Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer

Purpose

While their negative impact on bone health is well established, the effects of aromatase inhibition (AI) on Wnt inhibitors and osteoprotegerin (OPG) are unknown. The aim of the study was to investigate the effects of AI on serum levels of sclerostin, DKK-1 and OPG, as well as their associations with PINP and CTX as markers of bone turnover and bone mineral density (BMD) assessed by DXA.

Methods

We conducted a prospective longitudinal analysis of 70 postmenopausal women with hormone receptor-positive early breast cancer (BC) treated with anastrozole. All measurements were performed at baseline, 12 and 24 months of treatment. We measured the association of the investigated variables with circulating bone turnover markers, as well as with the BMD.

Results

After 24 months of AI therapy, sclerostin and OPG concentrations increased from 29.5 pmol/l (SD = 15.1) and 6.8 pmol/l (SD = 2.2) at baseline to 43.2 pmol/l (SD = 20.6) (p < 0.001) and 7.4 pmol/l (SD = 2.2) (p = 0.028), respectively. DKK-1 levels decreased from 34.3 pmol/l (SD = 13.5) at baseline to 29.7 pmol/l (SD = 12.3) at the 24-month visit (p = 0.005). Sclerostin levels significantly correlated with PTH, OPG and BMD of the lumbar spine, while DKK-1 correlated with the BMD of the femoral neck and of the total hip.

Conclusions

The observed increase in sclerostin levels indicates a central role of osteocytes in bone turnover in women with BC.     

Production of prostaglandin E2 in monocytes stimulated in vitro by Chlamydia trachomatis, Chlamydophila pneumoniae, and Mycoplasma fermentans

Chlamydia trachomatis (CT) as well as Chlamydophila pneumoniae (CP) cause chronic inflammatory diseases in humans. Persistently infected monocytes are involved in the pathogenesis by inducing mediators of inflammation. An in vitro system of chlamydial persistence in human peripheral blood monocytes (HPBM) was used to investigate prostaglandin E(2) (PGE(2)) production and the expression of the key enzyme for prostaglandin production, cyclooxygenase-2 (COX-2). PGE(2) production was determined by PGE(2)-ELISA of HPBM-culture supernatants. Cox-2 mRNA expression was measured by real-time RT-PCR of total RNA isolated from HPBM. Both, CT and CP, stimulated PGE(2) production of HPBM in vitro. Equivalent numbers of CT per host cell induced a higher PGE(2)-response compared to CP. The amount of synthesized PGE(2) depended on the chlamydial multiplicity of infection (MOI). Even at an MOI of 10 the amount of CT- and CP-induced prostaglandin, respectively, was lower than the amount of prostaglandin induced by E. coli lipopolysaccharide (LPS) at a concentration of 10microg/ml. In contrast to stimulation with LPS, Chlamydia-induced PGE(2) production as well as cox-2 mRNA decreased after day 1 post infection (p.i.). These data indicate that Chlamydia stimulate PGE(2) production in human monocytes. Since Chlamydia are often contaminated by mycoplasma, the influence of mycoplasma on the prostaglandin production was investigated additionally. Mycoplasma fermentans (MF) also stimulated PGE(2) production. The co-infection of mycoplasma and Chlamydia resulted in an additive effect in the production of PGE(2). Thus it is important to use host cells and Chlamydia free of mycoplasma contamination for the analysis of Chlamydia-induced prostaglandin production.     

Tobacco smoke: Unraveling a controversial subject

Cigarettes are a modern and industrial form of tobacco use and obviously involve more than just tobacco. A multitude of physical processes and chemical reactions occur inside the burning zone of a cigarette. Cigarette smoke is an aerosol of liquid droplets (the particulate phase) suspended within a mixture of gases and semi-volatile compounds. Two kinds of smoke with different composition and properties are produced during smoking: mainstream smoke inhaled by the smoker and sidestream smoke, which is released into the environment between puffs from the lit end of the cigarette. Several techniques and modifications have altered the design of the cigarette during the last 50 years and changed smoke composition, with the effect of lower tar and nicotine smoke yields. An enormous amount of research has been done since the 1950s on smoke composition. With regard to the numerous toxic or carcinogenic constituents identified in tobacco smoke, there is a strong focus in the industry and with the authorities on the over 40 compounds, called "Hoffmann analytes". The yields of tar and nicotine in mainstream smoke of a cigarette brand as printed on the pack are measured with smoking machines under highly standardized conditions. Yields must comply with regulatory limits set in a number of countries. Smoking by machine is different from the smoking behavior of humans. There is a growing movement to develop more "realistic" methods to estimate smoke yields. But it is unclear whether alternative smoking regimens are more representative of human smoking behavior and provide better predictions of human exposure. Tobacco smoke has strong biological and toxicological effects in vitro and in vivo. There is an obvious need for developing a unified and validated testing approach particularly for the assessment of additives and the evaluation of new potentially reduced exposure products (PREPs). This paper gives a comprehensive overview of cigarette design, the composition and toxicity testing of smoke, and the way machines and people smoke - with links to the more detailed literature.     

