Lipocalin-2 protects the brain during inflammatory conditions.

Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2-/- mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in wild-type (WT) mice injected with LPS, Lcn2-/- mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared with WT mice injected with LPS, Lcn2-/- mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, nucleotide-binding oligomerization domain-like receptor signaling and Janus kinase-signal transducer and activator of transcription signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae.

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.

Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

Commutability of the First World Health Organization International Standard for Human Cytomegalovirus.

Quantitative detection of cytomegalovirus (CMV) DNA has become a standard part of care for many groups of immunocompromised patients; recent development of the first WHO international standard for human CMV DNA has raised hopes of reducing interlaboratory variability of results. Commutability of reference material has been shown to be necessary if such material is to reduce variability among laboratories. Here we evaluated the commutability of the WHO standard using 10 different real-time quantitative CMV PCR assays run by eight different laboratories. Test panels, including aliquots of 50 patient samples (40 positive samples and 10 negative samples) and lyophilized CMV standard, were run, with each testing center using its own quantitative calibrators, reagents, and nucleic acid extraction methods. Commutability was assessed both on a pairwise basis and over the entire group of assays, using linear regression and correspondence analyses. Commutability of the WHO material differed among the tests that were evaluated, and these differences appeared to vary depending on the method of statistical analysis used and the cohort of assays included in the analysis. Depending on the methodology used, the WHO material showed poor or absent commutability with up to 50% of assays. Determination of commutability may require a multifaceted approach; the lack of commutability seen when using the WHO standard with several of the assays here suggests that further work is needed to bring us toward true consensus.

The prevalence and demographic distribution of treated epilepsy: a community-based study in Tasmania, Australia.

OBJECTIVES: To estimate the prevalence and demographic distribution of treated epilepsy in a community-based population. MATERIALS & METHODS: We surveyed all residents in Tasmania, Australia, who were supplied at least one antiepileptic drug prescription between July 1, 2001 and June 30, 2002, recorded on the national prescription database. We adjusted for the effect of disease-related non-response bias by imputation methods. RESULTS: After three mail contacts, 54.0% (4072/7541) responded, with 1774 (43.6%) indicating treatment for epilepsy, representing 86.0% of the estimated total possible cases in Tasmania. The adjusted treated epilepsy prevalence was 4.36 per 1000 (95% CI 4.34, 4.39); lower in women (prevalence ratio 0.92 (95% CI 0.84, 1.00)); greater with increasing age (P < 0.001); similar in the three main geographic regions; and similar with socioeconomic status of postcode of residence. CONCLUSIONS: Although our estimates are likely to be affected by access to health services, overall treated epilepsy prevalence of 4.4 per 1000 is similar to previous studies. Our finding of high elderly prevalence has been reported in a few recent studies in developed countries and has important clinical and public health implications in populations with similar aging demographics.

The impact of MELD/PELD revisions on the mortality of liver-intestine transplantation candidates.

Patients listed for liver-intestine transplantation suffer higher waiting list mortality than those listed for liver-only, thus leading to policy revisions seeking to close the gap. We sought to determine the impact of key model for end-stage liver disease (MELD)/pediatric end-stage liver disease (PELD) policy modifications on the waiting list mortality of adult and pediatric liver-intestine candidates as compared to liver-only candidates. Analysis of UNOS data separated into adult and pediatric categories and based on time periods of policy implementation revealed higher mortality in liver-intestine candidates over all time periods studied (p < 0.001 pediatric and adult). After implementation of a revision to augment their MELD scores based on a sliding scale, adult liver-intestine candidates with calculated MELD > 15 no longer suffered higher mortality although this change did not completely eliminate the mortality disparity for candidates with MELD < 15 (p < 0.01). The waiting list mortality of pediatric liver-intestine candidates dropped significantly after a revision that gave them 23 additional MELD/PELD points (p < 0.01) although the mortality disparity with pediatric liver-only candidates was not eliminated. Following this revision, mortality in pediatric liver-only and liver-intestine Status 1 candidates was similar, however more liver-intestine candidates were listed as Status 1B. This data demonstrates that a mortality disparity remains for liver-intestine candidates compared with candidates listed for liver-only.

