Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport.

OBJECTIVES: To test the hypothesis that meningococcal septicemia-related pulmonary edema is associated with a systemic abnormality of epithelial sodium and chloride transport and to investigate an association with hormones regulating Na transport. DESIGN: Prospective observational study. SETTING: The 24-bed pediatric intensive care unit and pediatric wards of Royal Liverpool Children's Hospital. PATIENTS: Consecutive children admitted to the pediatric intensive care unit and pediatric wards with a diagnosis of meningococcal septicemia and children (controls) with noninfectious critical illness receiving ventilatory support in the pediatric intensive care unit. MEASUREMENTS AND MAIN RESULTS: We measured sweat and saliva electrolytes, renal electrolyte excretion, nasal potential difference, and aldosterone, thyroxine, and cortisol levels. Pulmonary edema was diagnosed by chest radiography and its severity quantified by calculation of ventilation index at admission and duration of mechanical ventilation. We recruited 17 patients with severe meningococcal septicemia (nine patients with pulmonary edema), 14 patients with mild meningococcal septicemia, and 20 controls. Sweat and saliva Na and Cl concentrations and renal Na excretion were significantly (p < .05) higher in patients with pulmonary edema compared with controls. Nasal potential difference and amiloride response in patients with pulmonary edema were not significantly different to controls, but response to a low Cl solution was reduced in the nasal airway of patients with pulmonary edema (p < .05). Sweat and saliva chloride concentrations correlated significantly and better with ventilation index and duration of ventilation than sodium concentrations. Aldosterone, thyroxine, and cortisol levels were not significantly different between groups. CONCLUSIONS: We have confirmed that meningococcal septicemia-related pulmonary edema is associated with reduced systemic sodium and chloride transport. Features of reduced Cl transport were most closely associated with markers of respiratory compromise, and this was supported by the reduced chloride channel function detected on nasal potential difference measurement.     

Polymorphisms in XPD exons 10 and 23 and bladder cancer risk.

INTRODUCTION: The nucleotide excision repair gene, xeroderma pigmentosum complementation group D (XPD), has been hypothesized to have a role in cancer risk, but results from prior molecular epidemiologic studies and genotype-phenotype analyses are conflicting. MATERIALS AND METHODS: We examined the frequency of the XPD Asp312Asn polymorphism in exon 10 and the XPD Lys751Gln polymorphism in exon 23 in 505 incident bladder cancer cases and 486 healthy controls. RESULTS: Overall, the XPD exon 10 and 23 genotypes were not associated with bladder cancer risk, after adjusting for age, sex, ethnicity, and smoking status. A gender-specific role was evident that showed an increased risk for women, but not for men, associated with the variant genotypes for both exons. For example, when the exon 23 variant allele genotypes were combined (Lys/Gln + Gln/Gln), there was an increased bladder cancer risk in women [odds ratio (OR), 1.69; 95% confidence interval (95% CI), 1.12-2.58] but not in men (OR, 0.99; 95% CI, 0.79-1.24; P(interaction) = 0.041; OR, 1.62; 95% CI, 1.02-2.58). There was also a gene-smoking interaction that showed the variant alleles for either exon or the combination of both increase the risk of bladder cancer for light and heavy smokers. For exon 23 (P(interaction) = 0.057; OR, 1.21; 95% CI, 0.99-1.47), heavy smokers (> or = 20 pack-years) who carried the exon 23 variant allele genotypes had an OR of 4.13 (95% CI, 2.53-6.73), whereas heavy smokers with the wild-type genotypes were at lower risk (OR, 3.55; 95% CI, 2.19-5.75). Moderate smokers (1-19 pack-years) with the variant allele genotypes had an OR of 1.54 (95% CI, 0.94-2.53), whereas moderate smokers with the wild-type genotypes had an OR of 1.12 (95% CI, 0.63-1.98). CONCLUSIONS: Although we did not observe main effects associated with the XPD genotypes, these results do suggest the variant allele genotypes were associated with increased bladder cancer risk in women and smokers with statistically significant interactions in the exon 23 polymorphism. Although there is biological plausibility, these novel findings for gender and smoking should be interpreted with caution upon confirmation in larger studies.     

