IgE, IgGa, IgGb and IgG(T) serum antibody levels in offspring of two sires affected with equine recurrent airway obstruction

Equine recurrent airway obstruction (RAO) is a chronic lower airway disease of the horse caused by hypersensitivity reactions to inhaled stable dust, including mould spores such as Aspergillus fumigatus. The goals of this study were to investigate whether total serum IgE levels and allergen-specific IgE and IgG subclasses are influenced by genetic factors and/or RAO and whether quantitative trait loci (QTL) could be identified for these parameters. The offspring of two RAO-affected sires (S1: n=56 and S2: n=65) were grouped by stallion and disease status, and total serum IgE levels and specific IgE, IgGa, IgGb and IgG(T) levels against recombinant Aspergillus fumigatus 7 (rAspf7) were measured by ELISA. A panel of 315 microsatellite markers covering the 31 equine autosomes were used to genotype the stallions and their offspring. A whole-genome scan using half-sib regression interval mapping was performed for each of the IgG and IgE subclasses. There was no significant effect of disease status or sire on total IgE levels, but there was a significant effect of gender and age. rAspf7-specific IgGa levels were significantly higher in RAO-affected than in healthy horses. The offspring of S1 had significantly higher rAspf7-specific IgGa and IgE levels than those of S2. Five QTLs were significant chromosome-wide (P<0.01). QTLs for rAspf7-specific IgGa and IgE were identified on ECA 1, for rAspf7-specific IgGa and IgGb on ECA 24 and for rAspf7 IgGa on ECA 26. These results provide evidence for effects of disease status and genetics on allergen-specific IgGa and IgE.

[Recurrent febrile episodes--normal, periodic fever syndrome or immunodeficiency?]

Fever is one of the main symptoms leading to medical evaluation. Not only infections cause fever but also inflammatory disorders. To distinguish one from another, a thorough medical history and clinical evaluation are needed. Sometimes, only the clinical course will reveal the diagnosis. PFAPA-Syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis) is the most frequent periodic fever syndrome in Switzerland. No diagnostic test is available to support the diagnosis. Some important diseases have to be ruled out, such as Immunodeficiency, cyclic neutropenia, chronic viral infections and rheumatologic disorders. To know the diagnosis of the PFAPA-Syndrome can help avoiding antibiotic courses for febrile episodes in infants. There is a clinical overlap to hereditary periodic fever syndromes as familial Mediterranean fever (FMF), Hyper-IgD and fever syndrome (HIDS), Tumor-necrosis factor receptor associated periodic syndrome (TRAPS) and others, in which a genetic basis for the disease has already been found.

Influence of secondary infection on amputation in chronic critical limb ischemia

OBJECTIVES: To evaluate the influence of secondary infection on major amputation in chronic critical leg ischemia (CLI). DESIGN: Prospective, controlled observational study. MATERIALS AND METHODS: Sixty-seven patients with CLI and ischemic lesions participated in the study. Presence of infection was defined by clinical, laboratory and radiological criteria. Patients were categorized as having no local infection, soft tissue infection or osteomyelitis treated without antibiotics, amoxicillin/clavulanacid for 1 month or ciprofloxacin and clindamycin for 3 months, respectively. Clinical outcome was assessed at 2, 6 and 12 months. Study endpoints were major amputation and mortality. Analyses were performed using the Kaplan-Meier method. RESULTS: Forty-seven of 67 patients had a local infection. Major amputation was lower in patients with successful revascularization as compared to patients unsuitable for or with failed (without) revascularization (0% vs 26%, p<0.01). In patients with successful revascularization the probability of complete healing was lower with secondary infection (23% vs 71%, p=0.03). In patients without revascularization complete healing was rare (<10%), but secondary infection did not influenced major amputation, mortality or serious adverse events. CONCLUSION: Secondary infection reduces the likelihood of successful healing following revascularisation of CLI.