Academic careers and lifestyle characteristics of 171 transplant surgeons in the ASTS.

This manuscript reports the demographics, education and training, professional activities and lifestyle characteristics of 171 members of the American Society of Transplant Surgeons (ASTS). ASTS members were sent a comprehensive survey by electronic mail. There were 171 respondents who were 49 ± 8 years of age and predominantly Caucasian males. Female transplant surgeons comprised 10% of respondents. ASTS respondents underwent 15.6 ± 1.0 years of education and training (including college, medical school, residency and transplantation fellowship) and had practiced for 14.7 ± 9.2 years. Clinical practice included kidney, pancreas and liver organ transplantation, living donor surgery, organ procurement, vascular access procedures and general surgery. Transplant surgeons also devote a significant amount of time to nonsurgical patient care, research, education and administration. Transplant surgeons, both male and female, reported working approximately 70 h/week and a median of 195 operative cases per year. The anticipated retirement age for men was 64.6 ± 8.6 and for women was 62.2 ± 4.2 years. This is the largest study to date assessing professional and lifestyle characteristics of abdominal transplant surgeons.

Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia.

Clusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin directly influences cell death is lacking. Following neonatal H-I brain injury in mice (a model of cerebral palsy), there was evidence of apoptotic changes (neuronal caspase-3 activation), as well as accumulation of clusterin in dying neurons. Clusterin-deficient mice had 50% less brain injury following neonatal H-I. Surprisingly, the absence of clusterin had no effect on caspase-3 activation, and clusterin accumulation and caspase-3 activation did not colocalize to the same cells. Studies with cultured cortical neurons demonstrated that exogenous purified astrocyte-secreted clusterin exacerbated oxygen/glucose-deprivation-induced necrotic death. These results indicate that clusterin may be a new therapeutic target to modulate non-caspase-dependent neuronal death following acute brain injury.

Intestine transplantation in the United States, 1999-2008.

Improving short-term results with intestine transplantation have allowed more patients to benefit with nearly 700 patients alive in the United States with a functioning allograft at the end of 2007. This success has led to an increase in demand. Time to transplant and waiting list mortality have significantly improved over the decade, but mortality remains high, especially for infants and adults with concomitant liver failure. The approximately 200 intestines recovered annually from deceased donors represent less than 3% of donors who have at least one organ recovered. Consent practice varies widely by OPTN region. Opportunities for improving intestine recovery and utilization include improving consent rates and standardizing donor selection criteria. One-year patient and intestine graft survival is 89% and 79% for intestine-only recipients and 72% and 69% for liver-intestine recipients, respectively. By 10 years, patient and intestine survival falls to 46% and 29% for intestine-only recipients, and 42% and 39% for liver-intestine, respectively. Immunosuppression practice employs peri-operative antibody induction therapy in 60% of cases; acute rejection is reported in 30%-40% of recipients at one year. Data on long-term nutritional outcomes and morbidities are limited, while the cause and therapy for late graft loss from chronic rejection are areas of ongoing investigation.

What defines a transplant surgeon? A needs assessment for curricular development in transplant surgery fellowship training.

This study compares the perceptions of transplant surgery program directors (PDs) and recent fellowship graduates (RFs) regarding the adequacy of training and relevancy to practice of specific curricular content items in fellowship training. Surveys were sent to all American Society of Transplant Surgery approved fellowship PDs and all RFs in practice <5 years. For operative procedures, the RFs considered the overall training to be less adequate than the PDs (p = 0.0117), while both groups considered the procedures listed to be relevant to practice (p = 0.8281). Regarding nonoperative patient care items, although RFs tended to rank many individual items lower, both groups generally agreed that the training was both adequate and relevant. For nonpatient care related items (i.e. transplant-related ethics, economics, research, etc.), both groups scored them low regarding their adequacy of training although RFs scored them significantly lower than PDs (p = 0.0006). Regarding their relevance to practice, while both groups considered these items relevant, RFs generally considered them more relevant than PDs. Therefore, although there is consensus on many items, significant differences exist between PDs and RFs regarding their perceptions of the adequacy of training and the relevance to practice of specific curriculum items in transplant surgery fellowship training.

