Comparison of Intact Allergen Extracts and Allergoids For Subcutaneous Immunotherapy: The Effect of Chemical Modification Differs Both Between Species and Between Individual Allergen Molecules.

BACKGROUND: Allergen products for subcutaneous immunotherapy (SCIT) contain intact allergen extracts or chemically modified allergoids. Chemical modification was introduced to reduce allergenicity while retaining immunogenicity and thereby enable safer and more efficient allergy immunotherapy. METHODS: Experimental allergoids were produced from intact allergen extract for birch, grass, and house dust mite (HDM) to evaluate the effects of chemical modification. Preparations were compared with commercial allergoids and analyzed using SDS-PAGE/immunoblotting, IgE-inhibition assays, and crossed immunoelectrophoresis (CIE). Dermatophagoides pteronyssinus (Der p) vaccines were also tested for protease activity and immunizing capacity in a mouse model. RESULTS: The composition of IgE-binding epitopes in allergoids differed from that of intact allergen vaccines. Birch and grass allergoids produced smears of protein aggregates on SDS-PAGE, whereas intact allergen preparations showed distinct protein bands as expected. Der p allergoid vaccines, however, showed a distinct protein band corresponding to major allergen Der p 1 in both SDS-PAGE and CIE analysis, and commercial Der p allergoid vaccines showed Der p 1-related cysteine protease activity. CONCLUSION: Allergoids and intact allergen preparations differ with respect to the composition of IgE-binding epitopes. However, chemical cross-linking does not affect every allergen molecule to the same degree. Der p 1, for example, remains largely unmodified. Furthermore, the investigational HDM allergoid vaccines showed reduced and delayed immune responses when used for immunization of mice.

Impact of comorbidity on renal cell carcinoma prognosis: a nationwide cohort study.

BACKGROUND: Presence of comorbid diseases at time of cancer diagnosis may affect prognosis. We evaluated the impact of comorbidity on survival of patients diagnosed with renal cell carcinoma (RCC), overall and among younger (<70 years) and older (≥70 years) patients. METHODS: We established a nationwide register-based cohort of 7894 patients aged ≥18 years diagnosed with RCC in Denmark between 2006 and 2017. We computed 1- and 5-year overall survival and hazard ratios (HRs) for death according to the Charlson Comorbidity Index (CCI) score. RESULTS: Survival decreased with increasing CCI score despite an overall increase in survival over time. The 5-year survival rate of patients with no comorbidity increased from 57% among those diagnosed in 2006-2008 to 69% among those diagnosed in 2012-2014. During the same periods, the survival rate increased from 46% to 62% among patients with a CCI score of 1-2 and from 39% to 44% for those with a CCI score of ≥3. Patients with CCI scores of 1-2 and ≥3 had higher mortality rates than patients with no registered comorbidity (HR 1.15, 95% CI 1.06-1.24 and HR 1.56, 95% CI 1.40-1.73). Patterns were similar for older and younger patients. Particularly, diagnoses of liver disease (HR 2.09, 95% CI 1.53-2.84 and HR 4.01, 95% CI 2.44-6.56) and dementia (HR 2.16, 95% CI 1.34-3.48) increased mortality. CONCLUSION: Comorbidity decreased the survival of patients with RCC, irrespective of age, despite an overall increasing survival over time. These results highlight the importance of focusing on comorbidity in this group of patients.

Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis.

BACKGROUND: Wild-type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy. OBJECTIVE: To study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis. MATERIALS AND METHODS: A total of 250 patients, aged 50-89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0-4. All patients with grade 3-4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT-proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization. RESULTS: Amyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3-4; all had fibril type A (mixture of full-length TTR and fragmented TTR). Twenty-nine of 42 patients with grade 3-4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome. CONCLUSIONS: The prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.

Eligibility for sacubitril/valsartan in heart failure across the ejection fraction spectrum: real-world data from the Swedish Heart Failure Registry.

