Lack of association between level of Plasminogen Activator Inhibitor-1 and estimates of tumor angiogenesis in early breast cancer

Plasminogen Activator Inhibitor type-1 (PAI-1) is involved in tumor invasion and progression. High levels of PAI-1 are associated with poor prognosis in breast cancer, and PAI-1 has been shown to play a role in angiogenic processes. Since estimates of tumor angiogenesis may predict poor prognosis we studied the relationship between PAI-1 and estimates of angiogenesis in breast cancer. Tumor tissue specimens from 438 breast cancer patients were included. Median follow-up was 10.3 years. Protein levels of PAI-1 were measured using an ELISA. Angiogenesis scores were performed using a Chalkley grid. Median PAI-1 level was 0.70 ng/mg protein (range, 0 - 90 ng/mg protein) and median Chalkley count was 5.00 (range, 2.67 - 12.00). Chalkley counts were not correlated with PAI-1. In univariate analysis both increasing PAI-1 and increasing Chalkley counts evaluated as continuous parameters were significantly associated with poor disease-specific survival with RR 1.04 (95% CI 1.02 - 1.07) (p<0.0001) and RR 1.11 (95% CI 1.01 - 1.22) (p=0.04), respectively. High tertiles of PAI-1 were borderline significantly correlated with poor disease-specific survival (p=0.06), whereas high tertiles of Chalkley counts were significantly associated with poor disease-specific survival (p=0.004). Combining low/low versus high/high tertiles of Chalkley counts and PAI-1 showed actuarial 10-year survival rates of 82% versus 52% (p=0.004). High N-stage (p<0.0001), grade (p<0.0001) and increasing levels of PAI-1 (p=0.009) were independent markers of death from breast cancer. This study confirms high PAI-1 or high Chalkley counts as markers of poor prognosis in breast cancer patients, and suggests that the prognostic impact of PAI-1 is independent of its supposed involvement in tumor angiogenesis.     

Gene-environment interactions between smoking and a haplotype of RAI, ASE-1 and ERCC1 polymorphisms among women in relation to risk of lung cancer in a population-based study

Homozygous carriers of a haplotype consisting of ERCC1 Asn118Asn(A), ASE-1 G-21A(G), RAI IVS1 A4364G(A) are at increased risk of lung cancer especially among women. Here, we analyse for gene-environment interactions with the predefined haplotype in a case cohort study including 428 lung cancer cases and a comparison group of 800 persons, all from the prospective Diet, Cancer and Health cohort of 57,000 Danes. At high smoking intensity (>20g tobacco/day), there was only additional risk of smoking intensity among women who were homozygous carriers of the haplotype (IRR=2.03; 95% CI: 1.10-3.73 per 5 additional g tobacco/day).     

Generation of urinary albumin fragments does not require proximal tubular uptake

Urinary albumin excretion is an important diagnostic and prognostic marker of renal function. Both animal and human urine contain large amounts of albumin fragments, but whether these fragments originate from renal tubular degradation of filtered albumin is unknown. Here, we used mice with kidneys lacking megalin and cubilin, the coreceptors that mediate proximal tubular endocytosis of albumin, to determine whether proximal tubular degradation of albumin forms the detectable urinary albumin fragments. After intravenous administration of (125)I-labeled mouse albumin to knockout and control mice, we examined kidney uptake of albumin and urinary excretion of both intact albumin and its fragments using size exclusion chromatography. In control mice, all labeled albumin eluted as albumin fragments in the urine. In megalin/cubilin-deficient mice, we observed decreased uptake and degradation of albumin and increased urinary excretion of intact albumin; we did not, however, detect a decrease in the excretion of albumin fragments. These results show that the generation of urinary albumin fragments occurs independently of renal tubular uptake and degradation of albumin, suggesting that the pathophysiological implications of changes in urinary albumin fragments require reevaluation.     

CT of the paranasal sinuses is not a valid indicator for sinus surgery in CF patients

BackgroundNo guidelines comprise when or to what extent sinus surgery should be done in patients with cystic fibrosis (CF) or how a CT scan of the paranasal sinuses should influence the decision. Symptoms of rhinosinusitis and/or eradication of pathogenic bacteria from the sinuses are reasons for sinus surgery.MethodsIn this observational cross sectional study, 55 CF cases had their preoperative CT scans scored according to the Lund Mackay- and the Nair-system. Correlations between the CT scans, symptoms, surgical findings and cultures obtained during sinus surgery were made.ResultsThere was no significant correlation between the CT score and detection of pus, pathogenic bacteria or symptoms. Pus and pathogenic bacteria were found in several cases without sinus opacification on the CT scan. Non pathogenic and sterile cultures were also found in sinuses with opacification.ConclusionsA CT scan is not a valid criterion for sinus surgery in CF patients.     

The association between idiopathic environmental intolerance and psychological distress,and the influence of social support and recent major life events

Objectives  

Idiopathic environmental intolerance (IEI) is a disorder characterized by non-specific symptoms attributed to common airborne chemicals. Increasing evidence points to an association between IEI and symptoms of psychological distress. However, whether other risk factors influence this association has not been clarified. The objective of this study was to examine the association between psychological distress and IEI and to determine whether the association is confounded by social support and major life events.     

The Effect of Early Initiation of Rehabilitation After Lumbar Spinal Fusion: A Randomized Clinical Study

STUDY DESIGN.: A multicenter randomized clinical trial including 82 patients. OBJECTIVE.: To examine the effect of early initiation of rehabilitation after instrumented lumbar spinal fusion. SUMMARY OF BACKGROUND DATA.: Lumbar spinal fusion has been performed for more than 70 years. Yet, few studies have examined patients' subsequent rehabilitation. Group-based rehabilitation is both efficient and cost-effective in rehabilitation of lumbar spinal fusion patients. METHODS.: Patients with degenerative disc diseases undergoing instrumented lumbar spinal fusion were randomly assigned to initiate their rehabilitation 6 weeks (6-wk group) or 12 weeks after lumbar spinal fusion (12-wk group). Both groups received the same group-based rehabilitation. Primary outcome was the Oswestry Disability Index. Secondary outcome was the Dallas Pain Questionnaire, the Low Back Pain Rating Scale, and absence from work. Wilcoxon rank-sum test was used to compare the groups in terms of differences from baseline to 6 months and 1-year follow-up. Results are presented in median with 25th and 75th percentiles. RESULTS.: According to the Oswestry Disability Index, at 1-year follow-up, the 6-week-group had a median reduction of -6 (-19; 4) compared with -20 (-30;-7) in the 12-week group (P, 0.05). The Dallas Pain Questionnaire showed overall the same tendency, and within daily activities were significantly reduced in favor of the 12-week group (P, 0.05). For back pain, the 6-week group had a median reduction of -2.2 (-3.0; -0.7) similar with -3.3 (-4.7; -1.7) in the 12-week group (P, 0.05). The results at 6 months of follow-up were similar. No difference was found according to return to work 1 year postsurgery. CONCLUSION.: Early start of rehabilitation (6 wk vs. 12 wk) after lumbar spinal fusion resulted in inferior outcomes. The improvements in the 12-week group were 4 times better than that in the 6-week group, indicating that the start-up time of rehabilitation is an important contributing factor for the overall outcome.     

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes,risk factors and genotypes

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10^-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.