Perception versus reality?: Virtual crossmatch--how to overcome some of the technical and logistic limitations.

The goal of this work was to evaluate concordance between (a) actual flow cytometric crossmatch (FCXM) that is performed by the OPO laboratory servicing our transplant center and (b) virtual XM (vXM) prediction based on antibody identification by solid-phase methods performed in our laboratory. A total of 1586 FCXM, performed between June 2007 and September 2008, between all potential deceased donors in our region and sera from patients awaiting kidney or kidney-pancreas transplant, listed at Northwestern Memorial Hospital were evaluated. A key finding of this analysis was the understanding that a thorough vXM cannot be performed in some donor/recipient pairs due to the lack of certain antibody profile data specific to the donor in question. Obtaining more in depth and stringent information regarding antibody specificities, we demonstrate an excellent sensitivity and specificity of the vXM assays- 86.1% and 96.8%, respectively, with a positive likelihood ratio and negative likelihood ratios of 26.9 and 0.14, respectively. The vXM can serve as an outstanding tool to predict HLA compatibility between donor and recipient, with the caveat that the presence/absence of all antibodies against the potential donor and their strength have been thoroughly investigated.

Frequency of contamination of coagulation factor concentrates with novel human parvovirus PARV4.

Human parvovirus, PARV4 was identified in a plasma sample from a patient presenting with symptoms resembling acute HIV infection. Further strains of PARV4 and those of a closely related variant virus, were identified in plasma pools used in the manufacture of blood derivatives. DNA sequence analysis of these strains demonstrated two distinct PARV4 genotypes. It has subsequently been proposed that transmission of PARV4 occurs by parenteral routes. To investigate the risk of contamination of plasma-derived coagulation factor concentrates, we analysed 169 lots for PARV4 DNA by polymerase chain reaction. Positive samples were confirmed by nucleotide sequence analysis and quantification of the viral load. Twenty-one lots, representing eight different products were administered until the beginning of the 1980s and were not virally inactivated. Two lots examined were used in 1997, and 146 lots representing 13 products had been administered between October 2000 and February 2003. PARV4 DNA was detected in 7(33%) of the formerly administered lots, in one lot used in 1997, and in 13(9%) recently used lots. PARV4 genotype 2 DNA was predominantly present in the older concentrates, whilst genotype 1 was found more frequently in recently used lots. In three lots, both PARV4 genotypes were detected. Viral loads ranged between <100 and 10(5.8) copies mL(-1) of product, with higher viral loads in the older concentrates. The results show that PARV4 contamination can be detected in an appreciable proportion of clotting factor concentrates. Further studies are needed to determine whether or not PARV4 contamination of coagulation factors causes harm to the product recipients.

Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice.

Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiota ß-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host.

Calcium supplementation for improving bone mineral density in children.

