Rafal Kozielski

Effect of Dietary Advanced Glycation End Products on Mouse Liver

The exact pathophysiology of non-alcoholic steatohepatitis (NASH) is not known. Previous studies suggest that dietary advanced glycation end products (AGEs) can cause oxidative stress in liver. We aim to study the effects of dietary AGEs on liver health and their possible role in the pathogenesis of NASH. METHODS: Two groups of mice were fed the same diet except the AGE content varied. One group was fed a high AGE diet and the second group was fed a regular AGE diet. Liver histology, alanine aminotransferase, aspartate aminotransferase, fasting glucose, fasting insulin, insulin resistance and glucose tolerance were assessed. RESULTS: Histology revealed that neutrophil infiltration occurred in the livers of the high AGE group at week 26; steatosis did not accompany liver inflammation. At week 39 livers from both groups exhibited macro- or micro-steatosis, yet no inflammation was detected. Higher insulin levels were detected in the regular AGE group at week 26 (P = 0.034), compared to the high AGE group. At week 39, the regular AGE group showed higher levels of alanine aminotransferase (P<0.01) and aspartate aminotransferase (P = 0.02) than those of the high AGE group. CONCLUSIONS: We demonstrate that a high AGE diet can cause liver inflammation in the absence of steatosis. Our results show that dietary AGEs could play a role in initiating liver inflammation contributing to the disease progression of NASH. Our observation that the inflammation caused by high AGE alone did not persist suggests interesting future directions to investigate how AGEs contribute to pro-oxidative and anti-oxidative pathways in the liver.

Presenting Pattern of Pediatric Celiac Disease.

Objectives: Celiac disease (CD) is an autoimmune disease that can be complicated by impaired nutrition and growth. With the development of sensitive serologic tests, safe endoscopy, and efforts to educate primary care physicians, more children are diagnosed as having CD. The aim of this study is to evaluate the pattern of the presentation of pediatric CD in western New York. Methods: Chart review of pediatric patients with CD was undertaken. Patients’ demographics, presenting features, disaccharidase assay (DA), celiac serology, and Marsh score were reviewed from patients seen at the Digestive Diseases and Nutrition Center, State University of New York at Buffalo from January 2003 through March 2013. Results: A total of 165 patients with CD were evaluated. Mean age was 10.7 ± 4.3 years, 76 male patients. The presenting features were abdominal pain (n = 87, 52.7%), constipation (n = 65, 38.9%), diarrhea (n = 52, 31.1%), family history of first-degree relative (n = 47, 28.1%), diabetes mellitus type 1 (n = 37, 22.2%), failure to thrive (n = 36, 21.8%), reflux (n = 25, 15.1%), vomiting (n = 24, 14.5%), fatigue (n = 15, 9%), short stature (n = 9, 5.4%), thyroid disease (n = 9, 5.4%), Down syndrome (n = 8, 4.8%). We found no correlation between Marsh score and serum tissue transglutaminase (tTG) immunoglobulin (Ig) A level at diagnosis and no correlation between DA and serum tTG IgA level, presenting feature and tTG IgA level, presenting feature and Marsh score, tTG IgA and DA, or between the age and the presenting feature. Conclusions: Children newly diagnosed as having CD in western New York presented most frequently with abdominal pain and constipation and were older at the time of diagnosis than those described in the classical presentation of CD. We speculate that our patients may have a different long-term natural history and risk factors than originally described for patients with CD.

Induction of CYP2E1 in non-alcoholic fatty liver diseases.

Mounting evidence supports a contribution of endogenous alcohol metabolism in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is not known whether the expression of alcohol metabolism genes is altered in the livers of simple steatosis. There is also a current debate on whether fatty acids induce CYP2E1 in fatty livers. In this study, expression of alcohol metabolizing genes in the liver biopsies of simple steatosis patients was examined by quantitative real-time PCR (qRT-PCR), in comparison to biopsies of NASH livers and normal controls. Induction of alcohol metabolizing genes was also examined in cultured HepG2 cells treated with ethanol or oleic acid, by qRT-PCR and Western blots. We found that the mRNA expression of alcohol metabolizing genes including ADH1C, ADH4, ADH6, catalase and CYP2E1 was elevated in the livers of simple steatosis, to similar levels found in NASH livers. In cultured HepG2 cells, ethanol induced the expression of CYP2E1 mRNA and protein, but not ADH4 or ADH6; oleic acid did not induce any of these genes. These results suggest that elevated alcohol metabolism may contribute to the pathogenesis of NAFLD at the stage of simple steatosis as well as more severe stages. Our in vitro data support that CYP2E1 is induced by endogenous alcohol but not by fatty acids.

Multi-targeting therapeutic mechanisms of the Chinese herbal medicine QHD in the treatment of non-alcoholic fatty liver disease

Beneficial effects of the Chinese herbal medicine Qushi Huayu Decoction (QHD) were observed with non-alcoholic fatty liver disease (NAFLD) patients and animal models. The impact of QHD or its active components (geniposide and chlorogenic acid, GC) on NAFLD liver transcriptome and gut microbiota was examined with NAFLD rats. Increased expression for genes required for glutathione production and decreased expression for genes required for lipid synthesis was observed in NAFLD livers treated with QHD and GC. GC treatment decreased serum LPS, which could be explained by reduced mucosal damage in the colon of GC-treated rats. Further, our data suggest an increased abundance of Treg-inducing bacteria that stimulated the Treg activity in GC treated colon, which in turn down-regulated inflammatory signals, improved gut barrier function and consequently reduced hepatic exposure to microbial products. Our study suggests that QHD simultaneously enhanced the hepatic anti-oxidative mechanism, decreased hepatic lipid synthesis, and promoted the regulatory T cell inducing microbiota in the gut.