Effects of genetic and environmental factors on chronic lower airway disease in horses

BACKGROUND: Environment and genetics influence the manifestation of recurrent airway obstruction (RAO), but the associations of specific factors with mild, moderate, and severe clinical signs are unknown. HYPOTHESIS: We hypothesized that sire, feed, bedding, time outdoors, sex, and age are associated with clinical manifestations of mild, moderate, and severe lower airway disease. ANIMALS: Direct offspring of 2 RAO-affected Warmblood stallions (F1S1, n = 172; F1S2, n = 135); maternal half-siblings of F1S1 (mHSS1, n = 66); and an age-matched, randomly chosen control group (CG, n = 33). METHODS: A standardized questionnaire was used to assess potential risk factors and to establish a horse owner assessed respiratory signs index (HOARSI 1-4, from healthy to severe) according to clinical signs of lower airway disease. RESULTS: More F1S1 and F1S2 horses showed moderate to severe clinical signs (HOARSI 3 and HOARSI 4 combined, 29.6 and 27.3%, respectively) compared with CG and mHSS1 horses (9.1 and 6.2%, respectively; contingency table overall test, P < .001). Sire, hay feeding, and age (in decreasing order of strength) were associated with more severe clinical signs (higher HOARSI), more frequent coughing, and nasal discharge. CONCLUSIONS AND CLINICAL RELEVANCE: There is a genetic predisposition and lesser but also marked effects of hay feeding and age on the manifestation of moderate to severe clinical signs, most markedly on coughing frequency. In contrast, mild clinical signs were not associated with sire or hay feeding in our populations.

A region on equine chromosome 13 is linked to recurrent airway obstruction in horses

REASONS FOR STUDY: Equine recurrent airway obstruction (RAO) is probably dependent on a complex interaction of genetic and environmental factors and shares many characteristic features with human asthma. Interleukin 4 receptor a chain (IL4RA) is a candidate gene because of its role in the development of human asthma, confirmation of this association is therefore required. METHODS: The equine BAC clone containing the IL4RA gene was localised to ECA13q13 by the FISH method. Microsatellite markers in this region were investigated for possible association and linkage with RAO in 2 large Warmblood halfsib families. Based on a history of clinical signs (coughing, nasal discharge, abnormal breathing and poor performance), horses were classified in a horse owner assessed respiratory signs index (HOARSI 1-4: from healthy, mild, moderate to severe signs). Four microsatellite markers (AHT133, LEX041, VHL47, ASB037) were analysed in the offspring of Sire 1 (48 unaffected HOARSI 1 vs. 59 affected HOARSI 2-4) and Sire 2 (35 HOARSI 1 vs. 50 HOARSI 2-4), age 07 years. RESULTS: For both sires haplotypes could be established in the order AHT133-LEXO47-VHL47-ASB37. The distances in this order were estimated to be 2.9, 0.9 and 2.3 centiMorgans, respectively. Haplotype association with mild to severe clinical signs of chronic lower airway disease (HOARSI 2-4) was significant in the offspring of Sire 1 (P = 0.026) but not significant for the offspring of Sire 2 (P = 0.32). Linkage analysis showed the ECA13q13 region containing IL4RA to be linked to equine chronic lower airway disease in one family (P<0.01), but not in the second family. CONCLUSIONS: This supports a genetic background for equine RAO and indicates that IL4RA is a candidate gene with possible locus heterogeneity for this disease. POTENTIAL RELEVANCE: Identification of major genes for RAO may provide a basis for breeding and individual prevention for this important disease.

Classic and overlap chronic graft-versus-host disease (cGVHD) is associated with superior outcome after extracorporeal photopheresis (ECP)

