Cadmium-Induced Effects on Bone in a Population-Based Study of Women

High cadmium exposure is known to cause bone damage, but the association between low-level cadmium exposure and osteoporosis remains to be clarified. Using a population-based women’s health survey in southern Sweden [Women’s Health in the Lund Area (WHILA)] with no known historical cadmium contamination, we investigated cadmium-related effects on bone in 820 women (53–64 years of age). We measured cadmium in blood and urine and lead in blood, an array of markers of bone metabolism, and forearm bone mineral density (BMD). Associations were evaluated in multiple linear regression analysis including information on the possible confounders or effect modifiers: weight, menopausal status, use of hormone replacement therapy, age at menarche, alcohol consumption, smoking history, and physical activity. Median urinary cadmium was 0.52 μg/L adjusted to density (0.67 μg/g creatinine). After multivariate adjustment, BMD, parathyroid hormone, and urinary deoxypyridinoline (U-DPD) were adversely associated with concentrations of urinary cadmium (p < 0.05) in all subjects. These associations persisted in the group of never-smokers, which had the lowest cadmium exposure (mainly dietary). For U-DPD, there was a significant interaction between cadmium and menopause (p = 0.022). Our results suggest negative effects of low-level cadmium exposure on bone, possibly exerted via increased bone resorption, which seemed to be intensified after menopause. Based on the prevalence of osteoporosis and the low level of exposure, the observed effects, although slight, should be considered as early signals of potentially more adverse health effects

Tubular and Glomerular Kidney Effects in Swedish Women with Low Environmental Cadmium Exposure

Cadmium is a well-known nephrotoxic agent in food and tobacco, but the exposure level that is critical for kidney effects in the general population is not defined. Within a population-based women’s health survey in southern Sweden (Women’s Health in the Lund Area, WHILA), we investigated cadmium exposure in relation to tubular and glomerular function, from 1999 through early 2000 in 820 women (71% participation rate) 53–64 years of age. Multiple linear regression showed cadmium in blood (median, 0.38 μg/L) and urine (0.52 μg/L; density adjusted = 0.67 μg/g creatinine) to be significantly associated with effects on renal tubules (as indicated by increased levels of human complex-forming protein and N-acetyl-β-d-glucosaminidase in urine), after adjusting for age, body mass index, blood lead, diabetes, hypertension, and regular use of nephrotoxic drugs. The associations remained significant even at the low exposure in women who had never smoked. We also found associations with markers of glomerular effects: glomerular filtration rate and creatinine clearance. Significant effects were seen already at a mean urinary cadmium level of 0.6 μg/L (0.8 μg/g creatinine). Cadmium potentiated diabetes-induced effects on kidney. In conclusion, tubular renal effects occurred at lower cadmium levels than previously demonstrated, and more important, glomerular effects were also observed. Although the effects were small, they may represent early signs of adverse effects, affecting large segments of the population. Subjects with diabetes seem to be at increased risk

Biochemical characterisation and clinical correlation of neuropeptides in neuroblastoma with emphasis on neuropeptide Y

Neuropeptides influence cellular events involved in tumour growth and differentiation. Neuroblastoma, a malignant childhood tumour of neural crest origin, synthesises and releases monoamines and neuropeptides. The concentrations of some of these neuropeptides in plasma are correlated to clinical stage and outcome. The neuropeptides exist in various molecular forms in plasma and tumour tissue but their biochemical structure in vivo are poorly investigated. The aim of the present work was to combine radioimmunoassays (RIA), different forms of liquid chromatography, amino acid sequence analysis and mass spectrometry to identify and characterise molecular forms of neuropeptides present in neuroblastoma tumour tissue, and to identify correlations to clinical parameters. The hypothesis tested was that the processing of neuropeptide Y (NPY) and other peptides in neuroblastoma generates molecular forms that may have clinical significance. Vasoactive intestinal peptide-like immunoreactivity (VIP-LI) and somatostatin-like immunoreactivity (SOM-LI) in neuroblastoma and benign ganglioneuroma tumour tissue were found in the form of the intact, biologically active peptides VIP-28, SOM-14 and SOM-28. However, the results for SOM-LI may be influenced by presence of the recently identified somatostatin homologoue cortistatin, that was shown to have similar affinity as somatostatin for the antiserum used. Pancreastatin-like immunoreactivity (PST-LI) showed molecular heterogeneity in neuroblastoma. The concentration of PST-LI in tumour tissue and plasma was higher in favourable neuroblastomas whereas low concentrations in both plasma and tumour tissue were correlated to poor outcome. NPY-like immunoreactivity (NPY-LI) in both neuroblastoma and ganglioneuroma tumour tissue showed considerable heterogeneity in general, as demonstrated by using two antisera specific for different epitopes of the NPY molecule. However, no clinical correlation was identified related to this heterogeneity. By gel- permeation chromatography the degree of proNPY processing could be measured. A low degree of proNPY processing was seen only in primary tumour tissue from neuroblastomas with regional or metastatic spread and was correlated to poor outcome. Using a combination of "micro-preparative" RP-HPLC and mass spectrometry, intact NPY(1-36) and the metabolic fragments NPY(3-36) and NPY(31-36) were isolated and identified in neuroblastoma tumour tissue. The identification of these fragments shows that NPY processing in vivo generates NPY-metabolites known to have different receptor selectivity than intact NPY. C-flanking peptide of NPY (CPON)-like immunorectivity was found in similar concentrations as NPY-LI. The fragment CPON(1-26) was identified eluting with NPY after several chromatographic steps, indicating that CPON and NPY may interact by non-covalent forces. Taken together, "micropreparative" chromatography in combination with tandem mass spectrometry were useful tools for biochemical characterisation of neuropeptides and their metabolites in biological samples. The results provide evidence that the processing of proNPY and NPY in neuroblastoma have clinical implications