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

Background Inhaled nitric oxide (iNO) is being increasingly used in preterm infants < 34 weeks with hypoxemic respiratory failure (HRF) and/or pulmonary hypertension (PH). Objective To evaluate the risk factors, survival characteristics, and lung histopathology in preterm infants with PH/HRF. Methods Retrospective chart review was conducted to determine characteristics of 93 preterm infants treated with iNO in the first 28 days and compared with 930 matched controls. Factors associated with survival with preterm HRF and smooth muscle actin from nine autopsies were evaluated. Results Preterm neonates treated with iNO had a higher incidence of preterm prolonged rupture of membrane (pPROM ≥ 18 hours), oligohydramnios and delivered by C‐section. In infants treated with iNO, antenatal steroids (odds ratio [OR],3.7; confidence interval [CI], 1.2‐11.3; p = 0.02), pPROM (OR, 1.001; CI, 1.0‐1.004; p = 0.3), and oxygenation response to iNO (OR, 3.7; CI, 1.08‐13.1; p = 0.037) were associated with survival. Thirteen infants with all three characteristics had 100% (13/13) survival without severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL) compared with 48% survival (12/25, p = 0.004) and 16% severe IVH/PVL without any of these factors. Severity of HRF correlated with increased smooth muscle in pulmonary vasculature. Conclusion Preterm infants with HRF exposed to antenatal steroids and pPROM had improved oxygenation with iNO and survival without severe IVH/PVL. Precisely targeting this subset may be beneficial in future trials of iNO.

Immunoglobulin G4–related sclerosing disease with orbital inflammation in a 12-year-old girl

Immunoglobulin G4-related sclerosing disease is a rare but potentially debilitating cause of orbital inflammation, with a predilection for older males. We report the case of a 12-year-old African girl with immunoglobulin G4-related sclerosing disease, including possible extraorbital involvement. Because of an escalating severity of illness leading to oculomotor nerve palsy and cavernous sinus thrombosis that was resistant to steroids, systemic immunosuppressive therapy with rituximab was used to achieve disease remission. The diagnosis was histologically confirmed with a tissue biopsy.

Intussusception associated with adenovirus.

p JP A 7-month-old girl presented with irritability, bilious vomiting, and hematochezia. A week before presentation she had an upper respiratory tract infection. Initial evaluation showed distended bowel loops on abdominal film and intussusception of the ascending colon on ultrasound. While attempting a reduction with an air contrast enema, an air leak occurred, necessitating an ileocecal resection and reanastomosis. Gross examination of the specimen showed a partially necrotic segment of terminal ileum invaginated into the cecum. Mucosal thickening and lymphonodular hyperplasia in the ileocecal valve was consistent with a lead point (Fig. 1). hemorrhagic necrosis. inclusions (arrows) (H&E, original magnification 40). counterstain, original magnification 10).

Early Prenatal Detection of an Intra-abdominal Cryptorchid Testicular Teratoma

Intra-abdominal prenatally detected testicular neoplasms are rare; however, increased use of prenatal ultrasonography has led to the discovery of these uncommon neoplasms. We report the fifth case of a prenatally detected intra-abdominal testicular teratoma, which, in this instance, was detected early in pregnancy as a cystic mass within the fetal abdomen that subsequently underwent torsion later in pregnancy before delivery.

Vulvar Atypical Granular Cell Tumor in a Preadolescent Patient

BACKGROUND Granular cell tumor is an uncommon benign neoplasm with a predisposition for upper aerodigestive tract, skin and soft tissue involvement. Malignant and atypical granular cell tumors account for less than 2% of the lesions and in the pediatric population they are extremely rare and atypia has not been previously reported. CASE We present a case of a rapidly growing granular cell tumor of the vulva of a 12-year-old girl exhibiting atypical histology. The lesion demonstrated prominent Ki-67 proliferation index (up to 20%), localized areas of spindling of tumor cells, scattered apoptotic bodies and p53 overexpression. CONCLUSION The current histologic diagnostic criteria of atypical granular cell tumors are evaluated while physician awareness and the need for follow-up of patients for potential recurrences of this rare entity are emphasized.

A Young Man With Enlarging Unilateral Tonsil Mass

A young man in his late teens presented to a pediatric otolaryngologist for evaluation of enlarged tonsils and recurrent tonsillitis. The patient reported 2 episodes of streptococcal tonsillitis and infectious mononucleosis over the past 8 months, as well as frequent throat soreness and associated difficulty swallowing throughout the past year. Results from a review of systems were negative for weight loss, fevers, and malaise. On physical examination, he appeared well and had 2+ cryptic tonsils. A lobular mass was noted to be extending from the inferior pole of the right tonsil. There was no cervical lymphadenopathy. The patient was scheduled for tonsillectomy for recurrent tonsillitis and tonsillar asymmetry. His surgery was delayed for several months to accommodate his college schedule. In the operating room, the tonsils were noted to be 3+ bilaterally. The right tonsil had a smooth, pedunculated, flesh-colored mass extending inferiorly. The mass had enlarged since the prior examination. Both tonsils were removed without complication. The right tonsil with the attached mass was submitted to the pathology service fresh to allow evaluation by flow cytometry. Flow cytometry revealed no lymphoid abnormality. Grossly, the polypoid oval mass measured 2 × 1 × 1 cm, weighed 8.7 g, and had a narrow 0.4-cm-long stalk connecting it to the tonsil (Figure, A). Histologic sections revealed a polypoid structure composed of a fibrovascular core covered by stratified squamous epithelium (Figure, B). A subepithelial band of lymphoid tissue was noted (Figure, C) as well as lymphatic channels accentuated by D2-40 antibody (Figure, D). No cellular atypia was identified. Surgical specimen A