Citations

Introduction Acute lung injury (ALI) is a devastating condition that places a heavy burden on public health resources. Although the need for effective ALI prevention strategies is increasingly recognised, no effective preventative strategies exist. The Lung Injury Prevention Study with Aspirin (LIPS-A) aims to test whether aspirin (ASA) could prevent and/or mitigate the development of ALI. Methods and analysis LIPS-A is a multicentre, double-blind, randomised clinical trial testing the hypothesis that the early administration of ASA will result in a reduced incidence of ALI in adult patients at high risk. This investigation will enrol 400 study participants from 14 hospitals across the USA. Conditional logistic regression will be used to test the primary hypothesis that early ASA administration will decrease the incidence of ALI. Ethics and dissemination Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approval of both the protocol and informed consent documents were also obtained from the institutional review board of each participating institution prior to enrolling study participants at the respective site. In addition to providing important clinical and mechanistic information, this investigation will inform the scientific merit and feasibility of a phase III trial on ASA as an ALI prevention agent. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to Pub Med Central in accordance with the National Institute of Health Public Access Policy.

A 23-year-old gentleman presented to the emergency department with new onset neurological dysfunction and painful oral and genital ulcers. Biopsies of the lesions noted non-specific inflammatory changes. MRI of the brain revealed a large mass-like lesion involving the pons, medulla, midbrain and surrounding cerebral tissue with T2 signal enhancement that was not amenable for biopsy. Both the ulcer biopsy results and the MRI findings could be attributed to either central nervous system (CNS) lymphoma or CNS Behçet's disease. A diagnosis of CNS Behçet's disease was thought to be most likely based on the clinical presentation and MRI findings. He was treated with high-dose immunosuppression and made a significant recovery.

Background and PurposeAlternative splicing expands proteome diversity toGPCRs. Distinct receptor variants have been identified for a secretin familyGPCR, the calcitonin receptor (CTR). The possible functional contributions of these receptor variants are further altered by their potential interactions with receptor activity‐modifying proteins (RAMPs). One variant of the humanCTRlacks the first 47 residues at itsNterminus [Δ(1–47)hCT(a)]. However, very little is known about the pharmacology of this variant or its ability to interact withRAMPsto form amylin receptors.Experimental ApproachΔ(1–47)hCT(a)was characterized both with and withoutRAMPsinCos7and/orHEK293Scells. The receptor expression (ELISAassays) and function (cAMPandpERK1/2 assays) for up to six agonists and two antagonists were determined.Key ResultsDespite lacking 47 residues at theNterminus, Δ(1–47)hCT(a)was still able to express at the cell surface, but displayed a generalized reduction in peptide potency. Δ(1–47)hCT(a)retained its ability to interact withRAMP1and formed a functional amylin receptor; this also appeared to be the case withRAMP3. On the other hand, its interaction withRAMP2and resultant amylin receptor was reduced to a greater extent.Conclusions and ImplicationsΔ(1–47)hCT(a)acts as a functional receptor at the cell surface. It exhibits altered receptor function, depending on whether it associates with aRAMPand whichRAMPit interacts with. Therefore, the presence of this variant in tissues will potentially contribute to altered peptide binding and signalling, depending on theRAMPdistribution in tissues.

AbstractAmyloidosis is a rare group of diseases characterized by deposition of amyloid fibrils in soft tissues. More than 28 types of amyloid have been identified. They all share common ultrastructural and chemical characteristics. Treatments are available for many types but are type specific. Therefore, confirmation and typing of amyloid are essential before initiating treatment. Monoclonal protein studies should be performed on suspected cases, but the diagnosis requires a tissue biopsy. Congo red stain and electron microscopy are helpful to discriminate between amyloid and other pathologic fibrils. Once amyloid is confirmed, typing should be performed. Immunofluorescence and immunohistochemistry are frequently used and are helpful, but this approach has limitations, such as availability, specificity and sensitivity of commercial antibodies. Genetic mutational analysis is vital for ruling in and out hereditary amyloidoses but is unhelpful in nonmutated forms. The most advanced technique of amyloid typing is laser microdissection followed by mass spectrometry. Using proteomics, laser microdissection followed by mass spectrometry can directly identify proteins with or without mutations. Finally, imaging studies, such as cardiac MRI with gadolinium and 123I-labeled SAP scintigraphy not only assist in evaluation of patients with known amyloidosis but cardiac MRI has detected amyloid in patients previously unsuspected of the disease.

