Progranulin as a therapeutic target for dementia

Introduction: Progranulin (PGRN) is an acrosomal glycoprotein that is synthesized during spermatogenesis. It is overexpressed in tumors and has anti-inflammatory properties. The protein may be cleaved into granulins which display pro-inflammatory properties. In 2006, mutations in progranulin gene (GRN) that cause haploinsufficiency were found in familial cases of frontotemporal dementia (FTD). Patients with null mutations in GRN display very low-plasma PGRN levels; this analysis is useful for identifying mutation carriers, independent of the clinical presentation, and in those before the appearance of symptoms.

Areas covered: Here, we review the current knowledge of PGRN physiological functions and GRN mutations associated with FTD; we also summarize state of the art clinical trials and those compounds able to replace PGRN loss in preclinical models.

Expert opinion: PGRN represents a promising therapeutic target for FTD. Cohorts suitable for treatment, ideally at the preclinical stage, where pathogenic mechanisms ongoing in the brain are targeted, are available. However, PGRN may have side effects, such as the risk of tumorigenesis, and the risk/benefit ratio of any intervention cannot be predicted. Furthermore, at present, the situation is complicated by the absence of adequate outcome measures.     

Epicardial Versus Endocardial Pacemakers in the Pediatric Population: A Comparative Inquiry

Background: Most children in need of cardiac pacemakers remain dependent on the function of the permanent from childhood to adulthood. We sought to evaluate and compare the function between epicardial and endocardial pacemakers in pediatric groups with different conditions. Methods: Between 2012 and 2018, this single-canter study evaluated 44 pediatric patients with indications for epicardial or endocardial pacemakers. Results: The 2 groups, at a median age of 5 (0.1–16) years, were compared concerning the characteristics of the leads used (n = 80: bipolar, unipolar, steroid-eluting, and non–steroid-eluting), survival data, and complications. The reason for pacemaker implantation was congenital complete heart block in 11 (25%) cases and postoperative heart block in 33 (75%) cases. The commonest congenital heart disease accompanied by postoperative block was the ventricular septal defect. In the endocardial lead group, the mean ventricular pacing threshold immediately after the implantation and during the follow-up was less than that in the epicardial lead group (0.75 vs. 0.81 V; P = 0.01 and 0.8 vs. 2.4 V; P = 0.001). During the follow-up, the mean battery longevity was better in the endocardial group (last visit: 6.7 endocardial vs. 3.3 years epicardial). Lead failure was commoner in the epicardial pacemaker, and chronic high-pacing threshold pattern was seen in 14 patients in this group. After 3 years, freedom from lead failure was 94% and 63% in the endocardial and epicardial leads. Conclusions: Pacemakers with endocardial bipolar steroid-eluting leads showed better lead characteristics regarding survival and battery longevity than epicardial pacemakers without these lead characteristics. An appropriate pacemaker type should be selected based on the patient’s condition.     

Primary angioplasty with routine stenting compared with thrombolytic therapy in elderly patients with acute myocardial infarction

Background

Prior studies have yielded conflicting data on the advantage of primary angioplasty compared with thrombolysis in elderly patients with acute myocardial infarction (AMI). These studies, however, were performed before the contemporary widespread use of intracoronary stents and glycoprotien IIb/IIIa antagonists.

Methods

We prospectively compared the outcome of 130 consecutive elderly patients (aged ≥70 years) with ST-elevation AMI who were admitted to 2 similar neighboring medical centers. Patients were assigned to receive either thrombolytic therapy with accelerated tissue-type plasminogen activator (center I) or primary angioplasty with routine stenting (center II).

Results

Of the patients assigned to receive primary angioplasty, 91% underwent stenting. At 6 months, patients treated with primary angioplasty, compared with those treated with thrombolytic therapy, had a lower incidence of reinfarction (2% vs 14%, P = .053) and revascularization for recurrent ischemia (9% vs 61%, P < .001) and a significant reduction in the prespecified combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P < .01). Primary angioplasty remained an independent predictor of the triple combined end point after controlling for potential covariables (relative risk 0.63, 95% CI 0.38-0.84). Major bleeding complications were also significantly reduced in the primary angioplasty group (0% vs 17%, P = .03).

