin 25 mg/m² (Epi25) on a weekly intravenous regimen may be better in terms of health related quality of life (HRQOL) than with 100 mg/m² (Epi100) on a 4-weekly regimen. A total of 79 patients who filled out the EORTC-QLQ-C30 questionnaire for the assessment of HRQOL could be evaluated. Compared with the baseline, no changes in HRQOL function scales or significant changes in the following HRQOL symptom scales were found. The Epi25 group reported less pain during the first 3 months and the Epi100 group more dyspnoea after 4 weeks and less pain and less insomnia but more loss of appetite after 8 weeks. In both groups, toxicity was comparable, except for World Health Organisation grade II-III alopecia occurring in 82% in the Epi100 versus 31% in the Epi25 group. There were no significant differences between groups in response rates and survival. In this study, HRQOL was not improved which is in line with other studies using only epirubicine. Epirubicin as single agent therapy should not be used in future treatment of patients with HRPC.     

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.