Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events.

BACKGROUND: NSAIDs, including cyclooxygenase (COX)-2 inhibitors, are among the most widely prescribed medications worldwide. However, NSAIDs have been associated with gastrointestinal (GI) toxicity. The cardiovascular (CV) toxicity associated with COX-2 inhibitors and some other NSAIDs further complicates the choice of therapy. OBJECTIVE: The aim of this commentary was to appraise current NSAID treatment strategies and provide clinicians with guidance on the GI and CV risks of these strategies and choosing an appropriate treatment in individual patients. METHODS: A literature search of PubMed was conducted (1989-August 2009) to gather relevant studies, meta-analyses, reviews, and treatment guidelines using the following terms, either alone or in combination: NSAID, gastrointestinal, cardiovascular, toxicity, gastroprotection, proton pump inhibitor, COX-2 inhibitor, aspirin, fixed-dose combination, and adherence. RESULTS: Based on the data from the literature search, gastroprotective strategies (eg, proton pump inhibitors [PPIs]) are underused in patients at risk for NSAIDrelated GI complications, including in those patients most at risk. Risk factors for GI toxicity with NSAID use include high NSAID dose, a history of NSAID-associated GI adverse events or the presence of upper GI symptoms, advanced age, corticosteroid use, concurrent aspirin use, and certain comorbidities (eg, rheumatoid arthritis). Risk factors for CV toxicity with NSAID use include established CV disease or an estimated 10-year CV risk >20%. Findings from randomized controlled trials have suggested that, in patients with an increased risk for GI complications, the use of a nonselective NSAID with a PPI may be at least as effective as the use of a COX-2 selective inhibitor in preventing the recurrence of ulcer complications. In patients with a high GI risk and a moderate CV risk, the use of a COX-2 inhibitor with a PPI may be appropriate. CONCLUSIONS: The choice of NSAID should be tailored to the GI and CV risks in the patient. The risk profile can be affected by numerous factors, including NSAID dosing and concurrent aspirin use. Thus, individualized risk stratification should be the clinician's primary consideration when selecting treatment.

Relationship between adenovirus DNA replication proteins and nucleolar proteins B23.1 and B23.2.

Adenovirus infection subverts nucleolar structure and function. B23 is a nucleolar protein present in two isoforms (B23.1 and B23.2) and both isoforms have been identified as stimulatory factors for adenovirus DNA replication. Here, it is demonstrated that the two isoforms of B23, B23.1 and B23.2, interact and co-localize differently with viral DNA replication proteins pTP and DBP in adenovirus-infected cells. Thus, the mechanism by which the two proteins stimulate viral DNA replication is likely to differ. These data also demonstrate the importance of testing both isoforms of B23 for interactions with viral proteins and nucleic acids.

A role for transportin in the nuclear import of adenovirus core proteins and DNA.

Adenoviruses target their double-stranded DNA genome and its associated core proteins to the interphase nucleus; this core structure then enters through the nuclear pore complex. We have used digitonin permeabilized cell import assays to study the cellular import factors involved in nuclear entry of virus DNA and the core proteins, protein V and protein VII. We show that inhibition of transportin results in aberrant localization of protein V and that transportin is necessary for protein V to accumulate in the nucleolus. Furthermore, inhibition of transportin results in inhibition of protein VII and DNA import, whereas disruption of the classical importin alpha-importin beta import pathway has little effect. We show that mature protein VII has different import preferences from the precursor protein, preVII from which it is derived by proteolytic processing. While bacterially expressed glutathione S-transferase (GST)-preVII primarily utilizes the pathway mediated by importin alpha-importin beta, bacterially expressed GST-VII favours the transportin pathway. This is significant because while preVII is important during viral replication and assembly only mature VII is available during viral DNA import to a newly infected cell. Our results implicate transportin as a key import receptor for the nuclear localization of adenovirus core.

Efficiency in the pediatric orthopedic clinic and the effect on the parents: a comparison of military and civilian medical centers.

In a short-term comparison of similar pediatric orthopedic practices at a military and a civilian institution in the same geographical location, it was found that total appointment time, waiting time, and travel time were longer in the military setting. It appeared, however, that there was more leniency toward time off from work to accompany children to appointments in the military population. These factors may have considerable impact on time lost from the job for service member sponsors.