Conclusions

Compared with thrombolysis, primary angioplasty with routine stenting in elderly patients with AMI is associated with better clinical outcomes and a lower risk of bleeding complications.     

Films based on the biopolymer poly(3-hydroxybutyrate) as platforms for the controlled release of dexamethasone

Controlled drug delivery aims to achieve an effective drug concentration in the action site for a desired period of time, while minimizing side effects. In this contribution, biodegradable poly(3-hydroxybutyrate) films were evaluated as a reservoir platform for dexamethasone controlled release. These systems were morphological and physicochemically characterized. In vitro release assays were performed for five different percentages of drug in the films and data were fitted by a mathematical model developed and validated by our research group. When the profiles were normalized, a single curve properly fitted all the experimental data. Using this unique curve, the dissolution efficiency (DE), the time to release a given amount of drug (t_X%), and the mean dissolution time were calculated. Furthermore, the dissolution rate, the initial dissolution rate (a%) and the intrinsic dissolution rate were determined. The a% mean value was 1.968 × 10^?2% released/min, t_80% was about 14 days, and the DE was 59.6% at 14 days and 66.5% at 20 days. After 2 days, when approximately 40% of the drug was released, the dissolution rate decreased about 60% respect to the initial value. The poly(3-hydroxybutyrate) platforms behaved as an appropriate system to release and control the dexamethasone delivery, suggesting that they could be an alternative to improve drug therapy.     

Heterozygous TREM2 mutations in frontotemporal dementia

A causative association was recently demonstrated between homozygous TREM2 mutations and frontotemporal dementia (FTD)-like syndrome and between heterozygous TREM2 exon2 genetic variations and late-onset Alzheimer's disease (AD). The objective of this study was to evaluate whether heterozygous TREM2 genetic variations might be associated to the risk of FTD. TREM2 exon 2 was sequenced in a group of 1030 subjects—namely, 352 patients fulfilling clinical criteria for FTD, 484 healthy control subjects (HCs), and 194 patients with AD. The mutation frequency and the associated clinical characteristics were analyzed. We identified 8 missense and nonsense mutations in TREM2 exon 2 in 24 subjects. These mutations were more frequent in patients with FTD than in HCs (4.0% vs. 1.0%, p = 0.005). In particular, TREM2 Q33X, R47H, T66M, and S116C mutations were found in FTD and were absent in HCs. These mutations were associated with either the semantic variant of primary progressive aphasia or the behavioral variant FTD phenotypes. The FTD and AD groups were not significantly different with regard to TREM2 genetic variation frequency (AD: 2.6%, p = 0.39). Heterozygous TREM2 mutations modulate the risk of FTD in addition to increasing susceptibility to AD. Additional studies are warranted to investigate the possible role of these mutations in the pathogenesis of neurodegenerative disorders.     

An Overview on Biologic Medications and Their Possible Role in Apical Periodontitis

Introduction

Apical periodontitis (AP) is the expression of a deficient balance between infection and the host immune response.

Methods

If reducing the bacterial load from the root canal and preventing its reinfection may lead to clinical success, then the integrity of the nonspecific immune system has a relevant influence on the outcome of endodontic treatment.

Results

Compromised immune systems and/or genetic alterations of the host's response may as well play an important role on the development, progression, and healing of AP. Thus, immunomodulatory drugs might have the potential to influence both the severity of AP and the outcome of endodontic treatment. Biologic medications are a new class of drugs of monoclonal antibodies or fusion proteins that include fragments of a peculiar cytokine receptor. Specific inflammatory molecules or cells, such as tumor necrosis factor, interleukins, and T or B cells, are the selective targets of these drugs. They modulate the altered immune response and perform an important role in the short-term treatment of chronic inflammatory diseases such as rheumatoid arthritis, refractory Crohn disease, or ulcerative colitis. Despite the clinical positive outcomes and their widespread use, the consequences of administering biologic medications on the development of the dental diseases have not been adequately investigated.

Conclusions

The aim of this review was to give an overview of biologic medications, their composition, their mechanisms of action, and their possible implications on endodontic and other dental diseases.     

Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort

Endometrial cancer (EC) incidence rates vary ~10-fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low-risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow-up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m²), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m²) and HT use (to all non-HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.