Associations of obesity, sleep-disordered breathing, and wheezing in children

Although it has been speculated that rising asthma rates may be partly due to increasing obesity, the causal mechanisms that relate these conditions are unclear. We assessed the extent to which sleep-disordered breathing (SDB) may explain associations between obesity and wheezing/asthma. A total of 788 participants (aged 8-11 years) in a community-based cohort study were classified according to two outcomes: wheezing and asthma. Sleep apnea was defined as an increased number of apneas and hypopneas on overnight monitoring. SDB was identified on the basis of either sleep apnea or habitual snoring. Multiple logistic regression models showed that children with wheeze were significantly more likely to be male (odds ratio [OR] 1.62; confidence interval [CI] 1.15, 2.29), black (OR 1.90; CI 1.35, 2.29), obese (OR 1.57; CI 1.10, 2.44), and have a maternal history of asthma (OR 1.93; CI 1.16, 3.22). Further adjustment for SDB attenuated the association between obesity and wheeze (OR 1.45; CI 0.93, 2.26), but did not substantially alter the association between obesity and asthma. We conclude that SDB and obesity each are associated with asthma and wheeze. The relationship between obesity and wheeze may be partly mediated by factors associated with SDB.     

Molecular basis of cholestatic diseases of surgical interest

Cholestasis constitutes one of the most common and severe manifestations of acquired or inherited liver disease. When manifest in early infancy, it is often life-threatening and usually requires surgical management. In many cases, liver transplantation is the only effective therapy. Extensive knowledge about the molecular mechanisms underlying several pediatric cholestatic disorders has been gained in recent years from studies in both experimental models and clinical forms. In this review, we focus on recent contributions to the knowledge of molecular basis of main pediatric cholestatic disorders, such as biliary atresia, Alagille syndrome, and familial intrahepatic cholestasis. For some of them, putative targets of therapeutic interest, such as interferon-gamma and Farnesoid X receptor, have been proposed.     

Cognitive functions in classic phenylketonuria and mild hyperphenylalaninaemia: experience in a paediatric population

A study of 37 individuals with phenylketonuria (PKU; 17 females and 20 males, mean age 9y 9mo (standard deviation [SD] 5y 3mo), range 2y 8mo to 19y 4mo; and 35 individuals with hyperphenylalaninaemia (HPA; 20 females, 15 males, mean age 7y 10mo [SD 3y 2mo], range 2y 8mo to 17y 3mo) compared with 29 healthy controls (14 females and 15 males, mean age 9y 8mo [SD 4y 9mo], range 2y 6mo to 18y 10mo) was performed. The aim was to assess cognitive function in persons with HPA and to investigate the relation between cognitive function in PKU and the metabolic control of patients. A wide variety of neuropsychological tests was employed. Those with PKU showed lower values in intelligence and in visuo-spatial, fine motor, executive, and attention functions when compared with a control population. Plasma phenylalanine values from the first 6 years of life were negatively associated with intelligence and other cognitive functions. Executive function scores were significantly lower when comparing HPA patients with the control group. It was concluded that individuals with PKU under dietary treatment may present slightly decreased cognitive function scores when compared with control individuals, while those with HPA have scores mostly similar to those of controls, except for executive function tests. Good metabolic control of PKU seems necessary to prevent cognitive function impairments, especially during the first 6 years of life.     

Proliferative high-risk lesions of the breast: contribution and limits of US-guided core biopsy