The National Institutes of Health (NIH) classification of graft-versus-host disease (GVHD) is a significant improvement over prior classifications, and has prognostic implications. We hypothesized that the NIH classification of GVHD would predict the survival of patients with GVHD treated with extracorporeal photopheresis (ECP). Sixty-four patients with steroid refractory/dependent GVHD treated with ECP were studied. The 3-year overall survival (OS) was 36% (95% confidence interval [CI] 13-59). Progressive GVHD was seen in 39% of patients with any acute GVHD (aGVHD) (classic acute, recurrent acute, overlap) compared to 3% of patients with classic chronic GVHD (cGVHD) (P=.002). OS was superior for patients with classic cGVHD (median survival, not reached) compared to overlap GVHD (median survival, 395 days, 95% CI 101 to not reached) and aGVHD (delayed, recurrent or persistent) (median survival, 72 days, 95% CI 39-152). In univariate analyses, significant predictors of survival after ECP included GVHD subtype, bilirubin, platelet count, and steroid dose. In multivariate analyses overlap plus classic cGVHD was an independent prognostic feature predictive of superior survival (hazard ratio [HR] 0.34, 95% CI 0.14-0.8, p=.014). This study suggests that NIH classification can predict outcome after ECP for steroid refractory/dependent GVHD.

Multifocal posterior uveitis in Crohn's disease

PURPOSE To report a case of rare posterior eye manifestation of Crohn's disease preceding recurrence of inflammatory bowel disease. METHODS Case report with ophthalmoscopic findings, fluorescein/indocyanin green angiograms, automated perimetry and multifocal-ERG. RESULTS The perimetry revealed absolute and relative scotomas corresponding to multifocal inflammatory lesions in the retina and choroid, reduced a/b amplitudes in multifocal-ERG and hypofluorescent dots in angiography. Under oral prednisolone visual defects, ophthalmoscopic and angiographic findings resolved, while a/b amplitudes remained mildly reduced. The ocular changes occurred without systemic hypertension and were followed by a new episode of intestinal symptoms. CONCLUSION Multifocal inflammatory lesions in the retina and choroid in patients with Crohn's disease may occur and may precede a recurrent intestinal episode. Crohn's patients should be carefully followed up in collaboration with internal medicine specialists.

Is thermochemotherapy with the Synergo system a viable treatment option in patients with recurrent non-muscle-invasive bladder cancer?

OBJECTIVES To prospectively evaluate the outcome of combined microwave-induced bladder wall hyperthermia and intravesical mitomycin C instillation (thermochemotherapy) in patients with recurrent non-muscle-invasive bladder cancer. METHODS Between 2003 and 2009, 21 patients (median age 70 years, range 35-95 years) with recurrent non-muscle-invasive bladder cancer (pTaG1-2 n = 9; pTaG3 n = 3; pT1 n = 9; concurrent pTis n = 8) were prospectively enrolled. Of 21 patients, 15 (71%) had received previous intravesical instillations with bacillus Calmette-Guérin, mitomycin C and/or farmorubicin. Thermochemotherapy using the Synergo system was carried out in 11 of 21 patients (52%) with curative intent, and in 10 of 21 patients (48%) as prophylaxis against recurrence. RESULTS The median number of thermochemotherapy cycles per patient was six (range 1-12). Adverse effects were frequent and severe: urinary urgency/frequency in 11 of 21 patients (52%), pain in eight of 21 patients (38%) and gross hematuria in five of 21 patients (24%). In eight of 21 patients (38%), thermochemotherapy had to be abandoned because of the severity of the adverse effects (pain in 3/8, severe bladder spasms in 2/8, allergic reaction in 2/8, urethral perforation in 1/8). Overall, six of 21 patients (29%) remained free of tumor after a median follow up of 50 months (range 1-120), six of 21 patients (29%) had to undergo cystectomy because of multifocal recurrences or cancer progression and seven of 21 patients (33%) died (2/7 of metastatic disease, 5/7 of non-cancer related causes). CONCLUSIONS Given the high rate of severe side-effects leading to treatment discontinuation, as well as the limited tumor response, thermochemotherapy should be offered only in highly selected cases of recurrent non-muscle-invasive bladder cancer.

