Acute phase protein levels in dogs with mast cell tumours and sarcomas

<p><b>Context:</b> The acute phase protein response is part of a non-specific and complex host response to inflammation. It occurs shortly after tissue injury and may be induced by a range of different causes, including infectious, inflammatory, neoplastic, traumatic or immunological disease. Although it was conventionally believed that APPs were exclusively hepatocyte derived, there is increasing evidence to support extra-hepatic generation in neoplastic and other disease states. In people, C-reactive protein (CRP) has been shown to be of value in identifying metastatic disease from primary renal tumours as well as showing promise for monitoring rejection of renal transplants. Serum CRP correlates with survival in colorectal cancer and oesophageal squamous cell carcinoma while serum amyloid A (SAA) concentrations correlate with cancer activity, stage and prognosis in gastric tumours. Recent immunohistochemical studies in people with oesophageal carcinoma suggest that tumour tissue may itself elaborate APP with a poorer survival and outcome associated with tumours elaborating higher levels of CRP. A similar association has been seen between alpha-1 acid glycoprotein (AGP) and colorectal tumours and ovarian carcinoma.</p> <p>As yet, studies regarding APP values in neoplastic conditions in dogs are limited, and many are non-specific. In veterinary patients, elevated levels of AGP have been identified in dogs with a range of tumours with localisation to liver and splenic tissue in one study. Another study found higher levels of AGP in dogs with non-specific tumours of grade III-IV based on the WHO Tumour Node Metastasis (TNM) scale and elevated serum AGP has been documented in non-specific tumour-bearing cats. Elevated CRP levels have been documented in both dogs and cats with lymphoma and serum CRP may be used as an indicator of complete remission status in dogs with multicentric lymphoma. Elevated levels of CRP, Haptoglobin (Hp) and SAA have been identified in dogs with mammary tumours, with significant increases over normal in the presence of metastatic disease, primary tumours greater than 5cm in diameter and those with ulceration.</p> <p>In this study we evaluated an APP profile using four APPs (CRP, Hp, SAA and AGP), in dogs with mast cell tumours (MCTs) and sarcomas to assess whether the APP profile would change in reflection of tumour presence; whether the extent of any change would correlate with tumour grade; and whether the changes would differ with tumour type.</p> <p><b>Approach:</b> Patients with naturally occurring MCTs and sarcomas presenting for staging and treatment were included if they met the study criteria. Criteria for inclusion were that the patient was not currently being treated with steroids, did not have a recent history of infectious or inflammatory disease other than the tumour, a definitive histological diagnosis was available and a full staging procedure was completed prior to surgery using standard oncological protocols to identify metastatic disease where present. Following surgical resection each tumour was submitted for full histological evaluation and grading to include assessment of the margins of excision. Cases were only enrolled in the study if blood sampling formed part of the clinical investigation and/or treatment, and where residual blood was available after diagnostic sampling which would otherwise have been disposed of as clinical waste. In brief, the CRP levels were determined by immunoturbidometric assay and Hp by means of haemoglobin binding capacity assay. SAA was measured with a commercial canine ELISA kit (TriDelta Development, Dublin, Ireland) and AGP was measured with a commercial radial immunodiffusion assay (J-Path Inc, Tokyo, Japan).</p> <p><b>Results:</b> All comparisons using continuous data were checked for normality and equality of variances and appropriate statistical tests were employed (student’s t test operationalised as a two-sample Welch’s test for samples of unequal sizes and variances, Mann-Whitney, Chi-square and Fishers exact tests as appropriate). In MCTs, the CRP and AGP were elevated above reference ranges, Hp showed no significant change and SAA dropped relative to the reference range. In sarcoma patients CRP, Hp and AGP were all elevated above reference ranges. None of the tumour grade differences were significant apart from SAA in sarcoma patients where values in grade 2 sarcoma were significantly higher than those in grade 1.</p> <p><b>Interpretation and notes of caution:</b> The numbers in our groups were small which compromises the validity of statistical evaluation so our results must be interpreted with caution. However some interesting relationships have emerged from the initial evaluation which suggests that APP profiles may have potential for screening in patients with neoplastic disease. For patients with MCTs, CRP and AGP levels would be expected to increase, with a concurrent drop in SAA levels. In sarcoma patients CRP, AGP and Hp can all be expected to increase. These initial results need to be evaluated in larger numbers of cases with naturally occurring disease to validate the findings, to assess whether the presence and extent of metastatic disease has a significant effect, and also to confirm whether the values alter after surgical resection of the primary tumour.</p> <p><b>Significance of findings:</b> If there are consistent and specific changes in APP profiles associated with different tumour types in dogs, as is the case with a wide range of cancers in humans, then there may be potential for APP profiles on routine blood samples to be used as indicators of disease, or where monitoring for recurrence. Whether they could also have potential for assessment of the presence of metastatic disease and prognosis as in people is unknown as yet.</p&gt

