Unusual Presentation of Gastric Outlet Obstruction Due to Breast Cancer Metastasis: A Case Report.

Gastric outlet obstruction can be caused by various pathologies, including peptic ulcer disease, gastric polyps, and malignancies. The incidence rate of breast cancer metastasis to the stomach is only 0.3%. We describe a rare case of an 83-year-old female with a remote history of breast cancer who presented with symptoms of nausea and vomiting. She underwent an upper endoscopy, and biopsies revealed chronic gastritis. However, when she presented for the second time with similar symptoms, she underwent endoscopic ultrasound (EUS)-guided biopsies, which clinched the diagnosis of breast cancer metastasis causing gastric outlet obstruction. This case describes the importance of keeping a wide differential diagnosis for the causes of gastric outlet obstruction and the significance of deeper EUS-guided biopsies if initial endoscopic biopsies are inconclusive.

Early Onset Post-transplant Lymphoproliferative Disorder Presenting with Diarrhea Post-orthotopic Liver Transplant Treated Successfully with Single Rituximab Agent.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication seen in hematologic stem cell (HSC) and solid organ transplantation that results from immune suppressant medications needed to prevent allograft rejection. Epstein-Barr virus (EBV) has been implicated in a majority of these cases, specifically with B-cell-predominant lymphomas. We present a 57-year-old female who underwent an orthotopic liver transplant and presented with diarrhea and weight loss. At the time of transplantation, the patient's quantitative EBV titers were negative; however, repeat titers during her admission were positive. Infectious etiologies for diarrhea were negative so a colonoscopy was pursued which revealed large ulcerated areas and biopsies consistent with monomorphic, diffuse large B-cell lymphoma, plus EBV. Imaging revealed multiple areas below the diaphragm of lymphadenopathy. The patient was started on rituximab and antivirals, and immune suppressive medications were decreased with a resolution of her symptoms. PTLD after any transplantation can be difficult to diagnose, given the wide range of presenting symptoms. Identifying patients who are at high risk for developing PTLD may lead to a more timely diagnosis to initiate treatment and decrease mortality risk.

A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems.

A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.

ßA3/A1-crystallin is required for proper astrocyte template formation and vascular remodeling in the retina.

Nuc1 is a spontaneous rat mutant resulting from a mutation in the Cryba1 gene, coding for ßA3/A1-crystallin. Our earlier studies with Nuc1 provided novel evidence that astrocytes, which express ßA3/A1-crystallin, have a pivotal role in retinal remodeling. The role of astrocytes in the retina is only beginning to be explored. One of the limitations in the field is the lack of appropriate animal models to better investigate the function of astrocytes in retinal health and disease. We have now established transgenic mice that overexpress the Nuc1 mutant form of Cryba1, specifically in astrocytes. Astrocytes in wild type mice show normal compact stellate structure, producing a honeycomb-like network. In contrast, in transgenics over-expressing the mutant (Nuc1) Cryba1 in astrocytes, bundle-like structures with abnormal patterns and morphology were observed. In the nerve fiber layer of the transgenic mice, an additional layer of astrocytes adjacent to the vitreous is evident. This abnormal organization of astrocytes affects both the superficial and deep retinal vascular density and remodeling. Fluorescein angiography showed increased venous dilation and tortuosity of branches in the transgenic retina, as compared to wild type. Moreover, there appear to be fewer interactions between astrocytes and endothelial cells in the transgenic retina than in normal mouse retina. Further, astrocytes overexpressing the mutant ßA3/A1-crystallin migrate into the vitreous, and ensheath the hyaloid artery, in a manner similar to that seen in the Nuc1 rat. Together, these data demonstrate that developmental abnormalities of astrocytes can affect the normal remodeling process of both fetal and retinal vessels of the eye and that ßA3/A1-crystallin is essential for normal astrocyte function in the retina.

A developmental defect in astrocytes inhibits programmed regression of the hyaloid vasculature in the mammalian eye.

Previously we reported the novel observation that astrocytes ensheath the persistent hyaloid artery, both in the Nuc1 spontaneous mutant rat, and in human PFV (persistent fetal vasculature) disease (Developmental Dynamics 234:36-47, 2005). We now show that astrocytes isolated from both the optic nerve and retina of Nuc1 rats migrate faster than wild type astrocytes. Aquaporin 4 (AQP4), the major water channel in astrocytes, has been shown to be important in astrocyte migration. We demonstrate that AQP4 expression is elevated in the astrocytes in PFV conditions, and we hypothesize that this causes the cells to migrate abnormally into the vitreous where they ensheath the hyaloid artery. This abnormal association of astrocytes with the hyaloid artery may impede the normal macrophage-mediated remodeling and regression of the hyaloid system.