Clinical review 165: Markers of bone remodeling in metastatic bone disease

Many cancers have a strong propensity to spread to bone. The processes involved in cancer dissemination to bone are complex and variable, and the changes in bone metabolism, once bony metastases have occurred, are usually profound. This review surveys the usefulness of bone markers in the diagnosis and follow-up of patients with malignant bone disease. In patients with established bone metastases, most markers of bone remodeling are abnormal compared with healthy controls or cancer patients without bone lesions. Although bone markers may have a potential as diagnostic tools in cancer patients, the available data do not allow final conclusions regarding the accuracy and validity of any of the presently used markers in the diagnosis of bone metastases. As regards monitoring of anticancer therapy, most markers of bone remodeling respond to active treatments. These indices therefore may have the potential to be used in the monitoring of antitumor therapies. However, most if not all of the available evidence on the use of bone markers in monitoring anticancer therapy is observational, and it remains unclear whether they have any beneficial effects on overall outcome. The same is true for their prognostic value, although evidence suggests that suppressed levels of bone formation or high rates of bone resorption are independent predictors of poor survival.     

The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus

Helicobacter hepaticus causes chronic hepatitis and liver cancer in mice. It is the prototype enterohepatic Helicobacter species and a close relative of Helicobacter pylori, also a recognized carcinogen. Here we report the complete genome sequence of H. hepaticus ATCC51449. H. hepaticus has a circular chromosome of 1,799,146 base pairs, predicted to encode 1,875 proteins. A total of 938, 953, and 821 proteins have orthologs in H. pylori, Campylobacter jejuni, and both pathogens, respectively. H. hepaticus lacks orthologs of most known H. pylori virulence factors, including adhesins, the VacA cytotoxin, and almost all cag pathogenicity island proteins, but has orthologs of the C. jejuni adhesin PEB1 and the cytolethal distending toxin (CDT). The genome contains a 71-kb genomic island (HHGI1) and several genomic islets whose G+C content differs from the rest of the genome. HHGI1 encodes three basic components of a type IV secretion system and other virulence protein homologs, suggesting a role of HHGI1 in pathogenicity. The genomic variability of H. hepaticus was assessed by comparing the genomes of 12 H. hepaticus strains with the sequenced genome by microarray hybridization. Although five strains, including all those known to have caused liver disease, were indistinguishable from ATCC51449, other strains lacked between 85 and 229 genes, including large parts of HHGI1, demonstrating extensive variation of genome content within the species.     

Resistin gene 3'-untranslated region +62G-->A polymorphism is associated with hypertension but not diabetes mellitus type 2 in a German population

OBJECTIVES: Resistin, a peptide hormone produced by adipocytes, has been associated with diabetes mellitus type 2 (DM-2) in some rodent models. In humans the exact function of resistin remains unknown. Some, but not all studies have found associations between polymorphisms in the resistin gene with DM-2. Recently a 3'-untranslated region +62G-->A polymorphism of the resistin gene has been associated with decreased risk for DM-2 and for hypertension in diabetics in a Chinese population. Purpose of the present study was to examine for the first time in a German Caucasian population the possible association between this polymorphism and DM-2, hypertension, lipoprotein levels, resistin levels as well as atherosclerosis. DESIGN, SETTING AND SUBJECTS: A total of 818 subjects participated in the study. The presence of the +62G-->A polymorphism of the resistin gene was investigated using polymerase chain reaction-restriction fragment length polymorphism in 384 subjects with DM-2 [224 men, 160 women, age 63.4 +/- 10.6 years, body mass index (BMI) 28.7 +/- 5.1 kg m(-2)] and in 434 nondiabetic age- and sex-matched control subjects (248 men, 186 women, age 64.4 +/- 6.5 years, BMI 26.5 +/- 3.7 kg m(-2)). RESULTS: Thirty-four subjects were found to be carrying the +62G-->A polymorphism in the control and 24 in the diabetic group (allelic frequencies 4% and 3.2% respectively). Subjects with DM-2 were not found to have a different frequency of the genotypes (93.75% and 6.258%, for GG:GA/AA respectively) than the control subjects (92.2% and 7.8% for GG:GA/AA respectively) (OR 0.75, 95% CI 0.44-1.3, P = 0.31). In the total cohort, carriers of the A allele had a higher prevalence of hypertension (OR 1.82, 95% CI 1.03-3.21, P = 0.039). When analysed separately, the control group showed a strong association between the presence of the A allele and hypertension (OR 2.92, 95% CI 1.38-6.15, P = 0.005), whilst no such association could be established in the diabetic group (OR 1.05, 95% CI 0.43-2.54, P = 0.92). Multiple regression analysis confirmed that the presence of the A variant is associated with hypertension in control but not in diabetic subjects, independent of age and BMI. The polymorphism had no significant influence on the presence of atherosclerotic disease, BMI, and on triglyceride, HDL and LDL cholesterol levels, both, in the control and the diabetic groups. There was no difference in the serum resistin levels between the 62G-->A variant carriers and noncarriers. CONCLUSIONS: In conclusion, the present data suggest that in a German Caucasian population the +62G-->A polymorphism of the resistin gene is associated with hypertension but not with DM-2.     