Prediction of recurrent stroke with ABCD2 and ABCD3 scores in patients with symptomatic 50-99% carotid stenosis

Background: Although it is preferable that all patients with a recent Transient Ischemic Attack (TIA) undergo acute carotid imaging, there are centers with limited access to such acute examinations. It is controversial whether ABCD2 or ABCD3 scores can be used to triage patients to acute or delayed carotid imaging. It would be acceptable that some patients with a symptomatic carotid stenosis are detected with a slight delay as long as those who will suffer an early recurrent stroke are detected within 24 hours. The aim of this study is to analyze the ability of ABCD2 and ABCD3 scores to predict ipsilateral ischemic stroke among patients with symptomatic 50-99% carotid stenosis. Methods: In this secondary analysis of the ANSYSCAP-study, we included 230 consecutive patients with symptomatic 50-99% carotid stenosis. We analyzed the risk of recurrent ipsilateral ischemic stroke before carotid endarterectomy based on each parameter of the ABCD2 and ABCD3 scores separately, and for total ABCD2 and ABCD3 scores. We used Kaplan-Meier analysis. Results: None of the parameters in the ABCD2 or ABCD3 scores could alone predict all 12 of the ipsilateral ischemic strokes that occurred within 2 days of the presenting event, but clinical presentation tended to be a statistically significant risk factor for recurrent ipsilateral ischemic stroke (p = 0.06, log rank test). An ABCD2 score &gt;= 2 and an ABCD3 score &gt;= 4 could predict all 12 of these strokes as well as all 25 ipsilateral ischemic strokes that occurred within 14 days. To use ABCD3 score seems preferable over the ABCD2 score because a higher proportion of low risk patients were identified (17% of the patients had an ABCD3 score &lt;4 while only 6% had an ABCD2 &lt; 2). Conclusions: Although it is preferable that carotid imaging be performed within 24 hours, our data support that an ABCD3 score &gt;= 4 might be used for triaging patients to acute carotid imaging in clinical settings with limited access to carotid imaging. However, our findings should be validated in a larger cohort study

No outgrowth of chondrocytes from non-digested particulated articular cartilage embedded in commercially available fibrin matrix : an in vitro study

Background: Commercially available fibrin is routinely being used as both a matrix in certain cartilage repair techniques and a method for scaffold fixation. Chondrocytes from non-digested particulated cartilage fragments are proposed as a possible source for new cartilage tissue formation in some operative techniques. The goal of this study was to test that chondrocytes from particulated articular cartilage embedded in fibrin have an active role in the process of cartilage repair, as well as if commercially available fibrin should be used as a suitable matrix. Methods: Articular cartilage was obtained from patients undergoing total knee replacement surgery. The biopsies were particulated in small, 1-2-mm(3) pieces and embedded in fibrin. Two groups were compared in our study, particulated articular cartilage with and without collagenase treatment. The specimens were analyzed by optical microscopy after 2-5 weeks of cultivation in a special construct embedded in a cell culture medium containing particulated cartilage embedded in fibrin in the upper phase and cancellous bone in the lower phase under the perforated nylon membrane. Results: None of the biopsies taken from four different patients showed the outgrowth of chondrocytes or bone marrow-originated cells into the fibrin matrix in our experimental model. Conclusions: It has been shown in our experimental model in vitro little to support the theory that articular chondrocytes from particulated articular cartilage embedded in fibrin have an active role in cartilage repair in its early stage

Prediction of recurrent stroke with ABCD2 and ABCD3 scores in patients with symptomatic 50-99% carotid stenosis

