Epithelial Cdc42 Deletion Induced Enamel Organ Defects and Cystogenesis.

Cdc42, a Rho family small GTPase, regulates cytoskeleton organization, vesicle trafficking, and other cellular processes in development and homeostasis. However, Cdc42's roles in prenatal tooth development remain elusive. Here, we investigated Cdc42 functions in mouse enamel organ. Cdc42 showed highly dynamic temporospatial patterns in the developing enamel organ, with robust expression in the outer enamel epithelium, stellate reticulum (SR), and stratum intermedium layers. Strikingly, epithelium-specific Cdc42 deletion resulted in cystic lesions in the enamel organ. Cystic lesions were first noted at embryonic day 15.5 and progressively enlarged during gestation. At birth, cystic lesions occupied the bulk of the entire enamel organ, with intracystic erythrocyte accumulation. Ameloblast differentiation was retarded upon epithelial Cdc42 deletion. Apoptosis occurred in the Cdc42 mutant enamel organ prior to and synchronously with cystogenesis. Transmission electron microscopy examination showed disrupted actin assemblies, aberrant desmosomes, and significantly fewer cell junctions in the SR cells of Cdc42 mutants than littermate controls. Autophagosomes were present in the SR cells of Cdc42 mutants relative to the virtual absence of autophagosome in the SR cells of littermate controls. Epithelium-specific Cdc42 deletion attenuated Wnt/ß-catenin and Shh signaling in dental epithelium and induced aberrant Sox2 expression in the secondary enamel knot. These findings suggest that excessive cell death and disrupted cell-cell connections may be among multiple factors responsible for the observed cystic lesions in Cdc42 mutant enamel organs. Taken together, Cdc42 exerts multidimensional and pivotal roles in enamel organ development and is particularly required for cell survival and tooth morphogenesis.

Medical management of pneumatosis intestinalis in patients undergoing allogeneic blood and marrow transplantation.

Pneumatosis intestinalis (PI) occurs when gastrointestinal (GI) wall disruption, increased wall permeability or necrosis leads to wall infiltration by gas. It is associated with a spectrum of causal factors, including GI disease in allogeneic blood and marrow transplant patients. Traditionally, PI has been managed surgically with high morbidity and mortality. We describe our experience managing allogeneic blood and marrow transplant patients with PI. From January 1998 to May 2008, 320 patients underwent allogeneic blood and marrow transplant of whom 10 were identified with PI. PI diagnosis was established by computed tomography scan (n=7), plain film (n=2) or colonoscopy (n=1). A total of 9 of 10 patients had ongoing GI GvHD or received recent treatment for GI GvHD. Before April 2002, two patients underwent subtotal colectomy with ileostomy (n=1) and sigmoid colectomy with colostomy (n=1). One patient was managed with bowel rest and total parental nutrition (TPN) only. These three patients died 0.4, 1.1 and 3.9 years after PI diagnosis owing to GI GvHD (n=2) and surgical complications (n=1). Seven patients, diagnosed after September 2006, were treated with GI rest, TPN and antibiotics. PI treated with GI rest, TPN and antibiotics will resolve without surgical intervention. AlloBMT-associated PI is often a non-critical finding that does not represent true GI tract ischemia and/or GI tract perforation.