Some Aspects of Price Inflation in Ireland. ESRI General Research Series Paper No. 40, January 1968

In every country prices have risen sUbstantiaUy since the end of the war. In Ireland, as in six other European countries, consumer prices had almost doubled between 1948 and 1965--see Table 2. Is this situation of continuously rising prices in the indefinite future a fact of life which must be accepted and with which we must somehow cope, or does it mean that a sudden, and possibly catastrophic, fall in prices, like that of May 192o after World War I, is to be anticipated? History generally has a way of repeating itself and similarities are observable between our times and others, but with much longer time-lags between cause and effect in the more recent period. One might hope that, as governments nowadays have much greater control of their economies than in the past, and with the development of the social conscience, disastrous price falls can be avoided or mitigated. It is only a hope, however

GSH Attenuates Organ Injury and Improves Function after Transplantation of Fatty Livers

Ischemia-reperfusion injury (IRI) is increased after transplantation of steatotic livers. Since those livers are increasingly used for transplantation, protective strategies must be developed. Reactive oxygen species (ROS) play a key role in hepatic IRI. In lean organs, glutathione (GSH) is an efficient scavenger of ROS, diminishing IRI. The aim of this study was to evaluate whether GSH also protects steatotic allografts from IRI following transplantation. Fatty or lean livers were explanted from 10-week-old obese or lean Zucker rats and preserved (obese 4 h, lean 24 h) in hypothermic University of Wisconsin solution. Arterialized liver transplantation was then performed in lean syngeneic Zucker rats. Recipients of fatty livers were treated with GSH (200 mu mol/h/kg) or saline during reperfusion (2 h, n = 5). Parameters of hepatocellular damage and bile flow were measured. Transplantation of steatotic livers enhanced early reperfusion injury compared to lean organs as measured by increased aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase plasma levels. Bile flow was also reduced in steatotic grafts. Intravenous administration of GSH effectively decreased liver damage in fatty allografts and resulted in improved bile flow. Intravenous application of GSH effectively reduces early IRI in steatotic allografts and improves recovery of these marginal donor organs following transplantation. Copyright (C) 2010 S. Karger AG, Base

Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short- and long-term graft function

The early identification of renal transplant recipients at enhanced risk of developing acute and subclinical rejection would allow individualized adjustment of immunosuppression before functional graft injury occurs and would exclude these patients from drug-weaning studies. Protein and reverse transcriptase-polymerase chain reaction-based analyses of candidate markers in urine open the opportunity to closely monitor kidney-transplanted patients non-invasively. The chemokine interferon-inducible protein 10 (IP-10; CXCL10) might be an interesting candidate to uncover ongoing immune processes within the graft. Urine samples from kidney-transplanted recipients were retrospectively analyzed for IP-10 mRNA and protein expression. IP-10 levels were correlated with the incidence of acute rejection episodes proven by histology and long-term graft function assessed by the glomerular filtration rate 6 months post transplantation. IP-10 expression in urine identified patients with ongoing acute rejection episodes several days before a biopsy was indicated by rising serum creatinine levels. Most importantly, elevated levels of urinary IP-10 protein within the first four postoperative weeks were predictive of graft function at 6 months even in the absence of acute rejection. These data reveal a correlation between elevated IP-10 expression in urine at early time points post-transplantation and intragraft immune activation that leads to acute rejection and compromised long-term graft function

Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study

M. Winkler, J. Pratschke, U. Schulz, S. Zheng, M. Zhang, W. Li, M. Lu, D. Sgarabotto, G. Sganga, P. Kaskel, S. Chandwani, L. Ma, J. Petrovic, M. Shivaprakash. Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study. Transpl Infect Dis 2010: 12: 230–237. All rights reserve

Tissue engineering for the diaphragm and its various therapeutic possibilities - a systematic review

