Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival.

Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromsø study (1994-2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose-response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01-1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01-2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8-1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31-4.03) and 2.08 (95 % CI 1.16-3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70-0.97), and a 22 % reduction in overall mortality (95 % CI 0.62-0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre-diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution.

[Laboratory diagnosis of cobalamin deficiency. A comparative study of 2 serum cobalamin methods and serum methylmalonic acid]. / Laboratoriediagnostik af cobalaminmange. En sammenlignende undersøgelse af to serum-cobalaminmetoder og serum-metylmalonat.

The diagnosis of cobalamin deficiency is established traditionally by demonstration of lowered serum cobalamin, but, for many reasons it cannot be anticipated that the concentrations of cobalamins in the serum reflect the relationship between blood cobalamin and tissue cobalamin accurately. The blood methylmalonic acid which cannot be metabolized in cases of cellular cobalamin deficiency should, on the other hand, indicate the cobalamin available for the tissues. A blind, prospective, controlled investigation was undertaken to compare the clinical employability of a recently developed method for measurement of the concentration of methylmalonic acid in the serum with older and more recent methods of measuring serum cobalamins. The three methods classified 94, 72 and 74% of the patients correctly, respectively (n = 50). The results reveal that serum methylmalonic acid is a more sensitive and specific analysis for demonstrating whether cobalamin deficiency was present or not. Serum cobalamins measured by both methods are relatively insensitive and unspecific markers for cobalamin deficiency in the tissue. Low cobalamin concentrations do not indicate that the patient in question has cobalamin deficiency, and values in the lower half of the reference interval do not exclude cobalamin deficiency. Measurement of methylmalonic acid in the serum is recommended in patients with low-normal or low serum cobalamin.

HPV mRNA test in women with minor cervical lesions: experience of the University Hospital of North Norway.

In the Norwegian Cervical Cancer Screening Programme tests for detection of human papillomavirus (HPV) are used to triage women with minor cytological cervical lesions. The material in this study comprises samples from 1798 women in the period 2006-2008. The HPV test was performed according to the guidelines of the Norwegian Cancer Registry. The HPV mRNA test (PreTect HPV-Proofer) detects and types 5 high-risk genotypes (16, 18, 31, 33 and 45). The HPV mRNA results were compared to cytology and then biopsy up to December 2009. Women with minor cytological cervical lesions and negative HPV test were followed with a new PAP smear after 12 months. A total of 327 women (18%) were HPV mRNA positive. Of the 1798 women with minor cytological lesions, 232 women (13%) had moderate dysplasia, severe dysplasia or cancer and 144 women (8%) had severe dysplasia or cancer in biopsy. 57% of the women with a positive HPV mRNA test had moderate dysplasia, severe dysplasia or cancer. 37% had severe dysplasia or cancer. The sensitivity of the HPV mRNA test to detect moderate dysplasia, severe dysplasia or cancer was 81%. The specificity for moderate dysplasia, severe dysplasia or cancer was 91%. The negative predictive value (NPV) of the HPV mRNA test for moderate dysplasia, severe dysplasia or cancer was 97%. Of 11 women with cervical cancer, 10 were positive for HPV type 16 or 18. The HPV mRNA test seems more suitable than HPV DNA tests to triage women with minor cytological cervical lesions due to its higher specificity.

Circulating chromatin-anti-chromatin antibody complexes bind with high affinity to dermo-epidermal structures in murine and human lupus nephritis.

Murine and human lupus nephritis are characterized by glomerular deposits of electron-dense structures (EDS). Dominant components of EDS are chromatin fragments and IgG antibodies. Whether glomerular EDS predispose for similar deposits in skin is unknown. We analysed (i) whether dermo-epidermal immune complex deposits have similar molecular composition as glomerular deposits, (ii) whether chromatin fragments bind dermo-epidermal structures, and (iii) whether deposits in nephritic glomeruli predispose for accumulation of similar deposits in skin. Paired skin and kidney biopsies from nephritic (NZBxNZW)F1 and MRL-lpr/lpr mice and from five patients with lupus nephritis were analysed by immunofluorescence, immune electron microscopy (IEM) and co-localization TUNEL IEM. Affinity of chromatin fragments for membrane structures was determined by surface plasmon resonance. Results demonstrated (i) presence of EDS containing chromatin fragments and IgG in both organs in nephritic patients, (ii) chromatin fragments possessed high affinity for dermo-epidermal laminins and collagens, (iii) glomerular immune complex deposits did not predict similar interstitial deposits in skin, although such complexes were present in capillary lumina in glomeruli and skin of all nephritic individuals. Thus, chromatin-IgG complexes accounting for lupus nephritis seem to reach skin through circulation, but other undetermined factors are required for these complexes to deposit within skin membranes.

Frequency of acute asymptomatic myocardial infarction and an estimate of infarct age in cases of abrupt sudden death observed in a forensic autopsy material.

The aim of this study is to determine the frequency of acute infarcts at autopsy in cases of unexpected abrupt deaths in persons with coronary heart disease. In addition, we want to estimate the time between onset of infarct and death based on evolving tissue changes in the infarct known to occur during the first hours. Thirty cases of unexpected, abrupt deaths were selected from a forensic autopsy material. Half of them had a preliminary diagnosis of coronary heart disease, the other half a preliminary diagnosis not involving the heart or chest area. Complete autopsies were performed. The myocardium and the coronary arteries were sampled and examined without knowledge of the gross findings or to which group the case belonged. Myocardial infarcts and acute coronary changes were found in both groups, less frequently in the non-coronary group. The age of the myocardial and coronary lesions was estimated by observing morphological characteristics changing with time, e.g. increasing polymorphonuclear leucocytes in the infarcted myocardium, and increasing amount of fibrin in thrombi. The majority of cases in the coronary group died with an extensive asymptomatic myocardial infarction, which probably had lasted 5-6 hrs or less. Acute changes in the right coronary artery and its area of supply prevailed. Acute myocardial infarcts were observed also in a minority of the non-coronary group, but myocardial infarction was not the cause of death in any of them. Abrupt coronary death is most often preceded by an extensive asymptomatic myocardial infarction within the last 5-6 hrs.

Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis.

Antibodies to double-stranded (dsDNA) are associated with systemic lupus erythematosus (SLE) and directly involved in human lupus nephritis. Information about their glomerular target antigens is inconsistent, and whether availability of target antigens, antibody specificity or avidity are nephritogenic parameters, is not determined. In this study, we analyzed renal tissue from anti-dsDNA antibody-positive lupus patients with nephritis by morphological and immunological assays, including immune electron microscopy (IEM) and colocalization IEM, an EM-based confocal microscopy assay. IEM demonstrated that antibody deposits were confined to electron dense structures (EDS) in glomerular membranes. These autoantibodies colocalized with nucleosome-binding anti-dsDNA/-histone/-transcription factor antibodies. To confirm the colocalization IEM-data, we developed a colocalization terminal deoxynucleotidyl-transferase (TdT) biotin-dUTP nicked end-labeled (TUNEL) IEM assay where extracellular DNA was traced by TdT-mediated introduction of biotinylated nucleotides and autoantibodies by IEM. Results consistently demonstrated that DNA colocalized with autoantibodies in glomerular membrane-associated EDS. The colocalization IEM and colocalization TUNEL IEM assays thus demonstrate that intra-glomerular membrane-associated nucleosomes are targeted by anti-dsDNA autoantibodies in human lupus nephritis. The data provide a new approach to understand basic molecular and immunological processes accounting for antibody-mediated nephritis in human SLE.