Elevated inflammatory responses and targeted therapeutic intervention in a preclinical mouse model of ataxia-telangiectasia lung disease.

Ataxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder characterized by cerebellar degeneration, cancer predisposition, and immune system defects. A major cause of mortality in A-T patients is severe pulmonary disease; however, the underlying causes of the lung complications are poorly understood, and there are currently no curative therapeutic interventions. In this study, we examined the lung phenotypes caused by ATM-deficient immune cells using a mouse model of A-T pulmonary disease. In response to acute lung injury, ATM-deficiency causes decreased survival, reduced blood oxygen saturation, elevated neutrophil recruitment, exaggerated and prolonged inflammatory responses and excessive lung injury compared to controls. We found that ATM null bone marrow adoptively transferred to WT recipients induces similar phenotypes that culminate in impaired lung function. Moreover, we demonstrated that activated ATM-deficient macrophages exhibit significantly elevated production of harmful reactive oxygen and nitrogen species and pro-inflammatory cytokines. These findings indicate that ATM-deficient immune cells play major roles in causing the lung pathologies in A-T. Based on these results, we examined the impact of inhibiting the aberrant inflammatory responses caused by ATM-deficiency with reparixin, a CXCR1/CXCR2 chemokine receptor antagonist. We demonstrated that reparixin treatment reduces neutrophil recruitment, edema and tissue damage in ATM mutant lungs. Thus, our findings indicate that targeted inhibition of CXCR1/CXCR2 attenuates pulmonary phenotypes caused by ATM-deficiency and suggest that this treatment approach represents a viable therapeutic strategy for A-T lung disease.

The resuscitative endovascular balloon occlusion of aorta (REBOA) device-what radiologists need to know.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a novel device approved by the Food and Drug administration (FDA) in 2017 as an alternative to resuscitative emergent thoracotomy (RET). Due to advancements in placement of REBOA, including newly validated placement using anatomic landmarks, REBOA is now widely used by interventional radiologists and emergency physicians in acute subdiaphragmatic hemorrhage. Increased use of REBOA necessitates that radiologists are familiar with verification of proper REBOA placement to minimize complications. This review describes the REBOA device, indications, placement, and complications, summarizing the current available literature.

Stimulation of an alpha1-adrenergic receptor downregulates ecto-5' nucleotidase activity on the apical membrane of RPE cells.

The purines ATP and adenosine play an important role in the communication between the photoreceptors and the retinal pigment epithelium (RPE). While the RPE is known to release ATP into subretinal space, the source of extracellular adenosine is unclear. In other tissues, ecto-nucleotidases mediate the consecutive dephosphorylation of ATP to AMP, and AMP is converted to adenosine by ecto-5' nucleotidase (CD73). This study identifies ecto-5' nucleotidase on RPE cells and investigates modulation of enzyme activity. The RPE was the most active site of 5'AMP dephosphorylation in the posterior rat eye. The ecto-5' nucleotidase inhibitor alphabetamADP prevented the production adenosine by the apical membrane of the bovine RPE. Cultured human ARPE-19 cells expressed mRNA and protein for ecto-5' nucleotidase. The production of phosphate from 5'AMP by ARPE-19 cells was inhibited by alphabetamADP, but the ecto-alkaline phosphatase inhibitor levamisole had no effect. Degradation of 5'AMP was blocked by norepinephrine, epinephrine and phenylephrine, with inhibition by antagonists prazosin and corynanthine implicating the alpha1 adrenergic receptor. The block of enzyme activity by norepinephrine was rapid, occurring within 1 min, and was similar at both 4 and 37 degrees C, consistent with cleavage of the enzyme from its GPI anchor. HPLC measurements indicated norepinephrine reduced levels of adenosine in the bath. In the apical face of the bovine-RPE eyecup, norepinephrine reduced the production of phosphate from 5'AMP, suggesting that both receptor and enzyme face sub-retinal space. In conclusion, RPE cells express ecto-5' nucleotidase, with activity on the apical membrane, and stimulation of alpha-1 adrenergic receptors downregulates activity. As epinephrine is released at light onset, and adenosine can inhibit phagocytosis, the corresponding decrease in subretinal adenosine levels may contribute to the enhanced the phagocytosis of rod outer segments that occurs at this time.

Urinary morbidity in brachytherapy patients with median lobe hyperplasia.

PURPOSE: To investigate clinical course of prostate brachytherapy patients with radiographic evidence of median lobe hyperplasia (MLH). METHODS AND MATERIALS: Fifteen patients with median lobe hyperplasia were identified during our routine brachytherapy practice and implanted between June 1998 and March 2000, representing approximately 6% of the 245 brachytherapy patients treated during that time. Each patient was contacted at the time of this report preparation to update postimplant morbidity information, with follow-up ranging from 6 to 30 months (median: 18 months). RESULTS: Three of the 15 patients developed acute, postimplant urinary retention. The preimplant prostate volume, dMLH, and preimplant AUA scores were similar between patients who did or did not develop prolonged urinary retention. Compared with a control group of 62 control patients treated during a similar time interval at the University of Washington, patients with MLH had significantly higher AUA scores at last follow-up. There was no correlation between the change in AUA scores at last follow-up. CONCLUSIONS: Based on the data reported here, we consider MLH to be a weak contraindication to prostate brachytherapy. Considering that even patients with prolonged retention have gradually improved spontaneously, we do not advocate prophylactic prebrachytherapy resection of hypertrophic tissue in MLH patients.