Impact of genes related to immune tolerance and inflammation (tumour necrosis factor-alpha, interleukin-6) on blood pressure, protein excretion and oedema in pregnancy

OBJECTIVE: To test the hypothesis that genetically determined alterations of maternal immune tolerance to a foetal semi-allograft are important for the pathogenesis of hypertensive disorders in pregnancy. DESIGN: A genetic association study was performed to analyse the impact of genetic polymorphisms known to be involved in immune tolerance on markers of pre-eclampsia. SETTING: The study was conducted at the Obstetrics Department of the Charité University Hospital, Berlin, Germany. PARTICIPANTS: A total of 1480 Caucasian women were consecutively included after delivery and genotyped for two polymorphisms: tumour necrosis factor-alpha -308G>A and interleukin-6 -174G>C. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressures, urinary protein excretion and oedema during pregnancy. RESULTS: Only women carrying at least one mutant allele of both polymorphisms (tumour necrosis factor-alpha A and interleukin-6 C) have a significantly elevated mean systolic blood pressure and diastolic blood pressure at the end of pregnancy. The tumour necrosis factor-alpha A allele on its own is significantly associated with urinary protein excretion in the last trimenon, and the interleukin-6 C allele is independently and significantly associated with new-onset oedema. CONCLUSIONS: We demonstrate in a large population that common maternal polymorphisms of genes related to immune tolerance and inflammation are associated with blood pressure regulation, urinary protein excretion and oedema during pregnancy. The analysed polymorphisms seem to contribute to the multifactorial pathogenesis of gestational hypertension and pre-eclampsia. The findings support the hypothesis that genetically determined factors of maternal immune tolerance play a role in the pathogenesis of hypertensive disorders in pregnancy.     

Comparison of a silicon carbide-coated stent versus a noncoated stent in human beings: the Tenax versus Nir Stent Study's long-term outcome

Background Stents coated with amorphous hypothrombogenic silicon carbide (a-SiC:H) have low restenosis rates in humans. Recurrence in a-SiC:H at mid-term follow-up has been shown to be similar to a stainless steel device. The long-term outcome, however, may be different. Methods Four hundred ninety-seven patients (63.4 ± 9.8 years of age) received either the a-SiC:H-coated Tenax stent (Biotronik, Berlin, Germany) or the 316L Nir stent (Boston Scientific, Maple Grove, Minn). Lesions had to be covered with one stent only (diameter ≥2.8 mm, length <20 mm). Exclusion criteria comprised acute myocardial infarction and angiographic thrombus within the target vessel. Twenty-five of 497 (5%) patients were excluded for protocol violation. Clinical follow-up was completed in 450 of 472 (95.3%) and angiographic follow-up was completed in 365 of 472 (77.3%); 22 of 472 (4.7%) patients were lost to follow-up. Results Major adverse coronary events occurred in 28 of 233 (12%) of the Tenax recipients and in 31 of 217 (14.3%) of the Nir recipients (P = .50). Acute myocardial infarctions were less frequent in the Tenax recipients after ≥60 weeks. Premature target lesion revascularization was performed in 16 of 233 (6.9%) patients in the Tenax group and 11 of 217 (5.1%) (P = .54) patients in the Nir group. Coronary bypass operations were similar after Tenax or Nir stent deployment (3/233 [1.3%] vs 6/217 [2.8%], P = .43), as were deaths in 7 of 233 (3%) versus 8 of 217 (3.7%) (P = .88), respectively. Conclusions Both stents had a low rate of major adverse coronary events at 81 ± 12 weeks of follow-up, with no definite superiority of any of the devices. (Am Heart J 2003;145:e17.)     

N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor.

The galanin N-terminal fragment [galanin-(1-16)] has been prepared by solid-phase synthesis and by enzymic cleavage of galanin by endoproteinase Asp-N. This peptide fragment displaced 125I-labeled galanin in receptor autoradiography experiments on rat forebrain and spinal cord and in equilibrium binding experiments from high-affinity binding sites in the ventral hippocampus with an IC50 of approximately 3 nM. In tissue slices of the same brain area, galanin-(1-16), similarly to galanin, inhibited the muscarinic agonist-stimulated breakdown of inositol phospholipids. Upon intracerebroventricular administration, galanin-(1-16) (10 micrograms/15 microliters) also inhibited the scopolamine (0.3 mg/kg, s.c.)-evoked release of acetylcholine, as studied in vivo by microdialysis. Substitution of [L-Trp2] for [D-Trp2] resulted in a 500-fold loss in affinity as compared with galanin-(1-16). It is concluded that, in the ventral hippocampus, the N-terminal galanin fragment [galanin-(1-16)] is recognized by the galanin receptors controlling acetylcholine release and muscarinic agonist-stimulated inositol phospholipid breakdown as a high-affinity agonist and that amino acid residue [Trp2] plays an important role in the receptor-ligand interactions.     

