Citations

SummaryBackgroundUlcerative colitis (UC) and Crohn's disease can sometimes relapse and be refractory to standard treatment following orthotopic liver transplantation (OLT) despite post‐transplantation immunosuppressive therapy.AimTo evaluate the efficacy and safety of anti‐tumour necrosis factor (anti‐TNF) agents for the management of IBD following OLT.MethodsWe reviewed the records of patients with a diagnosis of IBD who underwent OLT at Mayo Clinic Rochester between 1985 and 2009. Patients were included if they had received anti‐TNF therapy post‐OLT. Clinical response was defined as a physician's assessment of improvement after 12 weeks of anti‐TNF usage, and mucosal healing was defined as the absence of ulcerations on follow‐up endoscopy.ResultsThe median age of the eight study patients was 42.0 years and 37.5% were female patients. All had been diagnosed with IBD prior to OLT (UC in three and Crohn's disease in five). Indication for OLT was cirrhotic stage primary sclerosing cholangitis (PSC), and three concomitantly had cholangiocarcinoma. Clinical response was demonstrated in seven of eight patients (87.5%) and mucosal healing was demonstrated in three of seven (42.9%). Four infections (oral candidiasis, Clostridium difficile colitis, bacterial pneumonia and cryptosporidiosis) in three patients were reported. One patient developed an Epstein–Barr virus‐positive post‐transplant lympho‐proliferative disorder. One death occurred due to complications from recurrent PSC.ConclusionsStarting Anti‐TNF therapy following orthotopic liver transplantation appears to be a potential option for inflammatory bowel disease management. Additional studies are needed, however, to confirm these findings and to further assess risks associated with this treatment strategy.

Rationale: Among the extracellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp endothelial cell precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and–sink mechanism. Objective: To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper's differential effects on Bmp4 signaling. Methods and Results: Using an array of biochemical and cell biology techniques, we report that LRP1 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures. Conclusions: Together, these data reveal a novel role for LRP1 in the regulation of Bmp4 signaling by regulating receptor complex endocytosis. In addition, these data introduce LRP1 as a critical regulator of vascular development. These observations demonstrate Bmper's ability to fine-tune Bmp4 signaling at the single-cell level, unlike the spatial regulatory mechanisms applied by other Bmp modulators.

Context.— Original surgical pathology materials from external sources are reviewed by our pathologists for referred patients before their clinical evaluation and treatment. Objective.— To identify the rate of major disagreements with diagnoses from external institutions and to characterize the nature and impact of discordant diagnoses on patient care. Design.— We identified and reviewed all surgical pathology cases, except for medical liver, medical renal, and cardiac pathology cases, for the period between January 1, 2005, and December 31, 2010, to determine the overall frequency of major disagreements, defined as any change in diagnosis having a substantial impact on patient management. Results.— Our review of 71 811 cases initially examined between 2005 and 2010 identified 457 major disagreements (0.6%). The most frequent areas of disagreement were gastrointestinal (80 cases; 17.5%), lymph node (73; 16.0%), bone/soft tissue (47; 10.3%), and genitourinary (43; 9.4%). For a subset of 166 cases reviewed between July 1, 2009, and December 31, 2010, follow-up data were available for 140 (84.3%). Treatment was affected by a changed diagnosis in 126 cases (90.0%), and prognosis was affected in 129 cases (92.1%). For 86 (51.8%) of the 166 cases, additional tissue was obtained. Revised diagnoses concurred with follow-up tissue diagnosis in 84.9% (73 cases), whereas they differed from follow-up tissue diagnosis in 15.1% (13 cases). Conclusions.— Our findings demonstrate the value of outside case review of pathology materials for referred patients, and suggest that it decreases the likelihood of diagnostic errors and provides better protection for patients.

The 15q13.3 microdeletion syndrome (OMIM #612001) is characterized by a wide range of phenotypic features, including intellectual disability, seizures, autism, and psychiatric conditions. This deletion is inherited in approximately 75% of cases and has been found in mildly affected and normal parents, consistent with variable expressivity and incomplete penetrance. The common deletion is approximately 2 Mb and contains several genes; however, the gene(s) responsible for the resulting clinical features have not been clearly defined. Recently, four probands were reported with small deletions including only the CHRNA7 gene. These patients showed a wide range of phenotypic features similar to those associated with the larger 15q13.3 microdeletion. To further correlate genotype and phenotype, we queried our database of >15,000 patients tested in the Mayo Clinic Cytogenetics Laboratory from 2008 to 2011 and identified 19 individuals (10 probands and 9 family members) with isolated heterozygous CHRNA7 gene deletions. All but two infants displayed multiple features consistent with 15q13.3 microdeletion syndrome. We also identified the first de novo deletion confined to CHRNA7 as well as the second known case with homozygous deletion of CHRNA7 only. These results provide further evidence implicating CHRNA7 as the gene responsible for the clinical findings associated with 15q13.3 microdeletion.

As the rate of obesity increases in childbearing-aged women, so too will the complications of obesity in pregnancy. An uncommon and likely underreported complication occurs in obese women who have received prepregnancy cardiac valve replacement with a prosthesis that is inadequately sized for body habitus, a condition referred to as patient-prosthesis mismatch (PPM). The physiologic changes of pregnancy as well as the increased weight gain combine to exacerbate PPM. We report a case of PPM that necessitated prosthesis replacement at 16-week gestation. As the incidence of this clinical scenario increases, it is important to understand the implications of prosthesis sizing, as well as the repercussions of having cardiopulmonary surgery to correct the undersized valve prosthesis while pregnant.

Abstract Blood–brain barrier (BBB) disruption is a common feature of numerous neurologic disorders. A fundamental question in these diseases is the extent inflammatory immune cells contribute to CNS vascular permeability. We have previously shown that CD8 T cells play a critical role in initiating BBB disruption in the peptide-induced fatal syndrome model developed by our laboratory. However, myelomonocytic cells such as neutrophils have also been implicated in promoting CNS vascular permeability and functional deficit in murine models of neuroinflammatory disease. For this reason, we evaluated neutrophil depletion in a murine model of CD8 T cell-initiated BBB disruption by employing traditionally used anti-granulocyte receptor-1 mAb RB6-8C5 and Ly-6G–specific mAb 1A8. We report that CNS-infiltrating antiviral CD8 T cells express high levels of granulocyte receptor-1 protein and are depleted by treatment with RB6-8C5. Mice treated with RB6-8C5, but not 1A8, display: 1) intact BBB tight junction proteins; 2) reduced CNS vascular permeability visible by gadolinium-enhanced T1-weighted magnetic resonance imaging; and 3) preservation of motor function. These studies demonstrate that traditional methods of neutrophil depletion with RB6-8C5 are broadly immune ablating. Our data also provide evidence that CD8 T cells initiate disruption of BBB tight junction proteins and CNS vascular permeability in the absence of neutrophil support.