BACKGROUND: Clinical trials have shown that calcium supplementation in children can increase bone mineral density (BMD) although this effect may not be maintained. There has been no quantitative systematic review of this intervention. OBJECTIVES: . To determine the effectiveness of calcium supplementation for improving BMD in children. . To determine if any effect varies by sex, pubertal stage, ethnicity or level of physical activity, and if any effect persists after supplementation is ceased. SEARCH STRATEGY: We searched CENTRAL, (Cochrane Central Register of Controlled Trials) (Issue 3, 2005), MEDLINE (1966 to 1 April 2005), EMBASE (1980 to 1 April 2005), CINAHL (1982 to 1 April 2005), AMED (1985 to 1 April 2005), MANTIS (1880 to 1 April 2005) ISI Web of Science (1945 to 1 April 2005), Food Science and Technology Abstracts (1969 to 1 April 2005) and Human Nutrition (1982 to 1 April 2005). Conference abstract books (Osteoporosis International, Journal of Bone and Mineral Research) were hand-searched. SELECTION CRITERIA: Randomised controlled trials of calcium supplementation (including by food sources) compared with placebo, with a treatment period of at least 3 months in children without co-existent medical conditions affecting bone metabolism. Outcomes had to include areal or volumetric BMD, bone mineral content (BMC), or in the case of studies using quantitative ultrasound, broadband ultrasound attenuation and ultrasonic speed of sound, measured after at least 6 months of follow-up. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data including adverse events. We contacted study authors for additional information. MAIN RESULTS: The 19 trials included 2859 participants, of which 1367 were randomised to supplementation and 1426 to placebo. There was no heterogeneity in the results of the main effects analyses to suggest that the studies were not comparable. There was no effect of calcium supplementation on femoral neck or lumbar spine BMD. There was a small effect on total body BMC (standardised mean difference (SMD) +0.14, 95% CI+0.01, +0.27) and upper limb BMD (SMD +0.14, 95%CI +0.04, +0.24). Only the effect in the upper limb persisted after supplementation ceased (SMD+0.14, 95%CI+0.01, +0.28). This effect is approximately equivalent to a 1.7% greater increase in supplemented groups, which at best would reduce absolute fracture risk in children by 0.1-0.2%per annum. There was no evidence of effect modification by baseline calcium intake, sex, ethnicity, physical activity or pubertal stage. Adverse events were reported infrequently and were minor. AUTHORS' CONCLUSIONS: While there is a small effect of calcium supplementation in the upper limb, the increase in BMD which results is unlikely to result in a clinically significant decrease in fracture risk. The results do not support the use of calcium supplementation in healthy children as a public health intervention. These results cannot be extrapolated to children with medical conditions affecting bone metabolism.

A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study.

One hundred seventy-nine patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to compare two schedules of delivery for single-agent fluorouracil (5-FU). The "standard" treatment was a schedule commonly employed in clinical practice, namely, a daily bolus dose administered intravenously (IV) for five consecutive days and repeated at 5-week intervals. The investigational treatment was a continuous infusion of 5-FU administered 24 hours a day for a protracted time (10 weeks or more). Both treatments were continued until the development of disease progression or unless interrupted for toxicity. Using stringent objective criteria requiring independent confirmation of x-ray or scan-documented response, the tumor response rate reached 7% (six of 87) for the bolus arm and 30% (26 of 87) for the infusion arms (P less than .001). Toxicity was substantially different for the two arms with major leukopenia observed only on the bolus arm, 22% developing grade 3 (severe) or grade 4 (life-threatening) leukopenia with four sepsis-related deaths. Hand-foot syndrome was observed only in the infusional arm, requiring treatment interruptions and dose reductions in 24% of patients, but with little impact on quality of life. In spite of the major difference in objective response rate, overall survival for the two groups was comparable. Administration of 5-FU as a continuous infusion for protracted periods clearly improves the therapeutic index for this agent in patients with advanced colon cancer with respect to response rate and reduced toxicity. This schedule appears workable in the community setting and yields response rates similar to those reported for 5-FU with high-dose leucovorin, but without the gastroin testinal toxicity profile of the latter combination.

Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program study.

An alternating regimen for the treatment of extensive-disease small-cell lung cancer (SCLC) was compared with standard treatment with cyclophosphamide, doxorubicin, and vincristine (CAV) in 170 patients. Overall severity of toxicity was similar in both arms, with four toxic deaths in each arm (4.7%). Response results were also similar, with 54% complete and partial responses with the standard regimen and 53% complete and partial responses with the alternating regimen. Median survival time was 6.9 months with the standard regimen and 9.2 months with the alternating regimen (P = .078). The 2-year survival rate was 1.2% for the standard regimen and 4.7% for the alternating regimen. Survival benefit for treatment with the alternating regimen reached statistical significance only in those subsets of patients with poorer prognosis (male sex, performance status 3, liver metastases, bone marrow metastases, and oat cell histologic subtype).

A study of infusional cisplatin and infusional fluorouracil for locally advanced or metastatic non-small-cell lung cancer: a Mid-Atlantic Oncology Program study.

