Validation of 64Cu-ATSM damaging DNA via high-LET Auger electron emission

Radioactive copper (II) (diacetyl-bis N4-methylthiosemicarbazone) (Cu-ATSM) isotopes were originally developed for the imaging of hypoxia in tumors. Because the decay of a ⁶⁴Cu atom is emitting not only positrons but also Auger electrons, this radionuclide has great potential as a theranostic agent. However, the success of ⁶⁴Cu-ATSM internal radiation therapy would depend on the contribution of Auger electrons to tumor cell killing. Therefore, we designed a cell culture system to define the contributions to cell death from Auger electrons to support or refute our hypothesis that the majority of cell death from ⁶⁴Cu-ATSM is a result of high-LET Auger electrons and not positrons or other low-LET radiation. Chinese hamster ovary (CHO) wild type and DNA repair–deficient xrs5 cells were exposed to ⁶⁴Cu-ATSM during hypoxic conditions. Surviving fractions were compared with those surviving gamma-radiation, low-LET hadron radiation, and high-LET heavy ion exposure. The ratio of the D₁₀ values (doses required to achieve 10% cell survival) between CHO wild type and xrs5 cells suggested that ⁶⁴Cu-ATSM toxicity is similar to that of high-LET Carbon ion radiation (70 keV/μm). γH2AX foci assays confirmed DNA double-strand breaks and cluster damage by high-LET Auger electrons from ⁶⁴Cu decay, and complex types of chromosomal aberrations typical of high-LET radiation were observed after ⁶⁴Cu-ATSM exposure. The majority of cell death was caused by high-LET radiation. This work provides strong evidence that ⁶⁴Cu-ATSM damages DNA via high-LET Auger electrons, supporting further study and consideration of ⁶⁴Cu-ATSM as a cancer treatment modality for hypoxic tumors.     

Physical Functioning,Mental Health,and Quality of Life in Different Congenital Heart Defects: Comparative Analysis in 3538 Patients From 15 Countries

BackgroundWe compared physical functioning, mental health, and quality of life (QoL) of patients with different subtypes of congenital heart disease (CHD) in a large international sample and investigated the role of functional class in explaining the variance in outcomes across heart defects.MethodsIn the cross-sectional Assessment of Patterns of Patient-Reported Outcome in Adults with Congenital Heart Disease-International Study (APPROACH-IS), we enrolled 4028 adult patients with CHD from 15 countries. Diagnostic groups with at least 50 patients were included in these analyses, yielding a sample of 3538 patients (median age: 32 years; 52% women). Physical functioning, mental health, and QoL were measured with the SF-12 health status survey, Hospital Anxiety and Depression Scale (HADS), linear analog scale (LAS) and Satisfaction with Life Scale, respectively. Functional class was assessed using the patient-reported New York Heart Association (NYHA) class. Multivariable general linear mixed models were applied to assess the relationship between the type of CHD and patient-reported outcomes, adjusted for patient characteristics, and with country as random effect.ResultsPatients with coarctation of the aorta and those with isolated aortic valve disease reported the best physical functioning, mental health, and QoL. Patients with cyanotic heart disease or Eisenmenger syndrome had worst outcomes. The differences were statistically significant, above and beyond other patient characteristics. However, the explained variances were small (0.6% to 4.1%) and decreased further when functional status was added to the models (0.4% to 0.9%).ConclusionsSome types of CHD predict worse patient-reported outcomes. However, it appears that it is the functional status associated with the heart defect rather than the heart defect itself that shapes the outcomes.     

Randomized controlled trial of sour milk on blood pressure in borderline hypertensive men

BACKGROUND: A double-blind randomized controlled trial was carried out to assess the effect of sour milk, containing two tripeptides (valine-proline-proline and isoleucine-proline-proline), on blood pressure (BP). METHODS: A total of 46 borderline hypertensive men aged 23 to 59 years were recruited at their workplace for this trial. Subjects were randomly allocated into two groups; sour milk drink group (S-group, n = 23) and placebo (acidified milk) drink group (P-group, n = 23) for 4 weeks. Blood pressure was measured twice at each occasion by a physician, at the health center of the company, with a mercury at baseline, 2 and 4 weeks. Statistical analysis was performed by SPSS 10.0J. RESULTS: The S-group and P-group showed no significant difference in baseline systolic BP (mean [SD], S: 147.6 [9.6], P: 145.3 [13.0]) or diastolic BP (S: 95.3 [9.9], P: 91.5 [9.6]). In the S-group, change in systolic BP at 2 and 4 weeks were -4.3 mm Hg (95% confidence interval [CI] -8.3 to -0.4; P = .032) and -5.2 mm Hg (95% CI -10.1 to -0.3; P = .039), both statistically significant. Diastolic BP showed change from -1.7 mm Hg (95% CI -5.4 to 2.0) at 2 weeks and -2.0 (95% CI -5.4 to 1.5) at 4 weeks, respectively. In the P-group, change in systolic BP were -0.5 (95% CI -5.8 to 4.8) at 2 weeks and -3.7 (95% CI -8.3 to 0.9) and change in diastolic BP were -0.6 (95% CI -4.7 to 3.6) and -0.3 (95% CI -3.9 to 3.3), which were not statistically significant. CONCLUSIONS: This trial demonstrated the beneficial effect of sour milk on BP in borderline hypertensive men who were not taking antihypertensive medication.     

