Olfactory receptor surface expression is driven by association with the beta2-adrenergic receptor

Olfactory receptors (ORs) comprise more than half of the large class I G protein-coupled receptor (GPCR) superfamily. Although cloned over a decade ago, little is known about their properties because wild-type ORs do not efficiently reach the cell surface following heterologous expression. Receptor-receptor interactions strongly influence surface trafficking of other GPCRs, and we examined whether a similar mechanism might be involved in OR surface expression. Olfactory neurons are known to express beta-adrenergic receptors (ARs), and we found that coexpression with beta(2)-ARs, but not any other AR subtypes, dramatically increased mouse 71 (M71) OR surface expression in human embryonic kidney 293 cells. A persistent physical interaction between M71 ORs and beta(2)-ARs was shown by coimmunoprecipitation and by cointernalization of the two receptors in response to their specific ligands. Also, coexpression of wild-type M71 ORs with beta(2)-ARs resulted in cAMP responses to the M71 ligand acetophenone. Finally, in situ hybridization studies showed extensive colocalization of M71 OR and beta(2)-AR expression in mouse olfactory epithelium. These data demonstrate the successful heterologous surface expression of a functional wild-type OR and reveal that persistent physical association with other GPCRs can control OR surface expression.     

Over the wire lead extraction and focused force venoplasty to regain venous access in a totally occluded subclavian vein

Introduction  Venoplasty allows the addition or replacement of leads despite subtotal or total subclavian occlusion. Methods  The threshold of the LV pacing lead implanted for biventricular pacing over a period of 18 months increased to greater than 5 V. A pre implant venogram revealed total subclavian occlusion. Venous access was maintained by extraction of the 4 F LV lead over a wire. Subsequently the sheath would not advance despite 6mm balloon inflation to 30 atm with no residual waist. A wire was placed beside the balloon and the balloon was reinflated. Results  The subclavian obstruction was eliminated without damage to the existing leads. Conclusion  The obstruction formed by the fibrous track around an extracted lead may persist despite what appears to be successful balloon dilation. Inflation with a wire beside the balloon increases the effect eliminating the resistant obstruction without damaging the leads. Acknowledgements of Sources of Financial Support:Dr. Worley receives compensation in various forms from Medtronic, Pressure Products, Guidant, and St Jude Medical. Dr. Gohn receives compensation in various forms from Medtronic. No financial support was provided for the creation of this case report     

A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study—a phase III, randomized, open-label, controlled study (N = 676)—to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2–6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0–3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03–0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.     

Managing and recognizing complications after treatment of acromioclavicular joint repair or reconstruction

Complications of the acromioclavicular joint injuries can occur as a result of the injury itself, conservative management, or surgical treatment. Fortunately, the majority of acromioclavicular surgeries utilizing modern techniques and instrumentation result in successful outcomes. However, clinical failures do occur with frequency. The ability to identify the causative factor of failures makes revision surgery more likely to be successful. The purposes of this review are to highlight common problems that can occur following acromioclavicular joint surgery and discuss techniques that can be utilized in revision surgery.     

Transcatheter aortic valve replacement: Protect the kidneys to protect the patient

• Transcatheter aortic valve replacement (TAVR) seems superior to surgical aortic valve replacement (SAVR) for intermediate‐term outcomes in patients with aortic stenosis and moderate to severe chronic kidney disease (CKD).
• Intermediate‐term mortality and the major adverse cardiac and renal event increase if the renal function worsens soon after TAVR or SAVR.
• Patient's demographic profile, comorbid conditions, and procedural characteristics influence the clinical outcomes emphasizing the need for careful risk assessment in deciding TAVR versus SAVR in CKD patient.

     

The Macrophage Mediates the Renoprotective Effects of Endotoxin Preconditioning

Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and iron-handling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis.     

The utility of ultrasound for diagnosing purulent infections of the upper extremity

Background

The purpose of this study was to determine the test characteristics of formal ultrasound when used to diagnose upper extremity soft tissue abscess in the setting of suspected infection.

Methods

We completed a retrospective chart review of all patients who had formal ultrasounds at our institution for the indication of diagnosing upper extremity abscess between July 2010 and July 2013. Using presence of purulence as the gold standard for diagnosis of abscess, we calculated the test characteristics of ultrasound. We then performed a series of logistic regression models with ultrasound being the independent variable of interest.

Results

Using search criteria consistent with upper extremity abscess, we identified 512 patients who underwent ultrasound examinations during our study period. Of these, 178 met the enrollment criteria. Ultrasound reports revealed 110 negative findings, 37 definitively positive findings, and 31 ambiguous findings. Forty-four patients had a final diagnosis of abscess, and 15 of these patients had negative or ambiguous ultrasounds. The sensitivity of definitively positive ultrasound was 65.9 %. The specificity was 94.0 %. Positive predictive value (PPV) of a definitively positive ultrasound result was 78.4 %, and negative predictive value (NPV) of a definitively negative result was 90 %. Logistic regression demonstrated a statistically significant association between definitively positive ultrasound and abscess, but no association between ambiguous ultrasound and abscess after adjustment for significant covariates.

Conclusions

Ultrasound is not a sensitive method to detect the presence of abscess in the setting of upper extremity infection. However, in this population of patients with suspected abscess, the negative predictive value was high with and without the inclusion of ambiguous results, suggesting reasonable utility of ultrasound as a rule-out test.

Level of Evidence

Diagnostic study, Level II