Ventilation time and prognosis after stroke thrombectomy: the shorter, the better!

BACKGROUND AND PURPOSE: The aim was to investigate the clinical impact of the duration of artificial ventilation in stroke patients receiving mechanical thrombectomy (MT) under general anaesthesia. METHODS: All consecutive ischaemic stroke patients who had been treated at our centre with MT for anterior circulation large vessel occlusion under general anaesthesia were identified over an 8-year period. Ventilation time was analysed as a continuous variable and patients were grouped into extubation within 6 h ('early'), 6-24 h ('delayed') and >24 h ('late'). Favourable outcome was defined as modified Rankin Scale scores of 0-2 at 3 months post-stroke. Pneumonia rate and reasons for prolonged ventilation were also assessed. RESULTS: Amongst 447 MT patients (mean age 69.1 ± 13.3 years, 50.1% female), the median ventilation time was 3 h. 188 (42.6%) patients had a favourable 3-month outcome, which correlated with shorter ventilation time (Spearman's rho 0.39, P < 0.001). In patients extubated within 24 h, early compared to delayed extubation was associated with improved outcome (odds ratio 2.40, 95% confidence interval 1.53-3.76, P < 0.001). This was confirmed in multivariable analysis (P = 0.01). A longer ventilation time was associated with a higher rate of pneumonia during neurointensive care unit/stroke unit stay (early/delayed/late extubation: 9.6%/20.6%/27.7%, P < 0.01). Whilst stroke-associated complications represented the most common reasons for late extubation (>24 h), delayed extubation (6-24 h) was associated with admission outside of core working hours (P < 0.001). CONCLUSIONS: Prolonged ventilation time after stroke thrombectomy independently predicts unfavourable outcome at 3 months and is associated with increased pneumonia rates. Therefore, extubation should be performed as early as safely possible.

LGR5 rs17109924 is a predictive genetic biomarker for time to recurrence in patients with colon cancer treated with 5-fluorouracil-based adjuvant chemotherapy.

We recently found variants in cancer stem cell genes (CD44, ALCAM and LGR5) significantly associated with increased time to recurrence (TTR) in patients with stage III and high-risk stage II colon cancer treated with 5-fluorouracil (5-FU)-based chemotherapy. In this study, we validated these genetic biomarkers in a large and independent patient cohort (n=599). Patients who received 5-FU-based adjuvant chemotherapy (n=391) carrying at least one C allele in LGR5 rs17109924 had a significantly increased TTR compared with patients carrying the homozygous T/T variant (HR 0.38, 95%CI 0.19-0.79; P=0.006). In patients treated with surgery alone (n=208), no association between LGR rs17109924 and TTR was found (P=0.728). In the multivariate Cox-analysis, LGR5 rs17109924 remained statistically significant (HR 0.38, 95%CI 0.18-0.78; P=0.008) for patients who received adjuvant chemotherapy. We confirmed in a large and independent study cohort that LGR5 rs17109924 is a predictive genetic biomarker for TTR in patients with colon cancer treated with 5-FU-based adjuvant chemotherapy.

Anaphylaxis with clonal mast cells in normal looking skin - a new entity?

BACKGROUND: Patients with elevated basal tryptase (sBT) >15 µg/l and anaphylaxis may have an underlying mastocytosis. A monoclonal mast cell activation syndrome with aberrant mast cells (MC) at extracutaneous sites has been described in patients with severe hypotension or anaphylaxis. METHODS: As MC in patients with elevated sBT might be altered in the skin as well, we studied MC in normal neck skin in anaphylaxis and urticaria patients with elevated sBT. RESULTS: A mean of 93.1 (SD 19.1) MC/mm² was counted in normal neck skin in 14 patients with anaphylaxis, 84.0 (SD 13.6) in seven patients with urticaria, 142.0 (SD 24.0) in two patients with eczema, 124.4 (SD 43.2) in five patients with systemic mastocytosis (SM) in comparison with autopsy skin (39.1 MC/mm², SD 12.4). In five of 14 (35.7%) of the anaphylaxis and three of five (60%) SM patients more than 25% of MC were spindle shaped and expressed CD25 antigen. CONCLUSIONS: We could show for the first time that the normal skin can harbour clonal MC in anaphylaxis patients. Analogous to the criteria for mastocytosis, we suggest a skin score criteria including an elevated number of MC, spindle shape, CD25 expression, c-Kit mutation and sBT values >20 µg/l. In patients with anaphylaxis and elevated sBT, skin should be biopsied and, as with the approach for mastocytosis diagnosis in the bone marrow, MC should be analysed for their number, clonality and c-Kit mutation. This approach should be confirmed in further studies. Patients with aberrant skin MC should be handled as mastocytosis patients.

Evaluation of prognostic scoring systems for spinal metastases in 196 patients treated during 2005-2010.

