Nitric oxide/platelet activating factor cross-talk in mesangial cells modulates the interaction with leukocytes

BACKGROUND: The secondary hyperparathyroidism of chronic kidney disease (CKD) produces a high turnover osteodystrophy that is associated with peritrabecular fibrosis. The nature of the cells involved in the development of peritrabecular fibrosis may represent osteoprogenitors expressing a fibroblastic phenotype that are retarded from progressing through osteoblast differentiation. METHODS: To test the hypothesis that osteoblast differentiation is retarded in secondary hyperparathyroidism due to CKD producing bone marrow fibrosis, we administered bone morphogenetic protein 7 (BMP-7), a physiologic regulator of osteoblast regulation, to C57BL6 mice that had CKD produced by electrocautery of one kidney followed by contralateral nephrectomy two weeks later. Following the second surgical procedure, a subgroup of mice received daily intraperitoneal injections of BMP-7 (10 microg/kg). Three to six weeks later, the animals were sacrificed, blood was obtained for measurements of blood urea nitrogen (BUN) and parathyroid hormone (PTH) levels, and the femora and tibiae were processed for histomorphometric analysis. RESULTS: The animals had significant renal insufficiency with BUN values of 77.79 +/- 22.68 mg/dL, and the level of renal impairment between the CKD untreated mice and the CKD mice treated with BMP-7 was the same in the two groups. PTH levels averaged 81.13 +/- 51.36 and 75.4 +/- 43.61 pg/mL in the CKD and BMP-7 treated groups, respectively. The animals with CKD developed significant peritrabecular fibrosis. In addition, there was an increase in osteoblast surface and osteoid accumulation as well as increased activation frequency and increased osteoclast surface consistent with high turnover renal osteodystrophy. Treatment with BMP-7 eliminated peritrabecular fibrosis, increased osteoblast number, osteoblast surface, mineralizing surface and single labeled surface. There was also a significant decrease in the eroded surface induced by treatment with BMP-7. CONCLUSIONS: These findings indicate that BMP-7 treatment in the setting of high turnover renal osteodystrophy prevents the development of peritrabecular fibrosis, affects the osteoblast phenotype and mineralizing surfaces, and decreases bone resorption. This is compatible with a role of osteoblast differentiation in the pathophysiology of osteitis fibrosa.     

Detection of fetal cells in intrauterine lavage samples collected in the first trimester of pregnancy.

OBJECTIVES: The aim of the present study was first to evaluate the presence of fetal cells in transcervical cell (TCC) samples collected by intrauterine lavage in the first trimester of pregnancy, and then to compare different methods for the detection of these cells. METHODS: TCC samples were collected by intrauterine lavage before termination of pregnancy (TOP) from 81 pregnant women between 7 and 12 weeks of gestation. Samples of placental tissue were collected from each patient at TOP, whereas maternal peripheral blood samples were obtained in 57 cases. DNA extracted from 81 lavage and the corresponding placental samples was amplified by a polymerase chain reaction (PCR) assay using primers for SRY and HUMARA genes. All 81 lavage samples were also analysed by fluorescent in situ hybridisation (FISH) using direct-labelled probes for X chromosome alpha-satellite (DXZ1, Xp11.1-q11.1) and Y chromosome alpha-satellite (DYZ3, Yp11.1-q11.1) regions. In 57 cases, a quantitative fluorescent (QF) PCR assay, involving the use of two small tandem repeat (STR) markers (D21S11, D21S14.11) specific to chromosome 21 was employed to analyse DNA extracted from placental tissue, lavage and maternal blood samples. RESULTS: PCR analysis revealed that 40/81 placental samples were from male pregnancies. Correct sexing was achieved with the PCR technique in 30/40 (75%) lavage samples retrieved from pregnant women with male conceptuses and in all 41 (100%) samples collected from pregnancies with female fetuses. With the FISH analysis, nuclei bearing X and Y signals were observed in 32/40 cases (80%) from known male pregnancies, the rate of fetal cells ranging between 2% and 95%, whereas nuclei showing X and Y signals were not detected in any of the 41 lavage samples from known female pregnancies. Paternal peaks were present in 30/57 (52.6%) lavage samples tested by QF-PCR. CONCLUSION: The results suggest that fetal cells can be found, at a significant rate, in a very high proportion of intrauterine lavage samples. Therefore, this sampling technique can be regarded as a promising tool towards minimally invasive prenatal diagnosis. The FISH and PCR methods showed a similar efficiency in detecting fetal cells.     