A combination of cisplatin administered as a 24-hour infusion and fluorouracil administered as a 5-day infusion was used to treat 97 patients with non-small-cell lung (NSCLC) cancer in a phase II trial. Thirty patients had stage IIIB disease; 67 patients, stage IV disease (new international classification). Patients with stage IIIB disease also received thoracic radiation after chemotherapy. The regimen was well tolerated, with 24% or less grade 3 or greater toxicities of all types. One toxic death was attributed to fluid overload. The response rate, partial and complete, was 43% (95% confidence interval, 27% to 63%), and median survival was 13.8 months for patients with stage IIIB disease. Response rates refer to the chemotherapy response. For patients with stage IV disease, the response rate was 34% (95% confidence interval, 24% to 47%), and median survival was 6.2 months. On this regimen, stable-disease patients with stage IV disease had survivals at least equal to responders.

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.

PURPOSE: The administration of fluorouracil (5-FU) by continuous intravenous infusion (CI) is an alternative to the bolus administration of 5-FU in patients with advanced colorectal cancer. Although more than 1,200 patients have been enrolled onto randomized trials that compared these two treatment modalities, there is still no definitive evidence of an advantage of 5-FU CI, and the magnitude of this advantage, if any, is also controversial. A meta-analysis was performed to assess this benefit in terms of tumor response and survival, and to compare the toxicity profiles of these two modalities of administration of 5-FU. DESIGN: Individual data of 1,219 patients included in six randomized trials served as the basis for this meta-analysis, which was conducted by an independent secretariat in close collaboration with the investigators. RESULTS: Tumor response rate was significantly higher in patients assigned to 5-FU CI than in patients assigned to 5-FU bolus (22% v 14%; overall response odds ratio, 0.55; 95% confidence interval [95% CI], 0.41 to 0.75; P = .0002). Overall survival was also significantly higher in patients assigned to 5-FU CI (overall hazards ratio [HR], 0.88; 95% CI, 0.78 to 0.99; P = .04), although the median survival times were close. Multivariate analyses showed that randomized treatment and performance status were the only two significant predictors of tumor response, whereas the same plus primary tumor site were independent significant predictors of survival (patients with rectal cancer did somewhat better). Grade 3 or 4 hematologic toxicity was more frequent in patients assigned to 5-FU bolus (31% v 4%; P < 10(-16)), whereas hand-foot syndrome was more frequent in the 5-FU CI group (34% v 13%; P < 10(-7)). CONCLUSION: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival. The hematologic toxicity is much less important in patients who receive 5-FU CI, but hand-foot syndrome is frequent in this group of patients.

Immunocytochemical localization of granulin-1 to mononuclear phagocytic cells of the teleost fish Cyprinus carpio and Carassius auratus.

A new class of low-molecular-weight cysteine-rich regulatory growth factors, designated granulins, has been isolated from hematopoietic tissues of a teleost fish (Cyprinus carpio) and structurally characterized. Granulin-1, the predominant form found in carp spleen, was used to raise polyclonal antibodies in rabbits and to establish a radioimmunoassay. This permitted preliminary tissue distribution studies of granulin-1 to be undertaken in carp (Cyprinus carpio) and goldfish (Carassius auratus). Granulin-1 immunoreactivity was found in the melanomacrophage centers of the spleen and head kidney. Carp tissues anatomically involved in the first line of defense against infection, including skin, gills, gut, and also heart, showed intense granulin-1 immunoreactive staining within presumptive macrophage cells. Granulin-1 immunoreactive macrophages prepared from goldfish spleen and head kidney adhered to glass slides, actively phagocytosed carbon particles, and contained granulin-1 immunoreactivity as well as abundant endogenous peroxidase activity. This study demonstrates that granulin-1 is synthesized and stored in macrophages/monocytes of spleen, head kidney, and peripheral tissues of teleost fish.

Renal Transplantation in the Setting of Prior Urinary Diversion: A Case of Poorly Differentiated Adenocarcinoma in an Ileal Conduit.

Though rare, renal transplantation into a bowel containing urinary diversion is necessary in select clinical situations. Compared to renal transplant patients with functional native bladders, patients with urinary diversion have comparable long-term graft and patient survival rates. However, compounding the increased risk of malignancy in those on chronic immunosuppression are the inherent risks of urinary diversion. We present a case report of a high grade adenocarcinoma with neuroendocrine differentiation arising in an ileal conduit and discussion on the pathophysiology, management, and screening of this highly select population.