PURPOSE: To retrospectively correlate high-risk proliferative breast lesions (radial scar, atypical lobular hyperplasia, lobular carcinoma in situ and papillary lesions) diagnosed on core biopsy with the definitive histopathological diagnosis obtained after surgical excision or with the follow-up, in order to assess the role of core biopsy in such lesions. To discuss the management of the patient after a core biopsy diagnosis of high-risk proliferative breast lesion. MATERIAL AND METHODS: We evaluated 74 out of 1776 core biopsies consecutively performed on 67 patients. The histopathologic findings were as follows: 11 radial scars (RS), 3 atypical lobular hyperplasias (ALH), 3 lobular carcinomas in situ (LCIS), 57 benign papillary lesions. All patients underwent bilateral mammography, whole-breast ultrasound with a linear-array broadband transducer, and core biopsy with a 14 Gauge needle and a mean number of samples of 5 (range 4-7). Sixty-two of 67 patients, for a total of 69/74 lesions, underwent surgical biopsy despite benign histopathologic findings, mostly because of highly suspicious imaging for malignancy (BIRADS 4-5), whereas 5 patients refused surgery and have been followed up for a least 18 months and are still being followed up (2 with RS, 1 with ADH and 2 with papillary lesions). RESULTS: Among the core biopsied lesions with a diagnosis of RS (n = 11) pathology revealed one ductal carcinoma in situ (DCIS) (this case was characterized by granular microcalcifications on mammography and by a mass with irregular margins on ultrasound). Also in the group of ADH (n = 3) pathology revealed one DCIS (lesion not visible on mammography but depicted as a suspicious mass on US). In the group of LCIS (n = 3) pathologists found an invasive lobular carcinoma (ILC). Among the benign papillary lesions (n = 57) histopathologic analysis of the surgical specimen revealed 7 malignant lesions (4 papillary carcinomas and 3 DCIS), whose mammographic and ultrasound findings were indistinguishable from benign lesions. Altogether there were 10 false negative results (underestimation) out of 74 core biopsies with a diagnosis of high-risk proliferative breast lesions. CONCLUSION: The high rate of histological underestimation after core biopsy (10/74) (13.5%) demands a very careful management of patents with a core biopsy diagnosis of high-risk proliferative breast lesions, especially in the case of RS, lobular neoplasia and papillary lesions. However, the high imaging suspicion for malignancy prompts surgery. It is possible to assume that, when there is a low imaging suspicion for malignancy, when enough tissue has been sampled for pathology and no atypia is found within the lesions, surgery is not mandatory but a very careful follow-up is recommended. We must underline that there is no agreement regarding the quantity of tissue to sample. Vacuum-assisted biopsy may lead to better results, although there is as yet no proof that it can actually replace surgery in this group of lesions, since it seems only to reduce but not abolish the histological underestimation.     

Locally advanced breast cancer: comparison of mammography,sonography and MR imaging in evaluation of residual disease in women receiving neoadjuvant chemotherapy

The accuracy of mammography, sonography and magnetic resonance imaging (MRI) in identifying residual disease after neoadjuvant chemotherapy is evaluated and imaging findings are correlated with pathologic findings. Fifteen patients enrolled in an experimental protocol of preoperative neoadjuvant chemotherapy underwent clinical examination, mammography, sonography and dynamic MRI, performed in this order, before and respectively after 2 and 4 cycles of neoadjuvant chemotherapy. Four radiologists, two for mammography, one for sonography and one for MR, examined the images, blinded to the results of the other examinations. All patients underwent radical or conservative surgery, and imaging findings were compared with pathologic findings. MRI identified 2/15 (13.3.%) clinically complete response (CR), 9/15 (60%) partial response (PR), 3/15 (20%) stable disease (SD) and 1/15 (6.7%) progressive disease. Mammography identified 1/15 (6.7%) clinically CR, 8/15 (53.3%) PR and 4/15 (27%) SD, and was not able to evaluate the disease in 2/15 (13%) cases. Sonography presented the same results as MRI. Therefore, MRI and sonography compared to mammography correctly identified residual disease in 100 vs. 86%. MRI resulted in two false-negative results because of the presence of microfoci of in situ ductal carcinoma (DCIS) and invasive lobular carcinoma (LCI). MRI was superior to mammography in cases of multifocal or multicentric disease (83 vs. 33%). Sonography performed after MRI improves the accuracy in evaluation of uncertain foci of multifocal disease seen on MR images with an increase of diagnostic accuracy from 73 to 84.5%. MRI assesses response to neoadjuvant chemotherapy better than traditional methods of physical examination and mammography.     

Effect of adrenomedullin on c-Met receptor expression after reserpine-induced gastric damage in the rat

Here, we show an increase in c-Met receptor expression during reserpine-induced gastric damage in the rat, as assessed by immunohistochemistry. Pretreatment of animals with adrenomedullin prevented this increase in c-Met expression. c-Met immunoreactivity was localized in gastric glands. c-Met immunoreactivity was associated with increased phosphorylation of c-Met receptor and extracellular signal-regulated kinase (ERK(1/2)). Our results suggest that both adrenomedullin and c-Met act as parallel defence mechanisms during pharmacologically induced gastric mucosa injury.     