Background: Although it is preferable that all patients with a recent Transient Ischemic Attack (TIA) undergo acute carotid imaging, there are centers with limited access to such acute examinations. It is controversial whether ABCD2 or ABCD3 scores can be used to triage patients to acute or delayed carotid imaging. It would be acceptable that some patients with a symptomatic carotid stenosis are detected with a slight delay as long as those who will suffer an early recurrent stroke are detected within 24 hours. The aim of this study is to analyze the ability of ABCD2 and ABCD3 scores to predict ipsilateral ischemic stroke among patients with symptomatic 50-99% carotid stenosis. Methods: In this secondary analysis of the ANSYSCAP-study, we included 230 consecutive patients with symptomatic 50-99% carotid stenosis. We analyzed the risk of recurrent ipsilateral ischemic stroke before carotid endarterectomy based on each parameter of the ABCD2 and ABCD3 scores separately, and for total ABCD2 and ABCD3 scores. We used Kaplan-Meier analysis. Results: None of the parameters in the ABCD2 or ABCD3 scores could alone predict all 12 of the ipsilateral ischemic strokes that occurred within 2 days of the presenting event, but clinical presentation tended to be a statistically significant risk factor for recurrent ipsilateral ischemic stroke (p = 0.06, log rank test). An ABCD2 score &gt;= 2 and an ABCD3 score &gt;= 4 could predict all 12 of these strokes as well as all 25 ipsilateral ischemic strokes that occurred within 14 days. To use ABCD3 score seems preferable over the ABCD2 score because a higher proportion of low risk patients were identified (17% of the patients had an ABCD3 score &lt;4 while only 6% had an ABCD2 &lt; 2). Conclusions: Although it is preferable that carotid imaging be performed within 24 hours, our data support that an ABCD3 score &gt;= 4 might be used for triaging patients to acute carotid imaging in clinical settings with limited access to carotid imaging. However, our findings should be validated in a larger cohort study

Low CSF/serum ratio of free T4 is associated with decreased quality of life in mild hypothyroidism : A pilot study

Background &amp; Objective: Patients with mild hypothyroidism often are depressed and have impaired quality of life despite serum free-T4 and T3 within reference values. Therefore, we investigated whether their symptoms were dependent on the concentrations of free -T4 and T3 in the circulation and cerebrospinal fluid (CSF). Methods: Twenty-five newly diagnosed, untreated hypothyroid subjects and as many age- and sex-matched healthy controls were investigated. Blood and CSF sampling was performed in the morning after an overnight fast. Quality of life (QoL) was assessed by a Likert scale. In the hypothyroid subjects, the MADRS rating scale was also used to evaluate symptoms of depression. Furthermore, the results obtained by the questionnaires were related to serum and CSF levels of free- T4 and T3 as well as the ratios between them in CSF and in serum. Results: Self-reported health was considerably lower in hypothyroid subjects. MADRS was considerably higher than the normal range for healthy individuals. Low CSF/serum free-T4 ratio was correlated with an increased depressed state according to MADRS (p &lt; 0.01), and in addition, CSF/serum free-T4 ratio correlated positively with the self-reported general health Likert scale (p &lt; 0.05). Concentrations of TSH, or free-T3 in serum or CSF, were not associated with an increased depressed state or self-reported general health. Conclusions: Low CSF/serum ratio of free-T4 was correlated with impaired general health and mood, in contrast to serum measurements not showing any correlations. These findings might partly explain why some patients with hypothyroidism suffer from mental symptoms, despite adequate serum levels of free-T4. However, the findings need to be confirmed in further and larger studies.Funding Agency:Sodra Sjukvardsregionen and Region Hallands forskningsfond </p

Higher CSF/serum free-T4 ratio is associated with improvement of quality of life during treatment with L-thyroxine

Up to 20% of individuals with primary hypothyroidism treated with L-thyroxine still suffer from severe symptoms. These are supposedly brain derived and involve both cognitive and emotional domains. Previously, no consistent relationship has been found between thyroid hormones (TH) or TSH levels in blood and quality of life (QoL). Recently, we reported an association between cerebrospinal fluid (CSF)/serum free-thyroxine (f-T4) ratio and QoL, in juvenile hypothyroid patients. Here, we investigated if CSF/serum f-T4 ratio and QoL estimates correlate also during L-thyroxine treatment. Moreover, the CSF biomarker neurogranin (Ng) was used as a biomarker for synaptic function and integrity in clinical research. Ng is partially controlled by TH and therefore we investigated the relationship between QoL parameters and Ng levels. Patients diagnosed with primary hypothyroidism were investigated using vital parameters, serum and CSF analyses of TH, TSH, Ng and QoL questionnaires. Similar procedures were performed after 6 months of treatment. The most marked associations with QoL were found for CSF/serum f-T4 ratio, which was strongly related to several QoL parameters such as the mental subscore of SF-36 (r = 0.83, p &lt; .0005). Ng, which did not differ from that in our healthy controls, was lower in some patients during treatment and higher in others. However, the change in Ng during treatment was significantly correlated with QoL parameters including the mental subscore of SF-36 (r = -0.86, p &lt; .0001). In addition, the CSF/serum f-T4 ratio correlated with the change in Ng (r = -0.75, p = .001). Our results suggest that the ratio between CSF and serum f-T4 is an important biomarker for QoL during treatment of patients with primary hypothyroidism, so far in research, but in the future maybe also in clinical settings. Moreover, this ratio also correlates with the changes in Ng levels during L-thyroxine treatment, further supporting the impact of the TH balance between serum and CSF on QoL