62例咽旁间隙肿瘤临床分析

目的：探讨咽旁间隙肿瘤的诊断和治疗方法及熟悉咽旁间隙解剖与肿瘤关系。方法：回顾性分析62例咽旁间隙肿瘤的临床资料。结果：咽旁间隙肿瘤中病理类型较多,但以神经鞘膜肿瘤比例较大,占41.9%,混合瘤22.6%,畸胎瘤、错构瘤、脊索瘤、恶性淋巴瘤及脑膜瘤等共占35.5%。进行以颈侧入路为主的4种手术入路,2例肿瘤复发（1例神经鞘膜瘤,1例转移癌）,再次手术治愈,其余均一次性手术治愈。结论：咽旁间隙肿瘤临床表现复杂,病理类型多样,肿瘤预后较好。其诊断较难,除症状体征外,CT、MRI及B超对咽旁间隙肿瘤的诊断有重要价值。手术径路是根据患者体征、影像学特征结合肿瘤位置、大小及性质而最终确定。颈侧入路为主要手术途径,气管切开为预防窒息措施。     

High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions

Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.Subject terms: Myeloma, Genetic translocation, Risk factors, Cancer genetics     

Physiologic effects of doxapram in idiopathic apnea of prematurity

Twelve premature infants with significant apnea of prematurity while receiving therapeutic doses of aminophylline were given an intravenous infusion of doxapram, 2 or 2.5 mg/kg/hr. The ventilatory effects of the medication were monitored by means of face mask spirometry and airway occlusion studies. Doxapram therapy was associated with significant increases in minute ventilation, tidal volume, mean inspiratory flow, and airway pressure 100 msec after occlusion. Respiratory frequency and the relative duration of inspiration and expiration were unchanged. Paco2 decreased significantly during the infusion. The apnea attack rate, monitored by continuous recording, was significantly reduced after the first 6 hours of therapy. Six hours after starting doxapram, mean arterial blood pressure was significantly elevated, and continued to increase during the 24 hours of therapy. Doxapram is effective in treatment of apnea of prematurity refractory to aminophylline, and appears to act by increasing respiratory center output.     

Aortic dilation, dissection, and rupture in patients with Turner syndrome

We report two patients with Turner syndrome who had aortic dissection and rupture, one with prior repair of coarctation. We also note the high incidence (8.8%) of unrecognized aortic root dilation in a group of 57 patients with Turner syndrome whom we prospectively evaluated by echocardiography. Our analysis and review of previously reported cases suggests that multiple risk factors may exist for aortic dissection, including coarctation, bicuspid aortic valve, and systemic hypertension, but that these need not be present. Aortic root dilation may be an additional finding that suggests the patient with Turner syndrome is also at risk. When it is present, magnetic resonance imaging visualizes the entire aorta and allows quantification of the site and degree of dilation. In patients with dissection, the aorta often exhibits pathologic evidence of cystic medial necrosis similar to the finding in patients with Marfan syndrome. Therapeutic methods to decrease risk, such as those directed toward prevention of bacterial endocarditis, blood pressure control, and perhaps prophylactic beta blockade or surgical reconstruction, may need to be considered. Patients with Turner syndrome, their families, and the physicians who care for them should be aware of the significance of unexplained chest pain, dyspnea, or hypotension as potential manifestations of aortic dissection or rupture.     

The C5b-9 membrane attack complex of complement activation localizes to villous trophoblast injury in vivo and modulates human trophoblast function in vitro

The complement system plays an important role in normal human pregnancy. Uncontrolled activation of this system has been associated with many disease states. We tested the hypothesis that the C5b-9 membrane attack complex (MAC) localizes to sites of villous injury and modulates trophoblast function. Placental sections from pregnancies with no complications, intrauterine growth restriction, or preeclampsia were immunostained and the surface density for MAC and fibrin was determined by morphometric analysis. Primary cytotrophoblasts from term placentas were cultured in a FiO(2) of <1%, 8% and 20% with 10% human serum containing active MAC or heat-inactivated control serum. Immunofluorescent MAC binding to trophoblast was quantified, and the neoepitopes formed in cytokeratin 18 filaments and poly-ADP-ribose polymerase during apoptosis were used to measure cell death. Trophoblast differentiation was assessed by HCG secretion, formation of syncytia, and expression of syncytin. MAC localized to fibrin deposits in normal placentas, and especially in placentas from IUGR and preeclampsia. MAC binding to cytotrophoblasts was inversely proportional to FiO(2) and enhanced apoptosis. MAC increased markers of differentiation in cultures at 72h (medium HCG, syncytia and syncytin expression). Our findings demonstrate that MAC associates with fibrin deposits at sites of villous injury in vivo. Hypoxia also enhances MAC deposition in cultured trophoblasts and MAC alters trophoblast function in a phenotype specific manner.