Body fat distribution,serum leptin,and cardiovascular risk factors in men with obstructive sleep apnea

STUDY OBJECTIVE:s: To determine whether traditional risk factors for cardiovascular disease (CVD) and regional fat distribution, especially the central obesity type and increased parapharyngeal fat pads, are associated with the degree of obstructive sleep apnea (OSA). To determine whether there are interrelationships between body fat, serum leptin levels, and the degree of OSA. DESIGN AND SETTING: Prospective mono-center cross-sectional study in a university hospital in Germany. PATIENTS: Eighty-five consecutive male patients who were referred for evaluation of suspected OSA. Measurements and results: The major dependent outcome variable was the apnea-hypopnea index (AHI), the average number of apneas and hypopneas per hour of sleep, determined by overnight polysomnography. Independent measures were anthropometric data, body composition analysis (bioelectrical impedance analysis [BIA]), cardiovascular risk factor evaluation (smoking, hypertension, serum lipoproteins, diabetes or impaired glucose tolerance, uric acid, fibrinogen), and leptin. Adipose tissue quantification of the abdominal and neck regions was performed by nuclear MRI (NMR). Significant linear relationships of AHI with fasting blood glucose, uric acid, fibrinogen, body weight, body mass index (BMI), sum of fat skin folds, and percentage of body fat could be established, whereas there was no correlation with age. The presence of OSA was independent of smoking, hypertension, and lipoproteins. NMR scans showed that AHI was significantly correlated with intra-abdominal fat and subcutaneous abdominal fat, whereas subcutaneous fat in the neck region and parapharyngeal fat in the airway vicinity were not correlated. Leptin concentrations correlated with AHI and with biochemical markers of the metabolic syndrome (lipoproteins, glucose) but were not dependent on AHI. Logistic regression analysis found percentage of body fat (BIA) and BMI as good predictors of AHI > 10 with a sensitivity of 95.5% but a low specificity (46.2%). Multiple regression analysis identified the sum of fat skin folds, body weight, and BMI as good predictors for the degree of OSA. CONCLUSIONS: We conclude that OSA is independent from most traditional risk factors for CVD. Regional body fat distribution predicts the presence and degree of OSA, but fat accumulation in the neck and parapharyngeal region are of minor importance. Leptin concentrations when controlled for body fat are not related to the degree of OSA.     

Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis

To develop murine models of leukemogenesis, a series of transgenic mice expressing BCR-ABL in different hematopoietic cell subsets was generated. Here we describe targeted expression of P210 BCR-ABL in stem and progenitor cells of murine bone marrow using the tet-off system. The transactivator protein tTA was placed under the control of the murine stem cell leukemia (SCL) gene 3' enhancer. Induction of BCR-ABL resulted in neutrophilia and leukocytosis, and the mice became moribund within 29 to 122 days. Autopsy of sick mice demonstrated splenomegaly, myeloid bone marrow hyperplasia, and extramedullary myeloid cell infiltration of multiple organs. BCR-ABL mRNA and protein were detectable in the affected organs. Fluorescence-activated cell sorter (FACS) analysis demonstrated a significant increase in mature and immature myeloid cells in bone marrow and spleen, together with increased bilineal B220+/Mac-1+ cells in the bone marrow. tTA mRNA was expressed in FACS-sorted hematopoietic stem cells expanded 26-fold after BCR-ABL induction. Thirty-one percent of the animals demonstrated a biphasic phenotype, consisting of neutrophilia and subsequent B-cell lymphoblastic disease, reminiscent of blast crisis. In summary, this mouse model recapitulates many characteristics of human chronic myeloid leukemia (CML) and may help elucidate basic leukemogenic mechanisms in CML stem cells during disease initiation and progression.     

Standardization of the Food Composition Database Used in the Latin American Nutrition and Health Study (ELANS)

Between-country comparisons of estimated dietary intake are particularly prone to error when different food composition tables are used. The objective of this study was to describe our procedures and rationale for the selection and adaptation of available food composition to a single database to enable cross-country nutritional intake comparisons. Latin American Study of Nutrition and Health (ELANS) is a multicenter cross-sectional study of representative samples from eight Latin American countries. A standard study protocol was designed to investigate dietary intake of 9000 participants enrolled. Two 24-h recalls using the Multiple Pass Method were applied among the individuals of all countries. Data from 24-h dietary recalls were entered into the Nutrition Data System for Research (NDS-R) program after a harmonization process between countries to include local foods and appropriately adapt the NDS-R database. A food matching standardized procedure involving nutritional equivalency of local food reported by the study participants with foods available in the NDS-R database was strictly conducted by each country. Standardization of food and nutrient assessments has the potential to minimize systematic and random errors in nutrient intake estimations in the ELANS project. This study is expected to result in a unique dataset for Latin America, enabling cross-country comparisons of energy, macro- and micro-nutrient intake within this region.