Tacrolimus-associated Diffuse Gastrointestinal Ulcerations and Pathergy: A Case Report

Tacrolimus is a common immunosuppressive modality with a range of therapeutic applications, including for rheumatologic disease, nephrotic syndrome, and inflammatory bowel disease. The medication also plays an integral role in organ transplantation. However, tacrolimus has a significant side effect profile, which commonly includes nephrotoxicity, neurotoxicity, infection risk, and anemia. We describe an unusual case of tacrolimus toxicity in a cardiac transplant patient, manifesting as diffuse gastrointestinal ulcerations and pathergy. Our goal was to further characterize the toxicity of tacrolimus to include this rare presentation.     

Heterotopic gastric mucosa (inlet patch) in a patient with laryngopharyngeal reflux (LPR) and laryngeal carcinoma: a case report and review of literature

The inlet patch is an area of heterotopic gastric mucosa most commonly located in the postcricoid portion of the esophagus at, or just below, the level of the upper esophageal sphincter. Esophageal and supraesophageal symptoms are commonly associated with inlet patch, while esophageal adenocarcinoma rarely complicates it. Laryngeal adenocarcinoma associated with inlet patch is not described in the literature. Herein, we present the first reported case of inlet patch associated with laryngeal carcinoma. A 33-year-old female with long-standing asthma and presumed gastroesophageal reflux developed laryngeal cancer at age 22 years that was treated with concomitant radiation and induction chemotherapy. Subsequently, she had refractory heartburn, dysphagia, and cough. These symptoms continued despite two Nissen fundoplications, glottic web division, and optimal medical management. Upper endoscopy at our institution revealed an upper esophageal stricture and a 1 cm inlet patch. Biopsies showed columnar mucosa (predominantly gastric cardiac/fundic type) consistent with inlet patch, with focal intestinal metaplasia. Subsequent endoscopic mucosal resection of the inlet patch resulted in an amelioration of throat and chest pain, cough, and hoarseness. Dysphagia and regurgitation were improved by serial dilatations of the upper esophageal stricture. This case reveals a number of clinical findings associated with inlet patch – chest pain, dysphagia, cough, and hoarseness – as well as a clinical finding that has not been previously associated with inlet patch: laryngeal cancer. Symptoms refractory to optimal medical management and/or surgical intervention should make the clinician and endoscopist more cognizant of the inlet patch.     

Hypoxia alters the expression of inhibitor of apoptosis proteins after brain trauma in the mouse

Hypoxia worsens brain injury following trauma, but the mechanisms remain unclear. The purpose of this study was to determine the effect of traumatic brain injury (TBI) and secondary hypoxia (9% oxygen) on apoptosis-related protein expression, cell death, and behavior. Using a murine weight-drop model, TBI led to an early (6 h) increase followed by a later (24 h) decrease in neuronal apoptosis inhibitor protein (NAIP) expression in the olfactory and motor cortex; in contrast, TBI led to a sustained (6 h to 7 days) increase in NAIP in the striatum. The peak increase in the expression of NAIP (6-12 h) following TBI alone was delayed (1-7 days) when hypoxia was added to TBI. Hypoxia following TBI further depleted other apoptosis inhibitor proteins (IAPs) and activated caspases, as well as increased contusion size and worsened cell death. Hypoxia added to TBI also increased motor and feeding activity on days 2 and 4 compared to TBI alone. Hypoxia without TBI had no effect on the expression of IAPs or cell death. These findings show that IAPs have a potential role in the increased vulnerability of brain cells to hypoxia following TBI, and have implications for configuring future therapies for TBI.     

Peer-mediated social skills training program for young children with high-functioning autism

One of the most prevailing characteristics of children with autism is their deficit in social communication skills. The purpose of this study was to evaluate the effectiveness of a peer-mediated social skills training (SST) program combined with video feedback, positive reinforcement and token system in increasing social communication skills in young children with high-functioning autism. Four boys with high-functioning autism, ages 6-7 years, participated in the study. The social skills training, lasting 12 weeks, targeted six communication skills, selected after parent interviews and behavioral observation during a pre-training assessment period. One SST session was conducted each week, each session lasted 90min and had six structured activities. The training effectiveness was evaluated through direct observation of a structured interaction period, using an observational coding system. Improvement was observed in three out of four children, although individual differences among children were seen for changes in two global scales as well as subscales. These results suggest that the social skills training was effective in improving social communication skills for some children with high-functioning autism. Clinical and research implications and future directions for social skills training as well as this study's limitations are discussed.     

Evidence for the Use of Intravenous Immunoglobulins—A Review of the Literature

Intravenous immunoglobulins (IVIg) were first introduced in the middle of the twentieth century for the treatment of primary immunodeficiencies. In 1981, Paul Imbach noticed an improvement of immune-mediated thrombocytopenia, in patients receiving IVIg for immunodeficiencies. This opened a new era for the treatment of autoimmune conditions with IVIg. Since then, IVIg has become an important treatment option in a wide spectrum of diseases, including autoimmune and acute inflammatory conditions, most of them off-label (not included in the US Food and Drug Administration recommendation). A panel of immunologists and internists with experience in IVIg therapy reviewed the medical literature for published data concerning treatment with IVIg. The quality of evidence was assessed, and a summary of the available relevant literature in each disease was given. To our knowledge, this is the first all-inclusive comprehensive review, developed to assist the clinician when considering the use of IVIg in autoimmune diseases, immune deficiencies, and other conditions.     

