Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS?

Advancing research and clinical care, and conducting successful and cost-effective clinical trials requires characterizing a given patient population. To gather a sufficiently large cohort of patients in rare diseases such as amyotrophic lateral sclerosis (ALS), we developed the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) platform. The PRO-ACT database currently consists of >8600 ALS patient records from 17 completed clinical trials, and more trials are being incorporated. The database was launched in an open-access mode in December 2012; since then, >400 researchers from >40 countries have requested the data. This review gives an overview on the research enabled by this resource, through several examples of research already carried out with the goal of improving patient care and understanding the disease. These examples include predicting ALS progression, the simulation of future ALS clinical trials, the verification of previously proposed predictive features, the discovery of novel predictors of ALS progression and survival, the newly identified stratification of patients based on their disease progression profiles, and the development of tools for better clinical trial recruitment and monitoring. Results from these approaches clearly demonstrate the value of large datasets for developing a better understanding of ALS natural history, prognostic factors, patient stratification, and more. The increasing use by the community suggests that further analyses of the PRO-ACT database will continue to reveal more information about this disease that has for so long defied our understanding.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0336-z) contains supplementary material, which is available to authorized users.     

Similar Neutrophil-Driven Inflammatory and Antibacterial Responses in Elderly Patients with Symptomatic and Asymptomatic Bacteriuria

Differential diagnosis of asymptomatic bacteriuria (ASB) and urinary tract infection (UTI) is based on the presence of diverse symptoms, including fever (≥38.5°C), rigors, malaise, lethargy, flank pain, hematuria, suprapubic discomfort, dysuria, and urgent or frequent urination. There is consensus in the medical community that ASB warrants antibiotic treatment only for patients undergoing urological procedures that lead to mucosal bleeding, catheterized individuals whose ASB persists for more than 48 h after catheter removal, and pregnant women. Pyuria is associated with UTI and implicates host immune responses via release of antibacterial effectors and phagocytosis of pathogens by neutrophils. Such responses are not sufficiently described for ASB. Metaproteomic methods were used here to identify the pathogens and evaluate molecular evidence of distinct immune responses in cases of ASB compared to UTI in elderly patients who were hospitalized upon injury. Neutrophil-driven inflammatory responses to invading bacteria were not discernible in most patients diagnosed with ASB compared to those with UTI. In contrast, proteomic urine analysis for trauma patients with no evidence of bacteriuria, including those who suffered mucosal injuries via urethral catheterization, rarely showed evidence of neutrophil infiltration. The same enzymes contributing to the synthesis of leukotrienes LTB₄ and LTC₄, mediators of inflammation and pain, were found in the UTI and ASB cohorts. These data support the notion that the pathways mediating inflammation and pain in most elderly patients with ASB are not quantitatively different from those seen in most elderly patients with UTI and warrant larger clinical studies to assess whether a common antibiotic treatment strategy for elderly ASB and UTI patients is justified.     

Interactions of <Emphasis Type="Italic">GST</Emphasis> Polymorphisms in Air Pollution Exposure and Respiratory Diseases and Allergies

Purpose of Review

The purpose of this review is to summarize the evidence from recently published original studies investigating how glutathione S-transferase (GST) gene polymorphisms modify the impact of air pollution on asthma, allergic diseases, and lung function.

Recent Findings

Current studies in epidemiological and controlled human experiments found evidence to suggest that GSTs modify the impact of air pollution exposure on respiratory diseases and allergies. Of the nine articles included in this review, all except one identified at least one significant interaction with at least one of glutathione S-transferase pi 1 (GSTP1), glutathione S-transferase mu 1 (GSTM1), or glutathione S-transferase theta 1 (GSTT1) genes and air pollution exposure. The findings of these studies, however, are markedly different. This difference can be partially explained by regional variation in the exposure levels and oxidative potential of different pollutants and by other interactions involving a number of unaccounted environment exposures and multiple genes.

Summary

Although there is evidence of an interaction between GST genes and air pollution exposure for the risk of respiratory disease and allergies, results are not concordant. Further investigations are needed to explore the reasons behind the discordancy.

     

Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up.Proper development of neuronal circuits, as well as efficient information storage during learning and memory, are thought to depend upon the presence of homeostatic mechanisms that stabilize neuronal excitability (1–3). One such mechanism is synaptic scaling, which compensates for perturbations in average firing by scaling up or down the postsynaptic strength of all of a neuron’s excitatory synapses (4). Synaptic scaling is a cell-autonomous process in which neurons detect changes in their own firing through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of AMPA receptors (AMPAR) at synaptic sites and thus increase or decrease synaptic strength (4–6). Despite great recent interest, the AMPA receptor-trafficking events that underlie synaptic scaling remain largely obscure. Defects in synaptic scaling have been postulated to contribute to disorders as diverse as Alzheimer’s disease (7) and epilepsy (8), so illuminating the underlying AMPAR trafficking steps could shed light into the genesis of a wide range of neurological disorders.Most neocortical AMPAR are heteromeric receptors composed of both GluA1 and GluA2 subunits, which have unique phosphorylation sites and interact with distinct trafficking proteins (9). During synaptic scaling up in response to action potential blockade, synaptic strength is increased through enhanced synaptic accumulation of GluA1 and GluA2-containing AMPAR (5, 10–13) and requires the C-terminal domain of the GluA2 subunit (12), but which subunit-specific interactions underlie synaptic scaling remain controversial (12, 14). Several trafficking proteins are known to interact with the GluA2, but not the GluA1, C-tail, including glutamate receptor interacting protein-1 (GRIP1) (15) and protein interacting with C-kinase-1 (PICK1) (16). Many studies have examined the role of GRIP1 and PICK1 in AMPAR trafficking and surface accumulation (15, 17–22), but little is known about their potential roles in regulating AMPAR synaptic accumulation during synaptic scaling. It was recently shown that deletion of PICK1, which competes with GRIP1/2 for binding to GluA2, enhances AMPAR accumulation and occludes synaptic scaling up (23), suggesting GRIP/PICK1-GluA2 interactions as possible critical players in synaptic scaling.GRIP1 was one of the first AMPAR-binding proteins identified (15), and yet its exact function in synaptic transmission and plasticity remains controversial. GRIP1 is an abundant multi-PDZ domain-containing protein that interacts with GluA2 through its fourth and fifth PDZ domains (15) and has known interactions with several other signaling and trafficking proteins, including itself (24), ABP (25), EphB receptors (26); the rasGEF GRASP-1 (27), the scaffold protein liprin-α (28), and the microtubule motor protein KIF5, or kinesin 1 (29). The role of GRIP1 in AMPAR trafficking is complicated and may involve AMPAR trafficking to and stabilization at synapses (17), as well as microtubule-based transport into dendrites (29) and the regulation of AMPAR movement between intracellular recycling compartments and the cell surface (22, 30). How GRIP1 influences basal AMPAR trafficking is not entirely clear. Overexpression of GRIP1 or gain-of-function GRIP1 mutants have been consistently observed to enhance surface AMPAR levels (21, 31), but knockout or dominant-negative GRIP1 constructs have had inconsistent effects, with slower synaptic AMPAR accumulation observed in one study (17) but no effects on basal AMPAR recycling and transmission in others (22, 32). Interestingly, GRIP1 and -2 are critical for the expression of cerebellar long-term depression (LTD), where they play redundant roles in regulated AMPAR endocytosis (33, 34). Currently no direct role for GRIP1 in activity-dependent synaptic strengthening or homeostatic plasticity has been established.Here, we show that the GRIP1–GluA2 interaction plays an essential role in the activity-dependent synaptic AMPAR accumulation and enhanced excitatory synaptic strength that underlies synaptic scaling up. Activity blockade with TTX increased the accumulation of GRIP1 at synaptic sites, whereas directly enhancing synaptic GRIP1 accumulation through overexpression (OE) was sufficient to mimic synaptic scaling. GRIP1 was necessary for synaptic scaling, because scaling up was prevented by shRNA-mediated knock down (KD) of endogenous GRIP1 and rescued by replacement with an RNAi-insensitive (RNAiI) GRIP1 but not a GRIP1 mutant that lacks the GluA2 interaction domain. We showed previously that GluA2 KD blocks synaptic scaling (12). Here, we show that synaptic scaling after GluA2 KD can be rescued by wild-type (RNAiI) GluA2 or point mutants that do not interfere with GRIP1 binding but not by GluA2 point mutants (Y876E and S880E) that reduce GluA2- GRIP1 binding, strongly suggesting that GRIP1 mediates synaptic scaling through interactions with GluA2. Finally, TTX still induced GRIP1 synaptic accumulation even when AMPAR accumulation was prevented by expression of GluA2 Y876E; thus, during synaptic scaling GluA2 synaptic accumulation depends on GRIP1 binding, but GRIP1 translocation and synaptic accumulation occur independently of GluA2 binding. Together our data show that activity-dependent regulation of synaptic GRIP1 abundance is critical for the forward trafficking and accumulation of AMPA receptors at synapses during synaptic scaling.     

Sporadic cases of acute autochthonous hepatitis E in Spain

BACKGROUND/AIMS: In industrialized countries hepatitis E virus (HEV) infection is rare and its diagnosis is difficult because the utility of available tests is not well established. METHODS: We studied the presence of acute HEV infection markers in a cluster of 11 cases of acute hepatitis with IgG anti-HEV antibodies. RESULTS: Three cases were confirmed as acute hepatitis E and 8 as presumptive hepatitis E, two as a past HEV infection and one could not be determined. Three different HEV strains were identified in serum from 3 patients. Two strains belonged to genotype 3, the predominant genotype found in local urban sewage and the other strain belonged to genotype 1 and was considered an imported strain. CONCLUSIONS: Our findings demonstrate the presence of some autochthonous, sporadic acute hepatitis E cases as well as an imported case in our area and the transitory nature of virological and serological markers for HEV.