Effects of current cigarette smoking on clinical course of Crohn's disease and ulcerative colitis

Cigarette smoking worsens Crohn's disease (CD) but ameliorates ulcerative colitis (UC). In Israel, where there is no epidemiological association of smoking with CD, we examined the effects of current smoking on the course of CD and UC. Patients at nine public hospitals completed a questionnaire detailing their smoking history, disease course and treatments; subjects altering their smoking habit after the onset of disease were excluded. Sixty-four smokers and 144 nonsmokers had CD, and 34 smokers and 158 nonsmokers had UC. No differences were found between CD smokers and nonsmokers for hospitalizations, operations, and requirement for corticosteroid and immunosuppressive treatment. By contrast, UC smokers had less extensive disease than nonsmokers (P < 0.02) and fewer hospitalizations (P = 0.01) and operations (P = 0.025). Our results agree with a minority of studies showing no adverse effect of smoking on the course of CD, and confirm the protective effect of smoking in UC.     

N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains

Omenn's syndrome is an autosomal recessive primary immunodeficiency characterized by variable numbers of T lymphocytes of limited clonality, hypereosinophilia, and high IgE levels with a paradoxical absence of circulating B lymphocytes. We have previously attributed this disorder to missense mutations that render the RAG1/RAG2 recombinase only partially active. Here we report seven Omenn's patients with a novel class of genetic lesions: frameshift mutations within the 5' coding region of RAG1. Interestingly, we demonstrate in transient expression experiments that these frameshift deletion alleles remain partially functional for both deletional and inversional recombination and can hence explain the partial rearrangement phenotype observed in these patients. The rearrangement activity is mediated by truncated RAG1 proteins that are generated by alternative ATG usage 3' to the frameshift deletion and that demonstrate improper cellular localization. Taken together, our results suggest a novel mechanism for the development of immunodeficiency in a subset of Omenn's syndrome patients.     

Fetal hydrops due to a tachyarrhythmia progressing to organic pulmonary stenosis

We discovered supraventricular tachycardia with advanced hydrops in the setting of normal cardiac anatomy at 26 weeks of gestation which resolved successfully following administration of digoxin and flecainide to the mother. A female baby was born after a premature rupture of the membranes at 30.6 weeks. The neonate was in sinus rhythm, showed a progressive regression of right ventricular insufficiency, but developed signs of acquired pulmonary valvar and subvalvar stenosis at 2 months of age.     

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study

Introduction

Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty.

Chylous pleural effusion in tuberous sclerosis

We report on a male patient with tuberous sclerosis (adenoma sebaceum and digital fibromas, renal angiomyolipomas and subependymal brain calcifications), who presented with chylothorax. Chest CT scan did not show pulmonary parenchymal alterations, but only a moderate enlargement of the paracaval mediastinal lymph nodes. Tuberous sclerosis with lung involvement presents clinical, radiologic and pathologic manifestations similar to those of lymphangioleiomyomatosis. The pulmonary manifestations of tuberous sclerosis and lymphangioleiomyomatosis have been observed almost exclusively in women, and it has been suggested that they represent opposite ends of a spectrum of presentations of the same entity. Based on these considerations the formation of a chylothorax in a male with tuberous sclerosis constitutes an extremely rare finding.     

Identification and characterization of L-triiodothyronine receptors in cells of glial and neuronal origin

High affinity-low capacity binding sites for thyroid hormone have been identified in the nuclei of glial (C6) and neuronal (Neuro 2A) cultured cells. Equilibrium dissociation constants, determined by Scatchard analysis, were very similar in both types of cells (0.2-0.3 nM). The relative affinity of hormonal analogs was also similar: the affinity for T3 was lower than for triiodothyroacetic acid and higher than for T4 or tetraiodothyroacetic acid. The sedimentation coefficients obtained by gradient centrifugation of nuclear receptor extracted with 0.4 M KCl or excised by micrococcal nuclease digestion were 3.5 S and 6.5 S, respectively. These results suggest that the thyroid hormone receptor is not restricted to neuronal cells, but also appears in cells of glial origin.     

Dietary intake and risk of persistent human papillomavirus (HPV) infection: the Ludwig-McGill HPV Natural History Study

The association between dietary intake and persistence of type-specific human papillomavirus (HPV) infection, during a 12-month period, among 433 women participating in the Ludwig-McGill HPV Natural History Study was evaluated by use of a nested case-control design. Dietary intake was assessed by a food-frequency questionnaire at the month-4 visit. HPV status was assessed at months 0, 4, 8, and 12 by polymerase chain reaction (MY09/11). Only women who ever tested positive for HPV were included in the present study: 248 had transient HPV infections (1 of 4 positive tests or nonconsecutively positive), and 185 had persistent HPV infections (> or =2 consecutive tests positive for the same HPV type). Risk of type-specific, persistent HPV infection was lower among women reporting intake values of beta-cryptoxanthin and lutein/zeaxanthin in the upper 2 quartiles and intake values of vitamin C in the upper quartile, compared with those reporting intake in the lowest quartile. Consumption of papaya > or =1 time/week was inversely associated with persistent HPV infection.     

RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations

Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis.