Reduced risk of prostate cancer among patients with diabetes mellitus

Although diabetes mellitus is associated with an increased risk of several malignancies, a negative association with prostate cancer is biologically most plausible. The epidemiologic evidence is, however, inconsistent, limited and based mostly on small studies. We present results from a large, population-based cohort study in Sweden, where we assessed prostate cancer risk among patients hospitalized for diabetes mellitus. The cohort was composed of patients identified in the Swedish In-Patient Register as having a hospital discharge diagnosis of diabetes mellitus in 1965-1994. The follow-up was done by linkages with the national cancer register and other population-based registers. Standardized incidence ratios (SIRs), with 95% confidence interval (CI), were used as a measure of relative risk. After complete exclusion of the first year of follow-up (to avoid selection bias), 135,950 men remained in the cohort, contributing 827,099 years of follow-up to the study. A total of 2,455 incident cases of primary prostate cancer were identified during 1-31 years of follow-up, yielding an overall SIR of 0.91 (95% CI 0.87-0.94); this risk reduction was more pronounced among patients who have been hospitalized for diabetic complications (SIR = 0.82; 95% CI 0.74-0.91). We found no consistent trends in risk related to age at first hospitalization or to duration of follow-up. We did find a small, but significantly decreased risk of prostate cancer among men who had been hospitalized for diabetes mellitus.     

The need for preventive drugs and vaccines in global cancer control: a challenge for public health and for industry

Ten million new cancer patients are diagnosed worldwide each year. There will be a dramatic increase over the next 20 years in the number of people contracting cancer, especially in the developing, poorer part of the world. Many types of cancer vary in incidence and mortality by more than an order of magnitude between different populations, and every type is rare in some part of the world, suggesting that cancers are in principle preventable. Many specific causes of cancer are known, from factors related to lifestyle, diet, infections and occupations. The remarkable advances in molecular understanding of the carcinogenesis process over the past 25 years have transformed the approaches in cancer control. About 15% of cancers worldwide are caused by known infectious agents. Human papillomavirus vaccines, which are already being tested, may, in the long run, be able to prevent almost all cervical cancers. New promising disciplines in prevention, such as chemoprevention, have emerged. Chemoprevention has been successfully achieved in numerous animal experiments, and has been validated in several clinical trials. But more effective and safer chemopreventive agents and vaccines are needed. Rising prices of medicines and vaccines are putting them beyond the reach of many people, even in rich countries. Future enhanced efforts on an international basis are needed to guarantee access to these lifesaving drugs and vaccines. Putting prevention high on the agenda requires political courage and a long-term perspective.     

Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer's disease

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. The neuropathological hallmarks include extracellular senile plaques consisting of deposited beta-amyloid (Abeta) peptides and intraneuronal neurofibrillary tangles. Neuroinflammation and activation of astrocytes are also well-established features of AD neuropathology; however, the relationships between astrocytes and Abeta deposition remain unclear. Previous studies have shown that adult mouse astrocytes internalize and degrade Abeta deposits in brain sections prepared from human amyloid precursor protein (APP) transgenic mice. In the present study, we demonstrate that cultured adult, but not neonatal mouse astrocytes, respond morphologically and degrade Abeta deposits present in human AD brain. We also transplanted astrocytes isolated from enhanced green fluorescent protein expressing adult and neonatal mice into the hippocampi of human Abeta plaque-bearing transgenic APPSwe+PS1dE9 (APdE9) mice and their wild-type littermates and followed the migration and localization of these astrocytes by confocal microscopy upto 7 days after transplantation. Posttransplantation the astrocytes localized as aggregates or thin strings of many cells within the hippocampi of APdE9 and wild-type mice and showed limited migration from the injection site. Interestingly, most of the transplanted astrocytes were found near Abeta deposits in the hippocampi of APdE9 mice. In contrast to findings in ex vivo degradation assay, confocal microscopy revealed that both adult and neonatal transplanted astrocytes internalized human Abeta immunoreactive material in vivo. These results support the role of astrocytes as active Abeta clearing cells in the CNS that may have important implications for future development of therapeutic strategies for AD.     

Modulation of the mismatch negativity (MMN) to vowel duration changes in native speakers of Finnish and German as a result of language experience.