The appropriateness of surveillance colonoscopy intervals after polypectomy

BACKGROUND:

Adherence to surveillance colonoscopy guidelines is important to prevent colorectal cancer (CRC) and unnecessary workload.

OBJECTIVE:

To evaluate how well Canadian gastroenterologists adhere to colonoscopy surveillance guidelines after adenoma removal or treatment for CRC.

METHODS:

Patients with a history of adenomas or CRC who had surveillance performed between October 2008 and October 2010 were retrospectively included. Time intervals between index colonoscopy and surveillance were compared with the 2008 guideline recommendations of the American Gastroenterological Association and regarded as appropriate when the surveillance interval was within six months of the recommended time interval.

RESULTS:

A total of 265 patients were included (52% men; mean age 58 years). Among patients with a normal index colonoscopy (n=110), 42% received surveillance on time, 38% too early (median difference = 1.2 years too early) and 20% too late (median difference = 1.0 year too late). Among patients with nonadvanced adenomas at index (n=96), 25% underwent surveillance on time, 61% too early (median difference = 1.85) and 14% too late (median difference = 1.1). Among patients with advanced neoplasia at index (n=59), 29% underwent surveillance on time, 34% too early (median difference = 1.86) and 37% later than recommended (median difference = 1.61). No significant difference in adenoma detection rates was observed when too early surveillance versus appropriate surveillance (34% versus 33%; P=0.92) and too late surveillance versus appropriate surveillance (21% versus 33%; P=0.11) were compared.

CONCLUSION:

Only a minority of surveillance colonoscopies were performed according to guideline recommendations. Deviation from the guidelines did not improve the adenoma detection rate. Interventions aimed at improving adherence to surveillance guidelines are needed.     

Consequences of vanishing twins in IVF/ICSI pregnancies

BACKGROUND: Spontaneous reductions are a possible cause of the increased morbidity in IVF singletons. The aim of this study was to assess incidence rates of spontaneous reductions in IVF/ICSI twin pregnancies and to compare short- and long-term morbidity in survivors of a vanishing co-twin with singletons and born twins. METHODS: We identified 642 survivors of a vanishing co-twin, 5237 singletons from single gestations and 3678 twins from twin gestations. All children originated from pregnancies detected by transvaginal sonography in gestational week 8. By cross-linkage with the national registries the main endpoints were prematurity, birth weight, neurological sequelae and mortality. RESULTS: Of all IVF singletons born, 10.4% originated from a twin gestation in early pregnancy. Multiple logistic regression analyses adjusted for maternal age, parity and ICSI treatment showed for birth weight <2500 g an odds ratio (OR) of 1.7 [95% confidence interval (CI) 1.2-2.2] and for birth weight <1500 g OR 2.1 (95% CI 1.3-3.6) in singleton survivors of a vanishing twin versus singletons from single gestations; corresponding figures were seen for preterm birth. This increased risk was almost entirely due to reductions that occurred at >8 weeks gestation. We found no excess risk of neurological sequelae in survivors of a vanishing co-twin versus the singleton cohort; however, OR of cerebral palsy was 1.9 (95% CI 0.7-5.2). Furthermore, we observed a correlation between onset of spontaneous reduction, i.e. the later in pregnancy the higher the risk of neurological sequelae (r = -0.09; P = 0.02). Adjusted OR of child death within the follow-up period was 3.6 (95% CI 1.7-7.6) in the survivor versus the singleton cohort. CONCLUSIONS: One in 10 IVF singletons originates from a twin gestation. Spontaneous reductions that occur at >8 weeks gestation are one of the causes for the higher risk of adverse obstetric outcome in IVF singletons.     

Health and social service use among old people in the last 2 years of life

This study focuses on differences in health and social service use in the last 2 years of life among Finnish people aged 70–79, 80–89, and 90 or older and on the variation in service use in the various municipalities. The data set, derived from multiple national registers, consists of 75,578 people who died in 1998–2001. The services included hospitals and long-term-care facilities, use of regular home care, and prescribed medicines. General hospital and public long-term care were the services most commonly used: general hospitals for younger age groups and public long-term care for older groups. The number of inpatient days in hospital was lower with increasing age, but older age groups used long-term care more frequently. Men had more hospital inpatient days than women, but women used more long-term care. The number of hospital inpatient days increased rapidly in the last months of life, almost doubling in the final month. Days in public long-term care increased regularly in the last 2 years of life. Variation in both hospital and long-term care by municipality was remarkable. The results indicate that, among people aged 70 years and older, age is a major determinant of care in the last 2 years of life. The variation in the use of care by municipality and the differences between men and women deserve more detailed analysis in future.     

