Characterization of a novel,papain‐inducible murine model of eosinophilic rhinosinusitis

Background

Eosinophilic chronic rhinosinusitis (ECRS) is a disease characterized by eosinophilic inflammatory infiltrate and a local type 2 cytokine milieu. Current animal models fail to recapitulate many of the innate and adaptive immunologic hallmarks of the disease, thus hindering the development of effective therapeutics. In the present study, mice were exposed intranasally to the cysteine protease papain, which shares functional similarities with parasitic proteases and aeroallergens, to generate a rapidly inducible murine model of eosinophilic rhinosinusitis.

Methods

C57BL/6 mice were intranasally instilled with 20 μg papain or heat‐inactivated papain (HP) on days 0–2 and days 7–10, and then euthanized on day 11. Nasal lavage fluid (NALF) was analyzed to quantify eosinophils and inflammatory cytokine secretion. Sinonasal tissue was sectioned and stained for goblet cells or homogenized to analyze cytokine levels. Serum samples were assayed for immunoglobulin E (IgE) by enzyme‐linked immunoassay. Sinonasal mucosal tissue was dissociated and analyzed by flow cytometry.

Results

Compared with HP treatment, papain induced significant eosinophilia in NALF, goblet cell hyperplasia, innate and adaptive immune cell infiltration, type 2 cytokine production, and IgE responses. Flow cytometric analysis of sinonasal tissues revealed significant inflammatory cell infiltration and interleukin‐13–producing cell populations.

Conclusion

In this study, we demonstrated that the cysteine protease papain induces allergic sinonasal eosinophilic rhinosinusitis and resembles T‐helper 2 cell inflammation and innate immune characteristics of ECRS. This model permits further study into the molecular mechanisms underlying ECRS pathology and provides a model system for the evaluation of potential pharmacologic interventions.

     

Parathyroid hormone update

PTH is an exciting new treatment option for postmenopausal women and hypogonadal men who have osteoporosis. As an anabolic agent that affects bone metabolism, it represents an entirely new class of medication for osteoporosis and a novel approach to reducing fracture risk. Numerous clinical trials have demonstrated increases in trabecular and cortical BMD (trabecular more than cortical) in men and women, and reduction in vertebral and nonvertebral fractures in postmenopausal women. Studies suggest that it is safe for use for up to 2 years, but further studies are needed to tes longer intervals of use. Although the combination of PTH and bisphosphonates does not seem to be additive, sequential therapy of PTH followed by bisphosphonate yields maximum gains in BMD compared with combined use or monotherapy with antiresorptive agents. As our knowledge of PTH grows, this is an exciting time for researchers, clinicians, and patients who study, treat, and live with the devastating consequences of progressive osteoporosis.     

Frizzled‐related protein variants are risk factors for hip osteoarthritis

Objective

To examine the association of the Arg200Trp and Arg324Gly variants of FRZB with the risk and phenotype of radiographic osteoarthritis (OA) of the hip and serum levels of Frizzled‐related protein (FRP) in a prospective cohort of elderly Caucasian women.

Methods

Radiographic hip OA status of patients was defined by the presence of severe joint space narrowing (JSN) (feature grade ≥3), a summary grade ≥3, or definite osteophytes (grade ≥2) and JSN (grade ≥2) in the same hip. Genotypes were obtained in 569 patients with radiographic OA of the hip and in 1,317 and 4,136 controls for the Arg200Trp and Arg324Gly variants, respectively. Serum FRP levels were measured by enzyme‐linked immunosorbent assay. Multivariate logistic regression was performed.

Results

The minor allele frequency for the Arg200Trp polymorphism was 0.12 in the control group compared with 0.14 in the group with radiographic OA of the hip (P = 0.12), and the minor allele frequency for the Arg324Gly variant was 0.083 in the control group compared with 0.088 in the group with radiographic OA of the hip (P = 0.63). The multilocus genotypes available in 1,886 subjects suggested that inheritance of both minor alleles was a risk factor for developing OA characterized by JSN (P < 0.01). Patients with radiographic OA of the hip who were homozygous for the Arg200Trp minor allele had higher serum FRP levels than controls who were homozygous for the major allele.

Conclusion

Our data confirm findings of another study, that a rare haplotype with both Arg200Trp and Arg324Gly FRZB variants contributes to the genetic susceptibility to hip OA among Caucasian women, and that these polymorphisms may contribute to increased serum levels of proteins as biomarkers of OA.

     

Interruption of antiretroviral therapy blunts but does not abrogate CD4 T-cell responses to interleukin-2 administration in HIV infected patients

