Increased release of cervical nitric oxide in spontaneous abortion before clinical symptoms: a possible mechanism for preabortal cervical ripening

Nitric oxide (NO) affects cervical ripening. We studied cervical NO release in women with nonviable pregnancy before signs of abortion. Women with missed abortion (n = 56), blighted ovum (n = 36), or tubal pregnancy (n = 7) were selected by means of vaginal ultrasonographic examination from a population seeking early pregnancy termination; 140 women with amenorrhea-matched normal gestation were studied as controls. Cervical fluid samples were assessed for NO metabolites (Nox) by means of Griess reaction. Cervical fluid Nox was more often detectable in women with missed abortion (90%) and blighted ovum (87%) than in the control women (55%; P = 0.01), and Nox levels in women with missed abortion [median, 59.4 mumol/liter; 95% confidence interval (CI), 30.3-81.8] and blighted ovum (25.6 mumol/liter; 95% CI, 14.1-53.0) were 14 and 6 times higher (P < 0.001 and P = 0.002, respectively) than in the control group (4.3 mumol/liter; 95% CI, <3.8 to 6.4). Nox levels in women with tubal pregnancy were normal. In women with nonviable pregnancy, the lower the level of progesterone, expressed as a percentage of that in the control women, the higher (r = -0.69; P < 0.001) the level of cervical fluid Nox, and those with low pretreatment Nox levels failed to abort completely after mifepristone-misoprostol or expectant management more often (P = 0.04) than women with high Nox levels (28% vs. 4%); no such relationship was seen in the control group. Increased preabortal cervical NO release may contribute to cervical ripening and the onset of clinical abortion.     

Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma

A strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of 4 cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene, which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio = 4.11; P = .018). NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition.     

Associations between serum uric acid and markers of subclinical atherosclerosis in young adults. The cardiovascular risk in Young Finns study

Background and methodsSerum uric acid (SUA) is a suggested biomarker for established coronary artery disease, but the role of SUA in early phases of atherosclerosis is controversial. The relations of SUA with vascular markers of subclinical atherosclerosis, including carotid artery intima-media thickness (cIMT), carotid plaque, carotid distensibility (Cdist) and brachial flow-mediated dilatation (FMD) were examined in 1985 young adults aged 30–45 years. In addition to ordinary regression, we used Mendelian randomization techniques to infer causal associations.ResultsIn women, the independent multivariate correlates of SUA included BMI, creatinine, alcohol use, triglycerides, glucose and adiponectin (inverse association) (Model R² = 0.30). In men, the correlates were BMI, creatinine, triglycerides, C-reactive protein, alcohol use, total cholesterol and adiponectin (inverse) (Model R² = 0.33). BMI alone explained most of the variation of SUA levels both in women and men (Partial R² ～ 0.2). When SUA was modeled as an explanatory variable for vascular markers, it directly associated with cIMT and inversely with Cdist in age- and sex-adjusted analysis. After further adjustments for BMI or glomerular filtration rate, these relations were reduced to non-significance. No associations were found between SUA and FMD or the presence of a carotid plaque. Mendelian randomization analyses using known genetic variants for BMI and SUA confirmed that BMI is causally linked to SUA and that BMI is a significant confounder in the association between SUA and cIMT.ConclusionSUA is associated with cardiovascular risk markers in young adults, especially BMI, but we found no evidence that SUA would have an independent role in the pathophysiology of early atherosclerosis.     