A prospective study of anti-chromatin and anti-C1q autoantibodies in patients with proliferative lupus nephritis treated with cyclophosphamide pulses or azathioprine/methylprednisolone

OBJECTIVE: To study the prevalence and course of anti-chromatin (anti-nucleosome, anti-double-stranded (ds) DNA and anti-histone) and anti-C1q autoantibodies in patients with proliferative lupus nephritis (LN), treated in a randomised controlled trial with either cyclophosphamide or azathioprine plus methylprednisolone. METHODS: Autoantibody levels were measured and analysed in 52 patients with proliferative LN, during their first year of treatment. Levels in both treatment arms were compared and associations with clinical, serological and outcome parameters were studied. RESULTS: At study entry, prevalences for anti-nucleosome, anti-dsDNA, anti-histone and anti-C1q autoantibodies were 81%, 96%, 23% and 65%, respectively. Anti-chromatin autoantibodies correlated with each other, but not with anti-C1q levels. If patients were divided for their autoantibody titre at the start of treatment above or below the median, the only significant differences were higher SLE disease activity index with higher anti-nucleosome, and higher creatinine with higher anti-C1q autoantibodies. During the first year, a comparable rapid decline in the levels of anti-nucleosome, anti-dsDNA and anti-C1q autoantibodies was seen in both treatment arms. Anti-histone autoantibody levels were low and did not change. Renal flares were not preceded by rises in autoantibody titres. CONCLUSIONS: These results indicate that measurement of anti-chromatin and anti-C1q autoantibodies is useful for diagnosing LN, but not for monitoring disease course.     

幽门螺杆菌感染处理的当前观念——MaastrichtⅢ共识报告

名词缩写 欧洲幽门螺杆菌研究小组：European Helicobacter Study Group，EHSG 胃食管反流病：gastro-esophageal reflux disease，GERD     

Sex determination in skeletal remains from the medieval Eastern Adriatic coast – discriminant function analysis of humeri

Aim

To investigate the usefulness of humerus measurement for sex determination in a sample of medieval skeletons from the Eastern Adriatic Coast. Additional aim was to compare the results with contemporary female population.

Methods

Five humerus measurements (maximum length, epicondylar width, maximum vertical diameter of the head, maximum and minimum diameter of the humerus at midshaft) for 80 male and 35 female medieval and 19 female contemporary humeri were recorded. Only sufficiently preserved skeletons and those with no obvious pathological or traumatic changes that could affect the measurements were included. For ten samples, analysis of DNA was performed in order to determine sex using amelogenin.

Results

The initial comparison of men and women indicated significant differences in all five measures (P < 0.001). Discriminant function for sex determination indicated that as much as 85% of cases could be properly categorized, with better results in men (86%) than women (80%). Furthermore, the comparison of the medieval and contemporary women did not show significant difference in any of the measured features. Sex results obtained by anthropological and DNA analysis matched in all 10 cases.

Conclusion

The results indicate that humerus measurement in Croatian medieval population may be sufficient to determine the sex of the skeleton. Furthermore, it seems that secular changes have not substantially affected contemporary population, suggesting that the results of this study are transferable to contemporary population as well.Once the skeletal remains are uncovered, anthropologists initially aim to reconstruct the biological profile of the person, which includes sex, age, and height estimation. During the reconstruction process, numerous issues may arise, including bone fragmentation and poor preservation of skeletal remains, coupled with the complexity of human skeleton (1,2). Sex determination is one of the first and basic steps of assessing the biological profile. Although the analysis of DNA is the most reliable method for sex determination (3), it is also the most expensive and time consuming method, which can also be hindered by local conditions. This may especially be true in cases of poor preservation of the remains, inhibitors effects, or a small amount of extracted DNA from the sample.In absence of DNA results, skeletal remains can be used to infer subject’s sex via two methods, morphological and anthropometric. The morphological approach is based on the examination of the bones that show the strongest sexual dimorphism, principally the skull and the pelvis (4). However, this method is not always reliable, especially if the skull is fragmented or incomplete. Age can also affect the results, especially in elderly women, in which morphological characteristics of the skull tend to resemble those of men (5). Although morphological methods are very important for a preliminary sex assessment, they additionally rely on the experience of the examiner and are therefore rather subjective and unreliable.The second approach is based on anthropometric analysis, which relies on the bone measurements. The main analytic approach is based on discriminant function analysis, which attempts to classify subjects into each of the sexes, by using either one or more bones (6). This kind of analysis is a very important quantitative method (7) for sex determination as it reduces the subjectivity of the examiner (2,4,8). So far, only a few such studies have been published using Croatian bone samples. These include medieval and contemporary femurs and tibias (8-11) and medieval and contemporary mandibles and teeth (6,12). Such studies are important, since clear differences were observed in different populations (13-15), making this a locally-specific feature that requires the development of regional standards, applicable for local population (16).Besides already used femurs and tibias, humerus is another long bone from the body that is presumably informative for sex determination. This idea was initially derived from the empirical investigations of the skeletal remains, and further supported by the previously reported sexual dimorphism of humeri (7,17), even in cases of severe bone fragmentation (18). Furthermore, such location-specific results may be of interest in modern forensics as well, since observed changes in the skeleton marked predominantly by the increase in height (19), appear to be proportional, with no indication of sexual dimorphism in ancient and modern samples (20). Therefore, the aim of this study was to investigate the possibility to determine the sex of the subject based on anthropometric analysis of humeri measures.