BACKGROUND: Intermittent administration of interleukin (IL)-2 to HIV infected patients leads to CD4 T-cell expansions that are associated with decreased CD4 T-cell turnover. IL-2 is under evaluation in antiretroviral therapy (ART) interruption studies, but it is unclear how the emergence of viremia may affect CD4 expansions. METHODS: CD4 T-cell responses were evaluated in 27 HIV infected patients on long-term intermittent IL-2 therapy who underwent ART interruption immediately after an IL-2 cycle ('IL-2/off') and compared with responses from a previous IL-2 cycle while on continuous ART ('IL-2/on'). Immunophenotypic analysis, including intracellular Ki67 staining, of cryopreserved peripheral blood mononuclear cells was performed. RESULTS: CD4 T-cell increases, in naive and central memory CD4 T-cell subsets, were observed in the IL-2/on (106 and 327 cells/microl, respectively) and IL-2/off (84 and 184 cells/microl, respectively) cycles 1 month following IL-2 administration. These increases were greater during the IL-2/on cycle (P = 0.05, P = 0.01, respectively). In both cycles, the change in CD4 T-cell count correlated with the change in CD4/CD25 T cells. In the IL-2/off cycle, the change in the proportion of CD4 T cells expressing Ki67 was associated with both the changes in viral load (r = 0.64, P = 0.001) and the changes in CD4 T cells (r = -0.56, P = 0.01). CONCLUSIONS: IL-2 administration followed by ART interruption led to significant, although blunted, CD4 T-cell increases. IL-2 induced CD4 T-cell increases in the setting of emergent viremia were associated with decreased CD4 T-cell activation that counteracted the viremia-induced increases in CD4 T-cell activation.     

An international observational prospective study to determine the cost of asthma exacerbations (COAX)

Asthma is a common chronic condition that places substantial burden on patients and healthcare services. Despite the standards of asthma control that international guidelines recommend should be achieved, many patients continue to suffer sub-optimal control of symptoms and experience exacerbations (acute asthma attacks). In addition to being associated with reduced quality of life, asthma exacerbations are a key cost driver in asthma management. Routine clinical practice for the management of asthma exacerbations varies in different healthcare systems, so healthcare providers require local costs to be able to assess the value of therapies that reduce the frequency and severity of exacerbations. This prospective study, conducted in a total of 15 countries, assessed the local cost of asthma exacerbations managed in either primary or secondary care. Healthcare resources used were costed using actual values appropriate to each country in local currency and in Euros. Results are presented for exacerbations managed in primary care in Brazil, Bulgaria, Croatia, Czech Republic, Hungary, Poland, Russia, Slovakia, Slovenia, Spain and Ukraine, and in secondary care in Croatia, Denmark, Ireland, Latvia, Norway, Poland, Russia, Slovakia, Slovenia and Spain. Multiple regression analysis of the 2052 exacerbations included in the economic analysis showed that the cost of exacerbations was significantly affected by country (P<0.0001). Mean costs were significantly higher in secondary care (euro 1349) than primary care (euro 445, P=0.0003). Age was a significant variable (P=0.0002), though the effect showed an interaction with care type (P<0.0001). As severity of exacerbation increased, so did secondary care costs, though primary care costs remained essentially constant. In conclusion, the study showed that asthma exacerbations are costly to manage, suggesting that therapies able to increase asthma control and reduce the frequency or severity of exacerbations may bring economic benefits, as well as improved quality of life.     

The effect of random voice hand hygiene messages delivered by medical, nursing, and infection control staff on hand hygiene compliance in intensive care

Hand hygiene (HH) compliance in the intensive care unit has been studied extensively, with short-term, nonsustained compliance often because of lack of ongoing reinforcement. HH messages delivered by health care workers responsible for overseeing staff in the intensive care unit provided continuous reinforcement of HH. Compliance measured through product usage and reported as HH/bed-days increased by 60% for soap and sanitizer combined and 25% for sanitizer usage (P < 001).     

Predictors of outcome in Cryptococcus neoformans var. gattii meningitis

In Papua New Guinea, <it>Cryptococcus neoformans</it> var. <it>gattii</it> meningitis has a high fatality rate even in immunocompetent patients. Our retrospective study attempted to identify marker of poor prognosis. Of 88 immunocompetent patients, 30 (34.1%) died, usually soon after admission, and mortality was higher in men (<it>p</it> = 0.025) and older patients (<it>p</it> = 0.039). Death was associated with altered consciousness (<it>p</it>&lt;0.001), a history of convulsions prior to treatment (<it>p</it> = 0.002) and a maximum systolic blood pressure of &gt;150 mmHg (<it>p</it> = 0.017). These data suggest that death results from raised intracranial pressure and subsequent tentorial herniation. However, CSF opening pressure measured on admission was raised in 29/36 (81%) patients and did not predict outcome. In survivors, relapse was uncommon and was not predicted by discharge serum cryptococcal antigen titres, which were frequently raised on completion of therapy in asymptomatic patients. Mortality may be reduced if efforts are made to lower intracranial pressure in those patients who present with markers of poor prognosis.      

Imaging of hydrogel episcleral buckle fragmentation as a late complication after retinal reattachment surgery.

Hydrogel encircling bands were introduced in the early 1980s as a product that was superior to bands composed of silicone rubber or silicone sponge for the surgical treatment of retinal detachment. Late complications consisting of orbital swelling and diplopia requiring band removal began to be reported in the early 1990s. Pathologic studies of these expanded fragments of hydrogel material after removal showed in vivo hydrolysis with foreign body reaction and dystrophic calcification. We report the imaging findings in five patients in whom this late complication developed. Hydrogel fragmentation has a characteristic imaging appearance consisting of a circumferential orbital mass associated with rim enhancement. This appearance should prompt inquiries regarding previous scleral buckle procedures with hydrogel bands. Familiarity with this appearance will avoid misinterpretation and unwarranted biopsy before band removal.