Jejunitis and brown bowel syndrome with multifocal carcinogenesis of the small bowel

This is the first report describing a case where prolonged, severe malabsorption from brown bowel syndrome progressed to multifocally spread small bowel adenocarcinoma. This case involves a female patient who was initially diagnosed with chronic jejunitis associated with primary diffuse lymphangiectasia at the age of 26 years. The course of the disease was clinically, endoscopically, and histologically followed for 21 years until her death at the age 47 due to multifocal, metastasizing adenocarcinoma of the small bowel. Multiple lipofuscin deposits (so-called brown bowel syndrome) and severe jejunitis were observed microscopically, and sections of the small bowel showed dense lymphoplasmacytic infiltration of the lamina propria as well as blocked lymphatic vessels. After several decades, multifocal nests of adenocarcinoma cells and extensive, flat, neoplastic mucosal proliferations were found only in the small bowel, along with a loss of the mismatch repair protein MLH1 as a long-term consequence of chronic jejunitis with malabsorption. No evidence was found for hereditary nonpolyposis colon carcinoma syndrome. This article demonstrates for the first time multifocal carcinogenesis in the small bowel in a malabsorption syndrome in an enteritis-dysplasia-carcinoma sequence.

Spatial genomic heterogeneity within localized, multifocal prostate cancer

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

YKL -40, a vascular -associated serum marker for glioblastoma, correlates with chronic activation of AKT

YKL-40 is a secreted glycoprotein that has been reported to be expressed in pathologic conditions of extracellular matrix degradation and angiogenesis, such as rheumatoid arthritis, severe osteoarthritis, primary colorectal cancer, metastatic breast cancer, and recurrent ovarian cancer (Dehn, Hogdall et al. 2003). ^ We have identified YKL-40 as a serum marker for glioblastoma multiforme (GBM) using microarray analysis from samples of GBM. We compared the gene expression profile of 19 gliomas to pooled normal brain tissue using the Incyte 10,000 gene expression array. The most differentially expressed gene in this analysis was YKL-40; it was detected in GBM samples with a range of 3 to 62-fold elevation over normal brain. Western blot analysis of glioma samples for YKL-40 protein levels revealed substantial elevation in approximately 65% of GBMs, and undetectable levels in lower-grade gliomas and normal brain tissue. ELISA analysis on serum samples of glioma patients showed that YKL-40 levels were substantially elevated in many of the GBM patients. Statistical analysis indicated that in patients with glioma, serum YKL-40 levels correlate with tumor grade and potentially tumor burden in GBM. ^ Furthermore, we found that YKL-40 expression by in-situ hybridization on a brain tumor tissue array was limited to GBM's and gliosarcomas (GSA), and that YKL-40 expression was specific to the GBM component of GSA. Additional in-situ hybridization analysis, found it to be regionally associated with tumor vasculature as well as activated AKT expression in both human and mouse GBM's. Correlation of elevated YKL-40 with phospho-AKT was confirmed by Western blot analysis on a series of glioblastoma tumors, and inhibition of PI3 Kinase signaling by addition of LY294002 also decreased secretion of YKL-40 over a 7-day period in U87 glioblastoma cell tine. Lastly, YKL-40 expression was induced in response to serum starvation and altered by interaction with specific extracellular matrix (ECM) modules. In summary, we have identified the first accurate serum marker for high-grade gliomas. Furthermore, our findings indicate that YKL-40 is a highly expressed vascular-related glycoprotein in human GBM tissue and that it is affected by the AKT signaling pathway and interaction with components of brain ECM proteins. ^

Acute, posterior multifocal placoid pigment epitheliopathy: a case of 11 recurrences over 15 years

PURPOSE: To report the case of a patient with recurrent, acute posterior multifocal placoid pigment epitheliopathy. To the best of our knowledge, this is the longest documented course with the greatest number of recurrences reported. METHODS: Observational case report of one patient. A 27-year-old otherwise healthy male patient presented with recurrence of new scotomata over 15 years. Fundus photography, fluorescein angiography, indocyanine green angiography, fundus autofluorescence, and optical coherence tomography documented his clinical course. RESULTS: Over the course of 15 years, the patient developed 11 symptomatic (5 imaging-documented) recurrences of acute, posterior multifocal placoid pigment epitheliopathy affecting both eyes. Each episode manifested with new subjective scotomata and new lesions noted on imaging. Symptoms mostly resolved after each episode, and visual outcome remained excellent (20/20 in the right eye and 20/25 left eye at the last follow-up). CONCLUSION: Although typically monophasic, acute posterior multifocal placoid pigment epitheliopathy can rarely present with a recurrent course over a prolonged period of time and should be considered as a diagnosis in patients presenting with recurrent visual symptoms and new placoid lesions on imaging. In recurrent cases, visual recovery may still remain excellent.

