Citations

Objective Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection. Design and methods We undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis (n = 37) or bilateral adrenalectomy (n = 5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects. Results Neutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, P < 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all P < 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients (P < 0.01). Conclusions Adrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI.

Background and PurposeAngiotensin II (Ang II), whose generation largely depends on angiotensin‐converting enzyme (ACE) activity, mediates most of the renin‐angiotensin‐system (RAS) effects. Elastase‐2 (ELA‐2), a chymotrypsin‐serine protease elastase family member 2A, alternatively generates Ang II in rat arteries. Myocardial infarction (MI) leads to intense RAS activation, but mechanisms involved in Ang II‐generation in resistance arteries are unknown. We hypothesized that ELA‐2 contributes to vascular Ang II generation and cardiac damage in mice subjected to MI.Experimental ApproachConcentration‐effect curves to Ang I and Ang II were performed in mesenteric resistance arteries from male wild type (WT) and ELA‐2 knockout (ELA‐2KO) mice subjected to left anterior descending coronary artery ligation (MI).Key ResultsMI size was similar in WT and ELA‐2KO mice. Ejection fraction and fractional shortening after MI similarly decreased in both strains. However, MI decreased stroke volume and cardiac output in WT, but not in ELA‐2KO mice. Ang I‐induced contractions increased in WT mice subjected to MI (MI‐WT) compared with sham‐WT mice. No differences were observed in Ang I reactivity between arteries from ELA‐2KO and ELA‐2KO subjected to MI (MI‐ELA‐2KO). Ang I contractions increased in arteries from MI‐WT versus MI‐ELA‐2KO mice. Chymostatin attenuated Ang I‐induced vascular contractions in WT mice, but did not affect Ang I responses in ELA‐2KO arteries.Conclusions and ImplicationsThese results provide the first evidence that ELA‐2 contributes to increased Ang II formation in resistance arteries and modulates cardiac function after MI, implicating ELA‐2 as a key player in ACE‐independent dysregulation of the RAS.

Breast fungal infections are rare in nonlactating women. The present report is the first to describe a necrotizing cutaneous breast fungal infection. A 50-year-old woman with a remote history of breast cancer and autologous tissue reconstruction presented with a progressive cutaneous necrotic infection one year after implant augmentation of the reconstruction. Multiple eschars developed on the left breast, and pathological examination of debrided tissue revealed numerous fungal hyphae invading the epidermis, dermis and adipose tissue of the breast. Fungal cultures yielded Bipolaris species. She was treated with voriconazole. Five months later, the patient presented with an eschar on her back, indicative of disseminated disease. Bipolaris species are dematiaceous fungi; cutaneous or disseminated infections with Bipolaris species have rarely been reported in immunocompetent patients. Unresectable or recurrent lesions should be treated with antifun-gals. Cutaneous necrotizing breast fungal infections should be considered in patients who do not respond to antibacterial therapy.

AbstractPurposeStem cell transplant (SCT) recipients commonly undergo bronchoalveolar lavage (BAL) collection as an infectious pulmonary work‐up. Previous studies report the utility and overall diagnostic yield of fiberoptic bronchoscopy with BAL in this vulnerable population, though none focused purely on microbiologic yield or made comparisons with less invasive means of pathogen detection. We sought to determine and elaborate on the microbiologic yield of BAL in SCT recipients, assess a correlation between BAL studies and less invasive means of pathogen detection, and assess the utility of repeating a BAL within 30 days.MethodsBetween January 1, 2009, and July 31, 2013, we reviewed medical records of 125 SCT recipients who underwent 179 BALs. In addition to demographic information and details pertaining to their SCT, a comprehensive review of their microbiologic data was performed and recorded.ResultsOur study showed an overall BAL microbiologic yield of 40%, despite 92% of patients receiving broad‐spectrum antimicrobial therapy at the time of the BAL procedure.ConclusionsAlthough an initial BAL sample in this population provides crucial microbiologic information, repeating the procedure within 30 days may have minimal additional microbiologic yield. BAL continues to be an essential diagnostic tool in SCT recipients undergoing an infectious pulmonary work‐up.

SummaryBackgroundDuodenal injury persists in some coeliac disease patients despite gluten‐free diet, and is associated with adverse outcomes.AimTo determine the prevalence and clinical risk factors for persistent villus atrophy among symptomatic coeliac disease patients.MethodsA nested cross‐sectional analysis was performed on coeliac disease patients with self‐reported moderate or severe symptoms while following a gluten‐free diet, who underwent protocol‐mandated duodenal biopsy upon enrolment in the CeliAction clinical trial. Demographic factors, symptom type, medication use, and serology were examined to determine predictors of persistent villus atrophy.ResultsOf 1345 symptomatic patients, 511 (38%, 95% CI, 35–41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age (OR, 5.1 for ≥70 vs. 18–29 years, 95% CI, 2.5–10.4) was a risk factor while longer duration on gluten‐free diet was protective (OR, 0.37, 95% CI, 0.24–0.55 for 4–5.9 vs. 1–1.9 years). Villus atrophy was associated with use of proton‐pump inhibitors (PPIs; OR, 1.6, 95% CI, 1.1–2.3), non‐steroidal anti‐inflammatory drugs (NSAIDs; OR, 1.64, 95% CI, 1.2–2.2), and selective serotonin reuptake inhibitors (SSRIs; OR, 1.74, 95% CI, 1.2–2.5). Symptoms were not associated with villus atrophy after adjusting for covariates.ConclusionsA majority of symptomatic coeliac disease patients did not have active disease on follow‐up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study.

SummarySimtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase‐like‐2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open‐label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post‐polycythaemia vera MF and post‐essential thrombocythaemia MF. Fifty‐four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose‐proportionally between the 200‐mg and 700‐mg treatment groups. Therapy‐related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700‐mg group, 1 (6·7%) in the simtuzumab 200‐mg + ruxolitinib group, and 2 (13·3%) in the simtuzumab 700‐mg + ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.

Abstract BACKGROUND: Radiation-based treatment options of large intracranial arteriovenous malformations (AVM) must balance the likelihood of obliteration with the risk of adverse radiation effects (ARE). OBJECTIVE: To analyze the efficacy and risks of volume-staged stereotactic radiosurgery (VS-SRS) for AVM. METHODS: Retrospective study of 34 AVM patients having VS-SRS between 1997 and 2012. A median of 2 stages (range, 2-4) was used to treat a median AVM volume of 22.2 cm 3 (range, 7.4-56.7). The median AVM margin dose was 16 Gy (range, 14-18); the median radiosurgery-based AVM score was 2.81 (range, 1.54-6.45). The median follow-up after VS-SRS was 8.2 years (range, 3-13.3). RESULTS: Nidus obliteration was noted in 18 patients (53%) after VS-SRS. The rate of obliteration was 14% at 3 years, 54% at 5 years, and 75% at 7 years. Six patients (18%) had 11 bleeds after VS-SRS. Two patients (6%) remained neurologically stable, 2 (6%) patients had significant deficits, and 2 patients (6%) died. The actuarial risk of a first bleed after VS-SRS was 6% at 1 year, 12% at 3 years, and 19% at 7 years. Six patients (18%) underwent repeat SRS; all achieved nidus obliteration for an overall cure rate of 71%. Two patients (6%) had a permanent ARE after VS-SRS or repeat SRS. CONCLUSION: VS-SRS permitted large volume intracranial AVM to be treated with a low rate of ARE. Further study is needed on dose escalation and decreasing the treatment volume per stage to determine if this will increase the rate of obliteration with this technique.