Urinary calcium is a determinant of bone mineral density in elderly men participating in the InCHIANTI study

BACKGROUND: It is generally acknowledged that calcium excretion is a determinant of bone mineral density. Since data confirming this hypothesis are not conclusive, the present study evaluates the relationship between calcium excretion and volumetric bone mineral density (vBMD) in a sample of general population mostly composed of elderly subjects. METHODS: This relationship was studied in 595 subjects in good health (M/F 302/293), selected from the InCHIANTI population, an epidemiologic survey on aging in Tuscany (Italy). Of these subjects, 432 (72.6%) were 65 years old or older. Trabecular and cortical apparent vBMDs were measured by peripheral quantitative computed tomography at right tibia and standardized to age and body mass index (BMI) in each gender (z-score). RESULTS: Men in the highest tertile of calcium excretion had significantly lower trabecular vBMD, and were more likely to have a trabecular z-score of -1 or less. These results were confirmed in men older than 64 years, but not in women and younger men. Sodium excretion and 25-hydroxycolecalciferol (25(OH)D) were greater in men and women in the highest tertile. No differences among tertiles were observed for cortical vBMD, circulating levels of interleukin-1beta and interleukin-6, and intake of principal nutrients and calcium. The lower levels of vBMD z-score were confirmed in men in the highest tertile of calcium excretion, standardized to creatinine clearance, sodium excretion, plasma calcium, and logarithm of circulating 25(OH)D, and resulted to be associated with calcium excretion at multiple regression analysis in men. CONCLUSION: High calcium excretion is associated with a decreased trabecular BMD in elderly men and may predispose men to trabecular bone loss.     

Bone density and hemoglobin levels in older persons: results from the InCHIANTI study

Hypoxemia has been recognized as a risk factor for bone loss. The aim of the present study is to investigate the relationship of bone mass and density measures with anemia and hemoglobin levels in a large sample of older community-dwelling persons. The study is based on data from 950 participants enrolled in the Invecchiare in Chianti (Aging in the Chianti area, InCHIANTI) study. All the analyses were performed considering continuous hemoglobin levels as well as the dichotomous anemia variable (defined according to WHO criteria as hemoglobin <12 g/dl in women and <13 g/dl in men). A peripheral quantitative computerized tomography (pQCT) scan of the right calf was performed in all participants to evaluate total bone density, trabecular bone density, cortical bone density, and the ratio between cortical and total bone area. Linear regression analyses were used to assess the multivariate relationship of pQCT bone measures with anemia and hemoglobin levels after adjustment for demographics, chronic conditions, muscle strength and biological variables. Participants were 75.0 (SD 6.9) years old. In our sample, 101 participants (10.6%) were anemic. In women, coefficients from adjusted linear regression analyses evaluating the association between pQCT bone measures (per SD increase) and hemoglobin levels/anemia showed significant associations of anemia with total bone density (=–0.335, SE=0.163; P=0.04) and cortical bone density (=–0.428, SE=0.160; P=0.008). Relationships with borderline significance were found for the associations of anemia with trabecular bone density and the ratio between cortical and total bone area. Significant associations were found between hemoglobin levels and trabecular bone density (=0.112, SE=0.049; P=0.02), total bone density (=0.101, SE=0.046; P=0.03), cortical bone density (=0.100, SE=0.046; P=0.03) and the ratio between cortical bone and total area (=0.092, SE=0.045; P=0.04). In men, significant associations were found for hemoglobin levels with total bone density (=0.076, SE=0.036; P=0.03) and cortical bone density (=0.095, SE=0.41; P=0.02). A borderline significance was reported for the association between anemia and cortical bone density. We concluded that anemia and low hemoglobin levels are negatively and independently associated with bone mass and density. The bone loss associated with hemoglobin levels mainly occurs in the cortical bone. Women with lower hemoglobin levels demonstrate a higher bone loss than male counterparts.     