Sensitivity of HCV RNA and HIV RNA blood screening assays

BACKGROUND: The FDA requirement for sensitivity of viral NAT methods used in blood screening is a 95-percent detection limit of 100 copies per mL, whereas the NAT screening system should have a sensitivity of at least 5000 copies per mL per individual donation. According to the Common Technical Specifications of the European Directive 98/79/EC for in vitro diagnostics, viral standard dilutions (calibrated against the WHO standard) should be tested at least 24 times for a statistically valid assessment of the 95-percent detection limit. STUDY DESIGN AND METHODS: Viral standard dilution panels (PeliCheck, VQC-CLB) were prepared for HCV RNA genotypes 1 and 3 and for HIV RNA genotypes B and E. In a multicenter study, 23 laboratories tested the panels all together in 8 to 91 test runs per NAT method. RESULTS: The following 95-percent detection limits (and 95% CIs) were found on the HCV RNA genotype 1 reference panels (shown as geq/mL): Gen-Probe TMA, 85 (64-118); AmpliScreen, 126 (83-225); AmpliScreen with NucliSens Extractor, 21 (13-44); Amplicor with NucliSens Extractor, 69 (50-102), and Amplicor with Qiagen extraction technology, 144 (74-102). On HIV RNA genotype B dilution panels, the following 95-percent detection limits were found (shown as geq/mL): Gen-Probe TMA, 31 (20-52); AmpliScreen, 126 (67-311); AmpliScreen with NucliSens Extractor, 37 (23-69), and NucliSens QL assay, 123 (51-566). HIV RNA genotype E panels were detected with equal sensitivity as HIV RNA genotype B panels. In the Gen-Probe TMA assay, the 50-percent detection limits on HIV RNA type B and type E were 3.6 (2.6-5.0) and 3.9 (2.4-5.8) geq per mL, respectively. The HCV RNA genotype 1 and 3 standards were detected with equal sensitivity. CONCLUSION: The differences in sensitivity between NAT assays can be explained by the input of isolated viral nucleic acid in the amplification reactions. The FDA requirements for sensitivity of NAT blood screening assays can be met by the Gen-probe TMA, as well as by the AmpliScreen assays, particularly when combined with the NucliSens Extractor.     

Genetic modifiers of degeneration in the cathepsin D deficient Drosophila model for neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCLs) are pediatric, neurodegenerative, lysosomal storage disorders. Mutations in cathepsin D result in the most severe, congenital form of NCLs. We have previously generated a cathepsin D deficient Drosophila model, which exhibits the key features of NCLs: progressive intracellular accumulation of autofluorescent storage material and modest neurodegeneration in the brain areas related to visual functions. Here we extend the phenotypic characterization of cathepsin D deficient Drosophila and report that modest degenerative changes are also present in their retinae. Furthermore, by utilizing this phenotype, we examined the possible effect of 17 candidate modifiers, selected based on the results from other cathepsin D deficiency models. We found enhancers of this phenotype that support the involvement of endocytosis-, lipid metabolism- and oxidation-related factors in the cathepsin D deficiency induced degeneration. Our results warrant further investigation of these mechanisms in the pathogenesis of cathepsin D deficiency.     

Injuries as a result of treatment of tibial fractures in children: Claims for compensation submitted to the Patient Insurance Center in Finland

Background and purpose Tibial fractures comprise 10% of all fractures in children. To our knowledge there have been no previous reports of treatment injuries in these fractures. We analyzed compensation claims concerning treatment of these fractures in Finland. We used this information to determine preventable causes of treatment injuries.Material and methods In Finland, the Patient Insurance Center (PIC) provides financial compensation for patients who have sustained an injury in connection with medical treatment or operation. We retrospectively analyzed all claims for compensation arising from treatment of tibial fractures in children that had been received by the PIC between 1997 and 2004. The mode of treatment, complications, and permanent sequelae were assessed. We also estimated the number of avoidable treatment injuries.Results and interpretation The PIC received 50 claims for compensation during the 8-year study period. The claims were based on the following issues: pain, incorrect diagnosis and treatment, permanent disability, extra treatment expenses, inappropriate behavior of the medical personnel, and loss of income of the parents. 35/50 claims had received compensation, of which 32 were related to the treatment and 3 to infections. The treatment injuries that had led to compensation comprised a delay in diagnosis and treatment in 15 patients, inappropriate casting in 9, inappropriate operative treatment in 5, and other causes in 3 patients. An unsatisfactory standard of treatment and missed diagnosis were the most common reasons for compensation. In restrospect, all but 1 of the 35 injuries that had led to compensation were considered to be avoidable.