BACKGROUND: Randomized controlled trials (RCT) generalizability may be limited due to strict patient selection. OBJECTIVE: In a real-world heart failure (HF) population, we assessed eligibility for sacubitril/valsartan based on PARADIGM-HF (sacubitril/valsartan effective)/PARAGON-HF [sacubitril/valsartan effective in mildly reduced ejection fraction (EF)]. METHODS: Outpatients from the Swedish HF Registry (SwedeHF) were analysed. In SwedeHF, EF is recorded as <30, 30-39, 40-49 and ≥50%. In PARAGON-HF, sacubitril/valsartan was effective with EF ≤ 57% (i.e. median). We defined reduced EF/PARADIGM-HF as EF < 40%, mildly reduced EF/PARAGON-HF ≤ median as EF 40-49%, and normal EF/PARAGON-HF > median as EF ≥ 50%. We assessed 2 scenarios: (i) criteria likely to influence treatment decisions (pragmatic scenario); (ii) all criteria (literal scenario). RESULTS: Of 37 790 outpatients, 57% had EF < 40%, 24% EF 40-49% and 19% EF ≥ 50%. In the pragmatic scenario, 63% were eligible in EF < 50% (67% for EF < 40% and 52% for 40-49%) and 52% in EF ≥ 40% (52% for EF ≥ 50%). For the literal scenario, 32% were eligible in EF < 50% (38% of EF < 40%, 20% of EF 40-49%) and 22% in EF ≥ 40% (25% for EF ≥ 50%). Eligible vs. noneligible patients had more severe HF, more comorbidities and overall worse outcomes. CONCLUSION: In a real-world HF outpatient cohort, 81% of patients had EF < 50%, with 63% eligible for sacubitril/valsartan based on pragmatic criteria and 32% eligible based on literal trial criteria. Similar eligibility was observed for EF 40-49% and ≥50%, suggesting that our estimates for EF < 50% may be reproduced whether or not a higher cut-off for EF is considered.

Diagnoses and mortality in a population without acute myocardial infarction, but with elevated high-sensitive troponin I - a retrospective register-based single center study.

AIM: To explore, which differential diagnoses to consider in individuals with elevated troponins without acute myocardial infarction (AMI), and the mortality for those individuals. METHODS: Retrospective, register-based study on a representative sample of the Danish population with the following inclusion criteria: High-sensitive troponin I (hs-TnI) ⋝25 ng/L, age ⋝18 years, and exclusion of AMI. RESULTS: 3067 individuals without AMI but increased hs-TnI were included. Most frequent discharge diagnoses: Pneumonia (12.8%), Aortic valve disorder (11.3%), Medical observation (10.9%) and Heart failure (8.9%). The 30-days and one-year mortality was 15.8% and 32.0%, respectively. CONCLUSIONS: A selected number of alternative diagnoses must be considered in individuals with increased hs-TnI. Due to high mortality it is crucial to carefully evaluate these individuals despite the absence of AMI.

"Real World" Eligibility for Sacubitril/Valsartan in Unselected Heart Failure Patients: Data from the Swedish Heart Failure Registry.

PURPOSE: PARADIGM-HF demonstrated the superiority of sacubitril/valsartan over enalapril in patients with heart failure and reduced ejection fraction (HF-REF). How widely applicable sacubitril/valsartan treatment is in unselected patients with HF-REF is not known. We examined eligibility of patients with HF-REF for treatment with sacubitril/valsartan, according to the criteria used in PARADIGM-HF, in the Swedish Heart Failure Registry (SwedeHF). METHODS: Patients were considered potentially eligible if they were not hospitalized, had symptoms (NYHA class II-IV) and a reduced LVEF (≤ 40%), and were prescribed an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a dose equivalent to enalapril ≥ 10 mg daily. In these patients, we evaluated further eligibility according to the main additional PARADIGM-HF inclusion criteria. RESULTS: Of 12,866 outpatients in NYHA functional class II-IV with an LVEF ≤ 40%, 9577 were prescribed at least 10 mg of enalapril (or equivalent) daily. Complete additional data were available for 3099 of these patients (32.4%) and of them 75.5% were potentially eligible for treatment with sacubitril/valsartan. The most common reason for ineligibility was a low natriuretic peptide level (n = 462, 14.9%). Only a small proportion of patients were ineligible due to low eGFR or serum potassium level. Because only 78% of patients were taking ≥ 10 mg enalapril or equivalent daily, only 58.9% of all patients (75.5% of 78%) were eligible for sacubitril/valsartan. CONCLUSIONS: Between 34 and 76% of symptomatic patients with HF-REF in a 'real world' population are eligible for treatment with sacubitril/valsartan, depending on background ACEI/ARB dose. The most common reason for ineligibility is a low natriuretic peptide level.