Absence or low expression of fas-associated protein with death domain in acute myeloid leukemia cells predicts resistance to chemotherapy and poor outcome

In acute myeloid leukemia (AML), coexpression of death receptors and ligands of the tumor necrosis factor (TNF) receptor/TNF-alpha superfamily on leukemic cells after chemotherapy is not always accompanied by apoptosis, suggesting that the apoptotic death receptor signaling pathway is disrupted. Because Fas-associated protein with death domain (FADD) is the main adaptor for transmitting the Fas, TNF-related apoptosis-inducing ligand receptors, and TNF receptor 1 death signal, expression of FADD was analyzed by Western blot and immunocytochemistry in leukemic cells of 70 de novo AML patients treated with the European Organization of Research and Treatment of Cancer AML-10 randomized trial before initiation of induction chemotherapy. Thirty seven percent of patients (17 of 46) with FADD negative/low (FADD(-/low)) leukemic cells had a primary refractory disease compared with 12% of FADD(+) patients (3 of 24; P = 0.05). FADD(-/low) expression was significantly associated with a worse event-free survival [EFS (P = 0.04)] and overall survival (P = 0.04). In multivariate analysis, FADD(-/low) protein expression was independently associated with a poor EFS and overall survival (P = 0.002 and P = 0.026, respectively). Importantly, FADD(-/low) protein expression predicted poor EFS even in patients with standard- or good-risk AML (P = 0.009). Thus, we identified low or absent expression of the FADD protein in leukemic cells at diagnosis as a poor independent prognostic factor that can predict worse clinical outcome even for patients with standard- or good-risk AML.     

BRCA2 germline mutations in primary cancer of the fallopian tube

Germline mutations of BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. It has been recently reported that BRCA1/2 mutations may also predispose to fallopian tube cancer. We report the presence of germline BRCA2 gene mutations in three out of four subjects with fallopian tube cancer diagnosed in a two-year time span at our clinic. The mothers of two of these women suffered from breast or ovarian carcinoma. These results suggest on one hand that in patients with a history suggestive for a heredofamilial breast/ovarian cancer syndrome fallopian tube carcinoma is associated with high risk of BRCA2 mutation, and on the other hand that in patients/individuals with germline BRCA2 gene mutations in whom a prophylactic oophorectomy is performed, removal of fallopian tubes may be considered.     

Hepatitis C virus infection associated with liver-kidney microsomal antibody type 1 (LKM1) autoantibodies in children

OBJECTIVE: To evaluate the clinical pattern and evolution of chronic hepatitis C in children with liver/kidney microsomal antibody type 1 autoantibodies (LKM1). STUDY DESIGN: A multicenter, retrospective study, including the following groups of children with hepatitis C virus infection: (1). 21 consecutive LKM1-positive patients, (2). 42 age- and sex- matched LKM1-negative patients, and (3). 4 interferon-induced LKM1-positive cases. LKM1 reactivity to human microsomes and recombinant cytochrome P450IID6 (CYP2D6) was assayed by immunoblotting. RESULTS: Clinical and biochemical features overlapped in LKM1-positive and LKM1-negative children, but a fibrosis score >3 (range 0-6) was significantly more frequent (P =.04) in the former. Reactivity to microsomal protein and CYP2D6 was significantly (P =.02) associated with LKM1 titers >or=1:320 and was found in 39% of patients, including severe cases and both children (of 4 treated) who achieved a sustained alanine aminotransferase (ALT) normalization after steroid treatment. Five of 7 LKM1-positive children treated with interferon had an ALT exacerbation. CONCLUSIONS: LKM1-positive hepatitis C in children is characterized by a wide spectrum of biochemical, serologic, and histologic features. Whether autoimmunity may contribute to liver damage in a subgroup of patients with more severe liver disease, high LKM1 titers, and reactivity to CYP2D6 is a question deserving further investigation.