Antimicrobial stewardship programs (ASPs) are an effective strategy for improving the quality and safety of antimicrobial prescribing for hospitalized patients. Pediatric ASPs are in their early stages of development, and there are unique issues relevant to children. The imperative to ensure that antimicrobials are prescribed judiciously is highlighted by the ongoing epidemic increase in antimicrobial‐resistant infections and the simultaneous decline in the rate of new drug development. In this review we describe the process of ASP development for pediatrics, review existing data regarding the impact of pediatric ASPs, and describe the priorities and challenges for ASP research including study design and appropriate end points.

Background— Hundreds of nonsynonymous single nucleotide variants (nsSNVs) have been identified in the 2 most common long-QT syndrome-susceptibility genes ( KCNQ1 and KCNH2 ). Unfortunately, an ≈3% background rate of rare KCNQ1 and KCNH2 nsSNVs amongst healthy individuals complicates the ability to distinguish rare pathogenic mutations from similarly rare yet presumably innocuous variants. Methods and Results— In this study, 4 tools [(1) conservation across species, (2) Grantham values, (3) sorting intolerant from tolerant, and (4) polymorphism phenotyping] were used to predict pathogenic or benign status for nsSNVs identified across 388 clinically definite long-QT syndrome cases and 1344 ostensibly healthy controls. From these data, estimated predictive values were determined for each tool independently, in concert with previously published protein topology–derived estimated predictive values, and synergistically when ≥3 tools were in agreement. Overall, all 4 tools displayed a statistically significant ability to distinguish between case-derived and control-derived nsSNVs in KCNQ1 , whereas each tool, except Grantham values, displayed a similar ability to differentiate KCNH2 nsSNVs. Collectively, when at least 3 of the 4 tools agreed on the pathogenic status of C-terminal nsSNVs located outside the KCNH2/Kv11.1 cyclic nucleotide−binding domain, the topology-specific estimated predictive value improved from 56% to 91%. Conclusions— Although in silico prediction tools should not be used to predict independently the pathogenicity of a novel, rare nSNV, our results support the potential clinical use of the synergistic utility of these tools to enhance the classification of nsSNVs, particularly for Kv11.1’s difficult to interpret C-terminal region.

Aging is associated with increased retrograde and oscillatory shear in peripheral conduit arteries of humans. Although the mechanisms responsible for these age-related changes are not completely understood, augmented downstream α-adrenergic tone likely plays a significant role in this phenomenon. Therefore, in protocol 1, brachial artery diameter and blood velocity were measured via Doppler ultrasound during (1) rest (control), (2) endogenous norepinephrine release via intra-arterial infusions of tyramine, and (3) α-adrenergic blockade via infusions of phentolamine in young healthy humans (n=12). Tyramine increased brachial artery retrograde (−4.0±1.4 to −9.5±1.4 s –1 ) and oscillatory shear (0.05±0.02 to 0.18±0.05 arbitrary units), whereas phentolamine abolished retrograde and oscillatory shear ( P <0.05). Additionally, in protocol 2, we examined brachial artery shear patterns in young (n=12; 29±2 years) and older (n=13; 69±2 years) healthy adults during (1) rest (control), (2) sympathetic activation via lower body negative pressure, and (3) infusion of phentolamine. At rest, older adults exhibited greater brachial artery retrograde and oscillatory shear (−9.9±2.7 s –1 and 0.11±0.03 arbitrary units, respectively) compared with younger adults (−3.1±1.0 s –1 and 0.05±0.02 arbitrary units, respectively; P <0.05 for both). Lower body negative pressure increased retrograde and oscillatory shear in young ( P <0.05), but not older adults ( P =0.85–0.97), such that differences between young and older were eliminated ( P >0.05). During infusion of phentolamine, retrograde and oscillatory shear were abolished in young adults ( P <0.05) and markedly reduced, yet still persistent, in older adults ( P <0.01). Our data indicate that α-adrenergic vasoconstriction is a major contributor to age-related discrepancies in conduit artery shear-rate patterns at rest.