Left atrial rather than left ventricular impaired mechanics are associated with the pro-fibrotic ST2 marker and outcomes in heart failure with preserved ejection fraction.

AIMS: Left ventricular (LV) mechanics have been extensively investigated in heart failure with preserved ejection fraction (HFpEF) overshadowing for a long time the potential role of left atrium (LA) in that setting. Soluble suppression of tumorigenicity-2 receptor (ST2) is a novel biomarker of pro-fibrotic burden in HF. We hypothesized that due to the thinner LA wall, the fibrotic myocardial changes in HFpEF as indicated by elevated ST2 levels might more readily be reflected by impairments in the LA rather than the LV performance. METHODS AND RESULTS: In 86 patients with HFpEF, enrolled in the Karolinska Rennes (KaRen) biomarker prospective substudy, global LA strain (GL-LS) along with other echocardiographic as well as haemodynamic parameters and ST2 levels were measured. ST2 levels were inversely associated with LA-GS (r = -0.30, P = 0.009), but not with LA size, LV geometry, systolic or diastolic LV function (P > 0.05 for all). Furthermore, symptom severity correlated with ST2 and LA-GS, but not with LV structural or functional indices. Finally, during a median 18-month follow-up, LA-GS independently predicted the composite endpoint of HF hospitalization and all-cause mortality, even after adjustment for potential clinical and cardiac mechanical confounders, including LV global longitudinal strain and filling pressures (odds ratio: 4.15; confidence interval: 1.2-14, P = 0.023). CONCLUSIONS: Reduced LA-GS but not LV functional systolic and diastolic parameters were associated with the pro-fibrotic ST2 marker, HF symptoms and outcome in HFpEF.

Enhanced ventricular-arterial coupling during a 2-year physical activity programme in patients with rheumatoid arthritis: a prospective substudy of the physical activity in rheumatoid arthritis 2010 trial.

OBJECTIVE: To establish how guided physical activity in patients with rheumatoid arthritis (RA) without known cardiovascular disease affected vascular and cardiac function, and how these two entities were prospectively interconnected in this patient group. METHODS: Prospective substudy of 29 participants in the Physical Activity in RA (PARA) 2010 trial. All subjects were examined at baseline, at year 1 and 2 with measures of pulse wave velocity and arterial augmentation index, as well as echocardiographic evaluation of diastolic parameters and ventricular-arterial coupling. Muscle strength and aerobic exercise capacity were assessed at baseline and yearly. All participants performed physiotherapist-guided aerobic and muscle strength exercise during 2 years and were reminded through SMS to report physical activity progress. RESULTS: This cohort of patients with RA exhibited increased vascular stiffness despite normal blood pressure. At baseline, lower muscle strength was associated with increased vascular stiffness (ß = 0.68; P = 0.004), whereas lower aerobic working capacity was associated with left ventricular diastolic dysfunction (ß = 0.85; P = 0.03). There was a significant positive correlation between vascular stiffness and diastolic dysfunction at baseline (R2  = 0.64) and for the changes in those parameters observed during 2 years of guided physical activity. Finally, a significant improvement in ventricular-arterial coupling was observed after exercise (P < 0.001). CONCLUSION: These results indicate that although differentially associated with physical capacity parameters, improved vascular stiffness and improved diastolic dysfunction are interrelated, and that an optimization of the ventricular-arterial coupling may contribute to the beneficial effects of physical activity in patients with RA.

Comorbidities, risk factors and outcomes in patients with heart failure and an ejection fraction of more than or equal to 40% in primary care- and hospital care-based outpatient clinics.