Redefining the role of lymphocytes in gastroesophageal reflux disease and eosinophilic esophagitis

Eosinophilic esophagitis (EoE) and reflux esophagitis (RE) overlap clinically and histologically. RE is characterized by epithelial infiltration with small numbers of neutrophils and eosinophils, EoE by a prominent eosinophilic infiltrate. Lymphocytic esophagitis (LE), a new entity characterized by peripapillary lymphocytosis, questions the role lymphocytes play in esophageal inflammation. We test the hypothesis that lymphocyte infiltration in RE differs from EoE. One blinded pathologist read esophageal biopsies from 39 RE and 39 EoE patients. Both groups demonstrated significant numbers of lymphocytes (RE 22.7 ± 2.2/HPF, EoE 19.8 ± 1.8/HPF). Eosinophils/HPF in RE and EoE were 2.8 ± 0.7 and 74.9 ± 8.2, respectively (P < 0.001). Neutrophils were uncommon in RE (0.26 ± 0.16/HPF) and EoE (0.09 ± 0.04; P = 0.07). Eight of the 39 RE specimens had ≥50 lymphocytes in ≥1 HPF. Two were consistent with LE. There was an inverse correlation between numbers of eosinophils and lymphocytes in EoE (R = ?0.47; P = 0.002), and no correlation between them in RE (R = 0.18; P = 0.36). The patients with EoE who used antireflux medications had fewer lymphocytes (16.3 ± 1.3 vs 22.2 ± 2.3/HPF; P = 0.030) and eosinophils (55.6 ± 5.2 vs 76.0 ± 8.7/HPF; P = 0.042) than those who did not. The pathological role of lymphocytes in RE and EoE may be underestimated. Our observation that 5% of the RE specimens meet histopathological criteria for LE potentially blurs the line between these entities. The observation that eosinophil counts are lower in EoE when antireflux meds are used supports the notion that reflux plays a role in the clinical expression of EoE.     

Analysis of varicella zoster virus attenuation by evaluation of chimeric parent Oka/vaccine Oka recombinant viruses in skin xenografts in the SCIDhu mouse model

Varicella-zoster virus (VZV) is the only human herpes virus for which a vaccine has been licensed. A clinical VZV isolate, designated the parent Oka (pOka) strain was passed in human and non-human fibroblasts to produce vaccine Oka (vOka). The pOka and vOka viruses exhibit similar infectivity in cultured cells but healthy susceptible individuals given vaccines derived from vOka rarely develop the cutaneous vesicular lesions characteristic of varicella. Inoculation of skin xenografts in the SCIDhu mouse model of VZV pathogenesis demonstrated that vOka had a reduced capacity to replicate in differentiated human epidermal cells in vivo (Moffat, J.F., Zerboni, L., Kinchington, P.R., Grose, C., Kaneshima, H., Arvin A.M., 1998a. Attenuation of the vaccine Oka strain of varicella-zoster virus and role of glycoprotein C in alphaherpesvirus virulence demonstrated in the SCID-hu mouse. J Virol. 72:965-74). In order to investigate the attenuation of vOka in skin, we made chimeric pOka and vOka recombinant viruses from VZV cosmids. Six chimeric pOka/vOka viruses were generated using cosmid sets that incorporate linear overlapping fragments of VZV DNA from cells infected with pOka or vOka. The cosmid sets consist of pOka and vOka DNA segments that have identical restriction sites. As expected, the growth kinetics and plaque morphologies of the six chimeric pOka/vOka viruses were indistinguishable in vitro. However, the chimeric viruses exhibited varying capacities to replicate when evaluated in skin xenografts in vivo. The presence of ORFs 30-55 from the pOka genome was sufficient to maintain wild-type infectivity in skin. Chimeric viruses containing different vOka components retained the attenuation phenotype, suggesting that vOka attenuation is multi-factorial and can be produced by genes from different regions of the vOka genome.     

Marginal zone lymphoma

Marginal zone lymphomas (MZLs) comprise 3 distinct entities: extranodal MZL of mucosa-associated lymphoid tissue (MALT), splenic MZL, and nodal MZL. Gastric MALT lymphoma is the most common extranodal MZL and often develops as a result of chronic Helicobacter pylori gastritis. Such cases frequently respond to antibiotics directed against H. pylori. Antigen-driven lymphomatous disease can also be seen in the association of Borrelia burgdorferi with MALT lymphoma of the skin, Chlamydia psittaci with MALT lymphoma of the ocular adnexa, Campylobacter jejuni with immunoproliferative disease of the small intestine, and hepatitis C with splenic MZL. This article discusses the pathogenesis and clinical features of MZL and the treatment options available to patients.