While crucial for phoneme distinctions in the Finnish language, mere vowel duration is of lower relevance as a phonetically distinctive cue in the German language. To investigate the pre-attentive processing of vowel duration between these two languages, the mismatch negativity (MMN), a component of the auditory event-related potential (ERP) that is an index of automatic auditory change detection, was measured in Finnish and German native speakers for vowel duration changes embedded in the pseudoword sasa. Vowel duration changes thereby were presented as a shortening or a lengthening of either the first- or second-syllable vowel. An additional non-speech condition measured the MMN to duration and frequency changes in tones. In both language groups, diminished MMN amplitudes for the shortening of vowel duration in the word-final syllable suggested a generally more difficult discrimination of vowel duration in a word-final position. Further, shorter MMN latencies for the Finns than the Germans for vowel duration as well as tone duration deviants suggested a generally higher sensitivity to duration contrasts in the Finnish language group. No latency difference between the groups was found for tone frequency processing. Moreover, the Finns, but not the Germans, showed a leftward shift of the MMN scalp distribution for changes in vowel duration, whereas the MMN topography was highly similar between both groups in the tone condition. An enhanced phonetic processing of vowel duration changes and possibly an enhanced processing of sound duration in general is thus indicated for the Finns as a result of their extensive linguistic experience with phonetically distinctive vowel duration contrasts in the native language.     

Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1)

Polymorphonuclear leukocytes (PMNs) migrate from the blood into areas of inflammation by binding to the endothelial cells of blood vessels via adhesion molecules. Vascular adhesion protein-1 (VAP-1) is one of the molecules mediating leukocyte-endothelial cell interactions. It is also an endothelial cell-surface enzyme (amine oxidase) that produces reactive oxygen species during the catalytic reaction. To study the role of the enzymatic activity of VAP-1 in PMN extravasation, we used an enzymatically inactive VAP-1 mutant, specific amine oxidase inhibitors (including a novel small molecule compound), and anti-VAP-1 antibodies in several flow-dependent models. The enzyme inhibitors diminished PMN rolling on and transmigration through human endothelial cells under conditions of laminar shear stress in vitro. Notably, the enzyme inactivating point mutation abolished the capacity of VAP-1 to mediate transmigration. Moreover, the new VAP-1 inhibitor effectively prevented the extravasation of PMNs in an animal model of inflammation. These data show that the oxidase activity of VAP-1 controls PMN exit from the blood during the relatively poorly understood transmigration step.     

Bacterial components in the synovial tissue of patients with advanced rheumatoid arthritis or osteoarthritis: Analysis with gas chromatography‐mass spectrometry and pan‐bacterial polymerase chain reaction

Objective

To study the presence of bacterial components in the synovial tissue (ST) of patients with advanced rheumatoid arthritis (RA).

Methods

ST was collected during joint surgery from 41 RA patients. Tissue from 39 patients with osteoarthritis (OA), 4 patients with undifferentiated inflammatory arthritis (UA), and 3 cases of accidental deaths served as controls. The pan‐bacterial polymerase chain reaction (PCR) with primers for the 23S ribosomal RNA (rRNA) and 16S rRNA genes was used to detect bacterial DNA. In addition, synovial fluid (SF) samples from patients with chlamydial reactive arthritis (ReA) were also examined by the same method. The positive controls, bacterial DNA or ST spiked with different living bacteria, were analyzed alongside clinical samples. Most of the ST samples were also analyzed by gas chromatography‐mass spectrometry (GC‐MS) for determining the presence of bacteria‐derived muramic acid. Strict precautions were followed in the clinics and the laboratory to prevent contamination.

Results

In GC‐MS analysis, muramic acid was observed in the ST from 4 of 35 RA patients and from 2 of 14 OA patients, but not in ST from 2 patients with UA and 3 cadavers. Bacterial DNA was not detected by either one of the PCR primers used in ST from 42 patients with RA and 39 patients with OA. However, 5 of 15 SF samples from ReA patients were PCR positive. The sensitivity of GC‐MS to detect muramic acid was 2 pg/injected amount (227 pg muramic acid/mg ST), and that of the pan‐bacterial PCR was 2–20 bacteria colony forming units/reaction.

Conclusion

These results indicate that a bacterial component, muramic acid, is detectable by GC‐MS in ST from a few patients with advanced RA or OA. However, no bacterial DNA was detectable by PCR.

     

A rosette assay for identification of Ia-like alloantigens on chicken lymphoid cells

An Ia-rosette assay for the detection of Ia-like alloantigens on the chicken lymphoid cell surface is described. The method is based on the ability of cells treated with allo-antiserum to Ia and then with rabbit antiserum against the Fc portion of chicken IgG, to form rosettes with sheep erythrocytes (SRBC) coated with chicken anti-SRBC IgG antibody. Interference with Ia-rosette formation by Fc IgG receptors was eliminated by pronase treatment which removes Fc receptor activity without affecting Ia antigens. The Ia-rosette assay is at least as sensitive as the triple-layer immunofluorescence test for identification of Ia antigens. In addition, the assay allows morphological study and separation of the rosetting cells.