Prolonged effects of a home-based intervention in patients with chronic illness

Background: Data on the long-term benefits of nonspecific disease management programs are limited. We performed a long-term follow-up of a previously published randomized trial. Methods: We compared all-cause mortality and recurrent hospitalization during median follow-up of 7.5 years in a heterogeneous cohort of patients with chronic illness initially exposed to a multidisciplinary, homebased intervention (HBI) (n = 260) or to usual postdischarge care (n = 268). Results: During follow-up, HBI had no impact on all-cause mortality (relative risk, 1.04; 95% confidence interval, 0.80-1.35) or event-free survival from death or unplanned hospitalization (relative risk, 1.03; 95% confidence interval, 0.86-1.24). Initial analysis suggested that HBI had only a marginal impact in reducing unplanned hospitalization, with 677 readmissions vs 824 for the usual care group (mean +/- SD rate, 0.72 +/- 0.96 vs 0.84 +/- 1.20 readmissions/patient per year; P = .08). When accounting for increased hospital activity in HBI patients with chronic obstructive pulmonary disease during follow-up for 2 years, post hoc analyses showed that HBI reduced readmissions by 14% within 2 years in patients without this condition (mean +/- SD rate, 0.54 +/- 0.72 vs 0.63 +/- 0.88 readmission/patient per year; P =. 04) and by 21% in all surviving patients within 3 to 8 years (mean +/- SD rate, 0.64 +/- 1.26 vs 0.81 +/- 1.61 readmissions/ patient per year; P =. 03). Overall, recurrent hospital costs were significantly lower ( 14%) in the HBI group (mean +/- SD, $ 823 +/- $ 1642 vs $ 960 +/- $ 1376 per patient per year; P =. 045). Conclusion: This unique study suggests that a nonspecific HBI provides long-term cost benefits in a range of chronic illnesses, except for chronic obstructive pulmonary disease.

Osteomyelitis of the maxilla in a patient with Malignant Infantile Osteopetrosis

Osteopetrosis is characterized by a considerable increase in bone density resulting in defective remodeling, caused by failure in the normal function of osteoclasts, and varies in severity. It is usually subdivided into three types: benign autosomal dominant osteopetrosis; intermediate autosomal recessive osteopetrosis; and malignant autosomal recessive infantile osteopetrosis, considered the most serious type. The authors describe a case of chronic osteomyelitis in the maxilla of a 6-year-old patient with Malignant Infantile Osteopetrosis. The treatment plan included pre-maxilla sequestrectomy and extraction of erupted upper teeth. No surgical procedure was shown to be the best to prevent the progression of oral infection. Taking into account the patient's general condition, if the patient develops severe symptomatic and refractory osteomyelitis surgery should be considered. The patient and his family are aware of the risks and benefits of surgery and its possible complications.

Testosterone Therapy Differently Regulates The Anti- And Pro-inflammatory Cytokines In The Plasma And Prostate Of Rats Submitted To Chronic Ethanol Consumption (uchb).

Ethanol consumption damages the prostate, and testosterone is known by anti-inflammatory role. The cytokines were investigated in the plasma and ventral prostate of UChB rats submitted or not to testosterone therapy by ELISA and Western blot, respectively. Additionally, inflammatory foci and mast cells were identified in the ventral prostate slides stained by hematoxylin and eosin and toluidine blue, respectively. Inflammatory foci were found in the ethanol-treated animals and absent after testosterone therapy. Plasma levels of IL-6 and IL-10 were not changed while TNFα and TFG-β1 were increased in the animals submitted testosterone therapy. Regarding to ventral prostate, IL-6 did not alter, while IL-10, TNFα, and TFG-β1 were increased after testosterone therapy. Ethanol increases NFR2 in addition to high number of intact and degranulated mast cell which were reduced after testosterone therapy. So, ethanol and testosterone differentially modulates the cytokines in the plasma and prostate.