The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis

Synthetic glycopeptides have the potential to detect antibodies in multiple sclerosis (MS). In the present study, we analyzed the antibodies (IgM class, IgG class and IgG subclasses) to the synthetic glycopeptide CSF114(Glc) in the serum of 186 MS patients, 166 blood donors (BDs), 25 patients affected by meningitis/encephalitis, 41 affected by systemic lupus erythematosus (SLE) and 49 affected by rheumatoid arthritis (RA). The IgM antibody level to CSF114(Glc) was significantly increased in MS patients versus BDs (p<0.001) or versus other autoimmune diseases (SLE or RA, p<0.001). The IgG response was restricted to the subclass IgG2. IgM antibodies to CSF114(Glc) were found in 30% of relapsing/remitting MS patients and, at lower levels, in subjects affected by meningitis/encephalitis. The study of antibodies to CSF114(Glc) is a new, potential immunological marker of MS.     

Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression

BACKGROUND: Regression of left ventricular hypertrophy (LVH) in the setting of a well-planned intervention study has been associated with longer survival in hemodialysis patients. Whether changes in left ventricular mass (LVM) in clinical practice predict survival and cardiovascular events in these patients is still unknown. METHODS: In a prospective study in 161 hemodialysis patients we tested the prognostic value of changes in LVM on survival and incident cardiovascular events. Echocardiography was performed twice, 18 +/- 2 SD months apart. Changes in LVM occurring between the first and the second echocardiographic study were then used to predict mortality and cardiovascular events during the ensuing 29 +/- 13 months. The prognostic value of LVM changes was tested in a multivariate Cox's model with LVM index (LVMI) [expressed as LVM/height(2.71)], included as a covariate to control for regression to the mean. RESULTS: The rate of increase of LVMI was significantly (P= 0.029) higher in patients with incident cardiovascular events than in those without such events. Accordingly, cardiovascular event-free survival in patients with changes in LVMI below the 25th percentile was significantly (P= 0.004) higher than in those with changes above the 75th percentile. In a multiple Cox regression analysis, including age, diabetes, smoking, homocysteine, 1 g/m(2.7)/month increase in LVMI was associated with a 62% increase in the incident risk of fatal and nonfatal cardiovascular events [hazard ratio 1.62 (95% CI 1.13-2.33), P= 0.009]. CONCLUSION: Changes in LVMI have an independent prognostic value for cardiovascular events and provide scientific support to the use of repeated echocardiographic studies for monitoring cardiovascular risk in dialysis patients.     

Estrogen-mediated effects on depression and memory formation in females

Women are twice as likely to suffer from depression as men. It has been proposed that the ovarian hormones estrogen and progesterone contribute to the higher incidence of this potentially debilitating disorder. Depression can also be accompanied by a loss of cognitive performance. Here we review estrogen-mediated effects on depression and memory formation in females. We propose that changes in levels of estrogen are associated with sex differences in learning as well as changes in affect prior to menses, immediately after pregnancy and during perimenopause and the menopausal transition. Finally, we discuss the animal model of depression known as 'learned helplessness' and describe research from our laboratory demonstrating that exposure to an acute stressful experience compromises a female's later ability to acquire certain types of new memories. This response to stressful experience is opposite to that observed in males and is dependent on the presence of estrogen, and more specifically-changing levels of estrogen. This observation indicates that females and males can use different hormonal and neural mechanisms to respond to the same emotional event and underscore the importance of studying the unique and changing biology of females, especially when considering treatment strategies for depression and stress-related illness.