Trends in age and anthropometric data at start of growth hormone treatment for girls with Turner syndrome in Japan

The purpose of this study is to evaluate the trends in age and anthropometric data for girls with Turner syndrome (TS) at start of growth hormone (GH) treatment in Japan. The data for analysis were obtained from a retrospective cohort, the Foundation for Growth Science, Japan. We analyzed trends in starting age of GH treatment for girls with TS in Japan after dividing subjects (n=1,478) into three registration periods: 1991-1994, 1995-1999 and 2000-2004. We also assessed the ratio of the subpopulation of subjects under five years of age. As results, the mean age (standard deviation (SD)) at start of GH treatment was significantly different among the three groups (10.95 (3.63), 10.15 (3.39) and 8.78 (3.61), p<0.0001). The proportion of the subjects under five years of age increased significantly over time (5.11%, 7.11% and 16.85%, p<0.0001). Mean (SD) height SD scores were also significantly different (-3.41 (0.87), -3.26 (0.81) and -3.17 (0.79), p<0.0001). However, the proportions of the karyotype of 45,X were not significantly different among the three groups (p=0.25). We concluded that age and shortness at initiation of GH treatment had been improving over time. However, these favorable trends have not fully met the conditions recommended by international clinical guidelines for TS.     

Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) has a high mortality rate, and current therapies are only marginally effective. A serum biomarker that predicts clinical outcome would be useful to stage disease, indicate prognosis and the need for aggressive therapy, and help stratify patients for clinical trials. The goals of this study were to determine whether serum levels of surfactant protein-A (SP-A) or surfactant protein-D (SP-D) would distinguish between IPF and other types of interstitial lung disease and whether serum SP-A or SP-D levels predict outcome in patients with IPF. The authors found that serum SP-A and SP-D levels were significantly elevated in patients with IPF and systemic sclerosis compared to sarcoidosis, beryllium disease and normal controls, and that SP-D correlated with radiographic abnormalities in patients with IPF. In addition, the authors found that both serum SP-A and SP-D levels were highly predictive of survival in patients with IPF. This is the largest North American data set of surfactant protein measurements in idiopathic pulmonary fibrosis and the first report using multivariate analysis comparing serum surfactant proteins-A and -D to other commonly measured predictors of survival in idiopathic pulmonary fibrosis. Based on these results, the authors propose that serum surfactant proteins may prove to be useful biomarkers in patients with idiopathic pulmonary fibrosis.     

Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa,the Usher syndrome 1B protein

Mutations in the myosin VIIa gene (MYO7A) cause Usher syndrome type 1B (USH1B), a major type of the deaf-blind disorder, Usher syndrome. We have studied mutant phenotypes in the retinas of Myo7a mutant mice (shaker1), with the aim of elucidating the role(s) of myosin VIIa in the retina and what might underlie photoreceptor degeneration in USH1B patients. A photoreceptor defect has been described. Here, we report that the phagocytosis of photoreceptor outer segment disks by the retinal pigment epithelium (RPE) is abnormal in Myo7a null mice. Both in vivo and in primary cultures of RPE cells, the transport of ingested disks out of the apical region is inhibited in the absence of Myo7a. The results with the cultured RPE cells were the same, irrespective of whether the disks came from wild-type or mutant mice, thus demonstrating that the RPE is the source of this defect. The inhibited transport seems to delay phagosome-lysosomal fusion, as the degradation of ingested disks was slower in mutant RPE. Moreover, fewer packets of disk membranes were ingested in vivo, possibly because retarded removal of phagosomes from the apical processes inhibited the ingestion of additional disk membranes. We conclude that Myo7a is required for the normal processing of ingested disk membranes in the RPE, primarily in the basal transport of phagosomes into the cell body where they then fuse with lysosomes. Because the phagocytosis of photoreceptor disks by the RPE has been shown to be critical for photoreceptor cell viability, this defect likely contributes to the progressive blindness in USH1B.     

Anti-eosinophil peroxidase antibodies detected in patients with primary biliary cirrhosis.

OBJECTIVE:: The possible involvement of eosinophils in primary biliary cirrhosis (PBC) has been suggested for many years. Activated eosinophils release basic granule proteins and are thought to be involved in the tissue damage of PBC. Eosinophil peroxidase (EPO) is one of the eosinophilic granule proteins and is toxic to epithelial cells. In this study, we examined whether autoantibodies to EPO are present in sera of patients with PBC and we evaluated the relationship between the presence of anti-EPO antibodies and the clinical features of PBC. METHODS:: Sera obtained from 61 patients with PBC, 31 patients with autoimmune hepatitis (AIH), 87 patients with chronic viral hepatitis (CVH), 27 patients with bronchial asthma, and 20 healthy controls were examined. Enzyme-linked immunosorbent assay (ELISA) and Western blot methods were used for detection of anti-EPO antibodies. RESULTS:: The mean OD value of anti-EPO antibodies, as determined by ELISA, was significantly (p<0.01) higher in patients with PBC (0.197+/-0.121) than in patients with AIH (0.124+/-0.077), CVH (0.090+/-0.038) or bronchial asthma (0.073+/-0.025) and in healthy controls (0.072+/-0.029). The results of ELISA showed that 32 (52.5%) of the 61 patients with PBC, 9 (29.0%) of the 31 patients with AIH, 7 (8.0%) of the 87 patients with CVH, and 1 (3.7%) of the 27 patients with bronchial asthma were positive for anti-EPO antibodies. In addition, PBC patients who were positive for anti-EPO antibodies had a significantly smaller number of peripheral eosinophils than did patients who were negative for anti-EPO antibodies (99.2+/-54.4cells/mul versus 176.9+/-117.5cells/mul, p<0.01). However, there was no correlation between the titers of anti-EPO antibodies and those of AMA or AMA-M2, ANA or serum levels of IgM. CONCLUSIONS:: This is the first report of the detection of anti-EPO antibodies in patients with PBC. Further study is needed to clarify the role of anti-EPO antibodies in the pathogenesis of PBC.