OBJECTIVE: The aim of this study is to describe patients with heart failure and an ejection fraction (EF) of more than or equal to 40%, managed in both Primary- and Hospital based outpatient clinics separately with their prognosis, comorbidities and risk factors. Further to compare the heart failure medication in the two groups. DESIGN: We used the prospective Swedish Heart Failure Registry to include 9654 out-patients who had HF and EF ≥40%, 1802 patients were registered in primary care and 7852 in hospital care. Descriptive statistical tests were used to analyze base line characteristics in the two groups and multivariate logistic regression analysis to assess mortality rate in the groups separately. SETTING: The prospective Swedish Heart Failure Registry. SUBJECTS: Patients with heart failure and an ejection fraction (EF) of more than or equal to 40%. MAIN OUTCOME MEASURES: Comorbidities, risk factors and mortality. RESULTS: Mean-age was 77.5 (primary care) and 70.3 years (hospital care) p < 0.0001, 46.7 vs. 36.3% women respectively (p < 0.0001) and EF ≥50% 26.1 vs. 13.4% (p < 0.0001). Co-morbidities were common in both groups (97.2% vs. 92.3%), the primary care group having more atrial fibrillation, hypertension, ischemic heart disease and COPD. According to the multivariate logistic regression analysis smoking, COPD and diabetes were the most important independent risk factors in the primary care group and valvular disease in the hospital care group. All-cause mortality during mean follow-up of almost 4 years was 31.5% in primary care and 27.8% in hospital care. One year-mortality rates were 7.8%, and 7.0% respectively. CONCLUSION: Any co-morbidity was noted in 97% of the HF-patients with an EF of more than or equal to 40% managed at primary care based out-patient clinics and these patients had partly other independent risk factors than those patients managed in hospital care based outpatients clinics. Our results indicate that more attention should be payed to manage COPD in the primary care group. KEY POINTS 97% of heart failure patients with an ejection fraction of more than or equal to 40% managed at primary care based out-patient clinics had any comorbidity. Patients in primary care had partly other independent risk factors than those in hospital care. All-cause mortality during mean follow-up of almost 4 years was higher in primary care compared to hospital care. In matched HF-patients RAS-antagonists, beta-blockers as well as the combination of the two drugs were more seldom prescribed when managed in primary care compared with hospital care.

Efficacy and safety of glucagon-like peptide-1 agonists on macrovascular and microvascular events in type 2 diabetes mellitus: A meta-analysis.

AIMS: Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events. DATA SYNTHESIS: MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804-0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757-0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830-1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759-1.023; p = 0.097), HF (RR: 0.967; CI: 0.803-1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807-1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625-1.199; p = 0.385). CONCLUSIONS: Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality.

Extracorporeal shockwave therapy in the treatment of chronic diabetic foot ulcers: a prospective randomised trial.

OBJECTIVE: To investigate the efficacy of extracorporeal shockwave therapy (ESWT) on healing chronic diabetic foot ulcers (DFU). METHOD: Patients with chronic DFUs were randomised (1:1) to receive a series of six ESWT treatments over 3 weeks in combination with standard care or standard care alone. ESWT was performed on DFUs using 250 shocks/cm2 and 500 shocks on arterial beds supplying the ulcer location. RESULTS: We recruited 23 patients, 11 in the intervention group and 12 in the control. Transcutaneous oxygen tension was significantly increased in patients treated with ESWT compared with those receiving standard care alone at 3 weeks (p=0.044). Ulcer area reduction was 34.5% in the intervention group versus 5.6% in the control group at 7 weeks (p=0.387). Within-group analysis revealed a significant reduction of ulcer area in the intervention group (p<0.01), while healing was not demonstrated in the control group (p>0.05) (data tested for trend). CONCLUSION: This randomised study indicates a potential beneficial effect of ESWT on ulcer healing as well as tissue oxygenation. Owing to weaknesses of the study and the fact that ulcer healing was not significantly improved in the intervention group compared with the control group, a larger randomised trial with blinded design is suggested.

Heart failure and Alzheimer's disease.

It has recently been proposed that heart failure is a risk factor for Alzheimer's disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer's disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.

Adjuvant effects of aluminium hydroxide-adsorbed allergens and allergoids - differences in vivo and in vitro.

Allergen-specific immunotherapy (SIT) is a clinically effective therapy for immunoglobulin (Ig)E-mediated allergic diseases. To reduce the risk of IgE-mediated side effects, chemically modified allergoids have been introduced. Furthermore, adsorbance of allergens to aluminium hydroxide (alum) is widely used to enhance the immune response. The mechanisms behind the adjuvant effect of alum are still not completely understood. In the present study we analysed the effects of alum-adsorbed allergens and allergoids on their immunogenicity in vitro and in vivo and their ability to activate basophils of allergic donors. Human monocyte derived dendritic cells (DC) were incubated with native Phleum pratense or Betula verrucosa allergen extract or formaldehyde- or glutaraldehyde-modified allergoids, adsorbed or unadsorbed to alum. After maturation, DC were co-cultivated with autologous CD4(+) T cells. Allergenicity was tested by leukotriene and histamine release of human basophils. Finally, in-vivo immunogenicity was analysed by IgG production of immunized mice. T cell proliferation as well as interleukin (IL)-4, IL-13, IL-10 and interferon (IFN)-γ production were strongly decreased using glutaraldehyde-modified allergoids, but did not differ between alum-adsorbed allergens or allergoids and the corresponding unadsorbed preparations. Glutaraldehyde modification also led to a decreased leukotriene and histamine release compared to native allergens, being further decreased by adsorption to alum. In vivo, immunogenicity was reduced for allergoids which could be partly restored by adsorption to alum. Our results suggest that adsorption of native allergens or modified allergoids to alum had no consistent adjuvant effect but led to a reduced allergenicity in vitro, while we observed an adjuvant effect regarding IgG production in vivo.

The long-term efficacy of hydrocele treatment with aspiration and sclerotherapy with polidocanol compared to placebo: a prospective, double-blind, randomized study.

PURPOSE: We evaluate whether aspiration and sclerosing of hydrocele testis is an effective treatment. MATERIALS AND METHODS: Men with symptomatic hydrocele testis were included in this prospective, double-blind, randomized study with polidocanol and placebo. Patients were randomized to active treatment or placebo at the first treatment. Depending on hydrocele testis size (less than 100, 100 to 200 and greater than 200 ml), the patients were treated with 1, 3 or 4 ml polidocanol after aspiration. Patients with recurrence at the 5-week followup received active treatment. RESULTS: A total of 77 patients were included in the study. In group 1 (active treatment) there were 36 patients with a median age of 63 years (range 34 to 92). In group 2, comprised of 41 patients, the median age was 59 years (range 26 to 82). Median followup was 72 months. A significant difference between the groups was observed after the first and second treatments. Recurrence after the first treatment was seen in 16 (44%) patients from group 1 and in 32 (78%) from group 2 (p <0.05). Recurrence after re-treatment with the active drug in both groups was seen in 4 (25%) patients in group 1 and in 14 (44%) in the former placebo group (p <0.05). The overall success rate of treatment in the active group was 89%. There was no difference between the 2 groups in terms of volume of fluid aspirated, symptoms or complications. CONCLUSIONS: This long-term efficacy randomized study with placebo showed that polidocanol is effective for the treatment of hydrocele testis with a low recurrence rate.

Cardiac resynchronization therapy: a breakthrough in heart failure management.

Heart failure is now considered an epidemic. In patients with heart failure, electrical and mechanical dyssynchrony, evident primarily as prolongation of the QRS-complex on the surface electrocardiogram, is associated with detrimental effects on the cardiovascular system at several levels. In the past 10 years, studies have demonstrated that by stimulating both cardiac ventricles simultaneously, or almost simultaneously [cardiac resynchronization therapy (CRT)], the adverse effects of dyssynchrony can be overcome. Here, we provide a comprehensive overview of different aspects of CRT including the rationale behind and evidence for efficacy of the therapy. Issues with regard to gender effects and patient follow-up as well as a number of unresolved concerns will also be discussed.

