Food Allergies.

Food allergy is 1 of the 4 manifestations of the "atopic march," along with eczema, allergic rhinitis, and asthma. Depending on the pathophysiologic immune mechanisms behind a food allergy, it can be classified as immunoglobulin E-mediated, non-immunoglobulin E-mediated, or mixed. The prevalence of food allergies has risen worldwide during the past few decades, becoming a significant global health concern. Patients experiencing food allergies and their caregivers are heavily burdened personally, socially, emotionally, and financially. The health-care system is also considerably affected. Pediatricians, as primary health-care providers, are often challenged with these patients, becoming the first-line for the recognition and management of food allergies. The purpose of this review is to provide a comprehensive summary of food allergies, including the most up-to-date information, recent guidelines, and recommendations.

Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis.

The POT1 (protection of telomeres) protein binds the single-stranded G-rich overhang and is essential for both telomere end protection and telomere length regulation. Telomeric binding of POT1 is enhanced by its interaction with TPP1. In this study, we demonstrate that mouse Tpp1 confers telomere end protection by recruiting Pot1a and Pot1b to telomeres. Knockdown of Tpp1 elicits a p53-dependent growth arrest and an ATM-dependent DNA damage response at telomeres. In contrast to depletion of Trf2, which activates ATM, removal of Pot1a and Pot1b from telomeres initiates an ATR-dependent DNA damage response (DDR). Finally, we show that telomere dysfunction as a result of Tpp1 depletion promotes chromosomal instability and tumorigenesis in the absence of an ATM-dependent DDR. Our results uncover a novel ATR-dependent DDR at telomeres that is normally shielded by POT1 binding to the single-stranded G-overhang. In addition, our results suggest that loss of ATM can cooperate with dysfunctional telomeres to promote cellular transformation and tumor formation in vivo.

Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.

Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis.

Human carcinomas arise through the acquisition of genetic changes that endow precursor cancer cells with a critical threshold of cancer-relevant genetic lesions. This complex genomic alterations confer upon precursor cancer cells the ability to grow indefinitely and to metastasize to distant sites. One important mechanism underlying a cell's tumorigenic potential is the status of its telomere. Telomeres are G-rich simple repeat sequences that serve to prevent chromosomal ends from being recognized as DNA double-strand breaks (DSBs). Dysfunctional telomeres resemble DSBs, leading to the formation of dicentric chromosomes that fuel high degrees of genomic instability. In the setting of an intact p53 pathway, this instability promotes cellular senescence, a potent tumor suppressor mechanism. However, rare cells that stochastically lose p53 function emerge from this sea of genomic instability and progress towards cancer. In this review, we describe the use of mouse models to probe the impact of dysfunctional telomeres on tumor initiation and suppression.

Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence.

Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 ( R172P ) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 ( R172P ) mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.

POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination.

POT1 (protection of telomere 1) is a highly conserved single-stranded telomeric binding protein that is essential for telomere end protection. Here, we report the cloning and characterization of a second member of the mouse POT family. POT1b binds telomeric DNA via conserved DNA binding oligonucleotide/oligosaccharide (OB) folds. Compared to POT1a, POT1b OB-folds possess less sequence specificity for telomeres. In contrast to POT1a, truncated POT1b possessing only the OB-folds can efficiently localize to telomeres in vivo. Overexpression of a mutant Pot1b allele that cannot bind telomeric DNA initiated a DNA damage response at telomeres that led to p53-dependent senescence. Furthermore, a reduction of the 3' G-rich overhang, increased chromosomal fusions and elevated homologous recombination (HR) were observed at telomeres. shRNA mediated depletion of endogenous Pot1b in Pot1a deficient cells resulted in increased chromosomal aberrations. Our results indicate that POT1b plays important protective functions at telomeres and that proper maintenance of chromosomal stability requires both POT proteins.

Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres.

The terminal t-loop structure adopted by mammalian telomeres is thought to prevent telomeres from being recognized as double-stranded DNA breaks by sequestering the 3' single-stranded G-rich overhang from exposure to the DNA damage machinery. The POT1 (protection of telomeres) protein binds the single-stranded overhang and is required for both chromosomal end protection and telomere length regulation. The mouse genome contains two POT1 orthologs, Pot1a and Pot1b. Here we show that conditional deletion of Pot1a elicits a DNA damage response at telomeres, resulting in p53-dependent replicative senescence. Pot1a-deficient cells exhibit overall telomere length and 3' overhang elongation as well as aberrant homologous recombination (HR) at telomeres, manifested as increased telomere sister chromatid exchanges and formation of telomere circles. Telomeric HR following Pot1a loss requires NBS1. Pot1a deletion also results in chromosomal instability. Our results suggest that POT1a is crucial for the maintenance of both telomere integrity and overall genomic stability.

Alterations in growth hormone receptor abundance regulate growth hormone signaling in murine obstructive cholestasis.

Children with cholestatic liver diseases, in particular biliary atresia, may develop an acquired growth hormone (GH) resistance. This is characterized by normal GH secretion, reduced liver GH receptor (GHR) abundance, and reduced circulating insulin-like growth factor I (IGF-I). Consequences include linear growth failure, reduced muscle mass, and increased perioperative morbidity and mortality. However, the molecular basis for altered GH signaling in liver and skeletal muscle in cholestatic liver disease is not known. We hypothesized that reduced IGF-I expression in obstructive cholestasis would be associated with downregulation of the GHR and impaired phosphorylation of signal transducers and activators of transcription (STAT5). Body composition was determined in C57BL/6J male mice after bile duct ligation (BDL) relative to pair-fed (PF) and ad libitum-fed controls. GHR, STAT5, Sp3, and IGF-I expression and/or DNA binding were assessed using immunoblots, electrophoretic mobility shift assays, and/or real time RT-PCR. Fat-free mass was reduced in PF mice relative to ad libitum-fed controls. BDL led to a further reduction in fat mass and fat-free mass relative to PF controls. TNF-alpha was increased in liver and skeletal muscle of BDL mice. This was associated with reduced GH-dependent STAT5 activation and IGF-I RNA expression. GHR expression was reduced in BDL mice; in liver, this was associated with reduced Sp3 binding to a GHR gene promoter cis element. Wasting in murine obstructive cholestasis is due to combined effects of reduced caloric intake and biliary obstruction. GH resistance due to downregulation of GHR expression may be attributed primarily to the obstructive cholestasis; therapies that specifically increase GHR expression may restore GH signaling in this setting.