Diaphragmatic impairments exhibit high morbidity as well as mortality while current treatment options remain unsatisfactory. Tissue engineering (TE) approaches have explored the generation of an optimal biocompatible scaffold for diaphragmatic repair through tissue decellularization or de novo construction, with or without the addition of cells. We conducted a systematic review on the current state of the art in diaphragmatic tissue engineering (DTE) and found 24 articles eligible for final synthesis. The included approaches studied decellularization-based graft generation (9) and de novo bioscaffold construction (9). Three studies focused on in vitro host-scaffold interaction with synthesized, recellularized grafts (2) and decellularized extracellular matrix scaffolds (1). Another three studies investigated evaluation tools for decellularization efficacy. Among all studies, recellularization was performed in both decellularization-based (4) and de novo generated scaffolds (4). De novo constructed biocomposites as well as decellularized and recellularized scaffolds induced pro-regenerative remodeling and recovery of diaphragmatic function in all examined animal models. Potential therapeutic applications comprise substance defects requiring patch repair, such as congenital diaphragmatic hernia, and functional diseases demanding an entire organ transplant, like muscular dystrophies or dysfunction after prolonged artificial respiration

Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans

Decellularization of pancreata and repopulation of these non-immunogenic matrices with islets and endothelial cells could provide transplantable, endocrine Neo- Pancreata. In this study, rat pancreata were perfusion decellularized and repopulated with intact islets, comparing three perfusion routes (Artery, Portal Vein, Pancreatic Duct). Decellularization effectively removed all cellular components but conserved the pancreas specific extracellular matrix. Digital subtraction angiography of the matrices showed a conserved integrity of the decellularized vascular system but a contrast emersion into the parenchyma via the decellularized pancreatic duct. Islets infused via the pancreatic duct leaked from the ductular system into the peri- ductular decellularized space despite their magnitude. TUNEL staining and Glucose stimulated insulin secretion revealed that islets were viable and functional after the process. We present the first available protocol for perfusion decellularization of rat pancreata via three different perfusion routes. Furthermore, we provide first proof-of-concept for the repopulation of the decellularized rat pancreata with functional islets of Langerhans. The presented technique can serve as a bioengineering platform to generate implantable and functional endocrine Neo-Pancreata

Biliary microbial patterns in primary sclerosing cholangitis are linked to poorer transplant-free survival

BACKGROUND: Factors that determine individual disease course of patients with primary sclerosing cholangitis (PSC) are poorly understood. Although an association between gut microbes and disease outcome has been suggested, little is known about the role of microbes in the biliary tract. METHODS: We analyzed microbial cultures from bile specimens obtained during routine endoscopic retrograde cholangiopancreatography (ERCP) and intraoperatively before liver transplantation in 114 patients with PSC in our tertiary academic center. The presence of bacterial and fungal species was correlated with clinical characteristics and outcome data. RESULTS: A total of 87 patients (76%) had positive bile culture results. The presence of concomitant inflammatory bowel disease (IBD) was associated with positive bile culture results in multivariate analysis (OR, 4.707; 95% CI, 1.688-13.128; p=0.003). Enterococcus spp. in the bile was associated with a more frequent occurrence of liver transplantation and/or death (OR, 2.778; 95% CI, 1.147-6.728; p=0.021) and recurrent (≥3) cholangitis episodes (OR, 2.839; 95% CI, 1.037-7.768; p=0.037). Biliary candidiasis was linked to a higher frequency of recurrent (≥3) cholangitis episodes (OR, 5.677; 95% CI, 1.940-16.616; p=0.001). Proton pump inhibitor intake conferred a clinical feature associated with biliary candidiasis in multivariate analysis (OR, 3.559; 95% CI, 1.275-9.937; p=0.016). CONCLUSIONS: Our data indicate that in patients with PSC, presence of Enterococcus spp. and Candida spp. in bile is associated with an adverse outcome. Concomitant IBD is linked to presence of microbes in bile, and proton pump inhibitor intake is a feature associated with biliary candidiasis in patients with PSC

Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European liver transplant registry

This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with <1 month of follow-up were excluded from the analyses. In total, 4367 patients (prolonged-release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score-matched patients confirmed the significant survival advantages observed in the prolonged-release tacrolimus- versus tacrolimus BD-treated group. This large retrospective analysis from the ELTR identified significant improvements in long-term graft and patient survival in patients treated with prolonged-release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data