An alternative allergen:adjuvant formulation potentiates the immunogenicity and reduces allergenicity of a novel subcutaneous immunotherapy product for treatment of grass-pollen allergy.

BACKGROUND: Subcutaneous specific immunotherapy (SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide (AlOH). It has been shown that allergen-specific IgG antibodies are induced as a result of successful SIT. OBJECTIVE: To investigate the possibility of optimizing the formulation of AlOH-based grass-pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine. METHODS: Mice were immunized with various concentrations of Phleum pratense (Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p-specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed. RESULTS: Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo-induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation. CONCLUSION: The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity. CLINICAL RELEVANCE: This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing.

Rifampicin-soaked silver polyester versus expanded polytetrafluoro-ethylene grafts for in situ replacement of infected grafts in a porcine randomised controlled trial.

BACKGROUND: To compare the efficacy of in situ replacement with rifampicin-soaked silver-coated polyester (RSSCP) to that of expanded polytetrafluoroethylene (ePTFE) graft replacements in a porcine model for early aortic prosthetic vascular graft infection (PVGI). MATERIAL AND METHODS: Sixty pigs received polyester or silver-coated grafts with an 8 mm diameter implanted end-to-end in the infrarenal aorta, and the grafts were inoculated with approximately 10(6)Staphylococcus aureus. All developed S. aureus PVGI. Two weeks later, the 52 surviving pigs were randomised to undergo in situ graft replacement with ePTFE or RSSCP grafts followed by oral administration of 300 mg rifampicin and 750 mg ciprofloxacin twice a day, postoperatively. After three weeks, all pigs were sacrificed. In situ perigraft swabs and graft material were analysed for S. aureus quantitatively. RESULTS: Only one out of 25 RSSCP grafts were infected with S. aureus, whereas 15 of 27 ePTFE grafts were infected after 3 weeks (OR = 0.022, 95% CI: 0.002, 0.219, P = 0.001). CONCLUSIONS: In situ replacement with RSSCP grafts and oral rifampicin plus ciprofloxacin is more efficiency in eradicating S. aureus PVGI than ePTFE grafts treated with same oral antibiotics in a porcine aortic PVGI model.

Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation.

Analysis of extracellular matrix degradation systems has led to the insight that in cancer invasion there is often crucial interplay between cancer cells and several types of surrounding non-neoplastic stromal cells. Likewise, in normal tissue remodeling processes, the synthesis of proteolytic components is often distributed between several cell types, and there are strong similarities between neoplastic and non-neoplastic processes in the same tissue. Thus, tissue remodeling events are excellent models for studies of extracellular proteolysis in cancer. This has become even clearer by recent analyses of genetically modified mice.

A plasma kallikrein-dependent plasminogen cascade required for adipocyte differentiation.

Here we show that plasma kallikrein (PKal) mediates a plasminogen (Plg) cascade in adipocyte differentiation. Ecotin, an inhibitor of serine proteases, inhibits cell-shape change, adipocyte-specific gene expression, and lipid accumulation during adipogenesis in culture. Deficiency of Plg, but not of urokinase or tissue-type plasminogen activator, suppresses adipogenesis during differentiation of 3T3-L1 cells and mammary-gland involution. PKal, which is inhibited by ecotin, is required for adipose conversion, Plg activation and 3T3-L1 differentiation. Human plasma lacking PKal does not support differentiation of 3T3-L1 cells. PKal is therefore a physiological regulator that acts in the Plg cascade during adipogenesis. We propose that the Plg cascade fosters adipocyte differentiation by degradation of the fibronectin-rich preadipocyte stromal matrix.

Impaired wound healing in mice with a disrupted plasminogen gene.

Activation of plasminogen (Plg) has been proposed to play a role in proteolytic degradation of extracellular matrices in tissue remodeling events, including wound healing. However, there has been no definitive proof of involvement of Plg in such processes. We now report that healing of skin wounds is severely impaired in mice made deficient in Plg by targeted gene disruption. The results demonstrate that Plg is required for normal repair of skin wounds in mice and support the assumption that it also plays a central role in other disease processes involving extracellular matrix degradation, such as cancer invasion.