PURPOSE: Estimating the survival time of patients with spinal metastases based on pre-treatment parameters is important for the best choice of therapy. Following two previous studies, this sequel analyzes possible changes in the impact of various parameters and scoring systems and includes a comparison to the previous dataset for the purpose to find the most predictive parameters and scores for this patient group. METHODS: Included were 196 patients retrospectively with confirmed spinal metastases treated between 2005 and 2010 (35% surgery, 65% conservative). Possible prognostic factors [primary tumor, Karnofsky Performance Scale (KPS), visceral metastases, number of bone metastases, pathological fracture and neurologic status] and six scoring systems (Tokuhashi original/revised, Tomita, van der Linden, Bauer original and modified) were analyzed using Kaplan-Meier curves and Cox-regression models. RESULTS: Median overall survival was 7 months with 9% of all patients alive at the time of analysis. Stepwise multivariate analysis showed significant influence on survival for visceral metastases (p<0.0001), primary tumor (p<0.0001), KPS (p<0.0001) and number of spinal metastases (p=0.0271). All scoring systems significantly predicted longer survival at a better score (absolute scores, p<0.001) in this dataset. Significant differentiation between the prognostic groups was seen only for the Tokuhashi original, the Bauer original and modified scores (p<0.001). In comparison to the previous dataset with varying age, gender and primary tumor distribution, the Bauer original and modified scores were the least influenced by the different patient collectives. CONCLUSIONS: The Bauer modified score has shown consistent impact on predicting the remaining survival in patients with spinal metastases and is simultaneously simple in clinical use.

Revision rates after knee replacement. Cumulative results from worldwide clinical studies versus joint registers.

OBJECTIVE: To assess revision rates after knee arthroplasty by comparing the cumulative results from worldwide clinical studies and arthroplasty registers. We hypothesised that the revision rate of all clinical studies of a given implant and register data would not differ significantly. METHODS: A systematic review of clinical studies in indexed peer-reviewed journals was performed followed by internal and external validation. Parameters for measurement of revision were applied (Revision for any reason, Revisions per 100 observed component years). Register data served as control group. RESULTS: Thirty-six knee arthroplasty systems were identified to meet the inclusion criteria: 21 total knee arthroplasty (TKA) systems, 14 unicondylar knee arthroplasty (UKA) systems, one patello-femoral implant system. For 13 systems (36%), no published study was available that contained revision data. For 17 implants (47%), publications were available dealing with radiographic, surgical or technical details, but power was too weak to compare revision rates at a significant level. Six implant systems (17%) had a significant number of revisions published and were finally analysed. In general, developers report better results than independent users. Studies from developers represent an overproportional share of all observed component years. Register data report overall 10-year revision rates of TKA of 6.2% (range: 4.9-7.8%), rates for UKA are 16.5% (range: 9.7-19.6%). CONCLUSION: Revision rates of all clinical studies of a given implant do not differ significantly from register data. However, significant differences were found between the revision rates published by developers and register data. Therefore the different data need to be interpreted in the context of the source of the information.

Pulmonary vascular resistances during exercise in normal subjects: a systematic review.

The physiological range of pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR), and the impact of exercise, age and posture have been a matter of debate for many years. We performed a systematic literature review including all right heart catheterisation data where individual PVR and TPR of healthy subjects both at rest and exercise were available. Data were stratified according to age, exercise level and posture. Supine resting PVR in subjects aged <24 yrs, 24-50 yrs, 51-69 yrs and ≥70 yrs was 61±23, 69±28, 86±15 and 90±39 dyn·s·cm(-5), respectively. Corresponding TPR was 165±50, 164±46, 226±64 and 223±45 dyn·s·cm(-5), respectively. During moderate exercise in subjects aged ≤50 yrs, an 85% increase in cardiac output was associated with a 25% decrease in TPR (p<0.0001) and a 12% decrease in PVR (p<0.01). At 51-69 yrs of age there was no significant decrease in TPR and PVR. In individuals aged ≥70 yrs TPR even increased by 17% (p=0.01), while PVR did not change significantly. At higher exercise levels, TPR decreased in all age groups. In the upright position, based on a limited number of data, resting TPR and PVR were higher than in the supine position and decreased more prominently during exercise, suggesting the release of resting pulmonary vasoconstriction. These data may form a basis to define normal PVR at rest and exercise.

On the correlations of biomechanical properties of super-imposed temporal tissue layers and their age-, sex-, side- and post-mortem interval dependence.

Obtaining biomechanical properties of biological tissues for simulation purposes or graft developments is time and resource consuming. The number of samples required for biomechanical tests could be reduced if the load-deformation properties of a given tissue layer could be estimated from adjacent layers or if the biomechanical parameters were unaffected by age, bodyside, sex or post-mortem interval. This study investigates for the first time potential correlations of multiple super-imposed tissue layers using the temporal region of the human head as an area of broad interest in biomechanical modelling. Spearman correlations between biomechanical properties of the scalp, muscle fascia, muscle, bone and dura mater from up to 83 chemically unfixed cadavers were investigated. The association with age, sex and post-mortem interval was assessed. The results revealed sporadic correlations between the corresponding layers, such as the maximum force (r = 0.43) and ultimate tensile strength (r = 0.33) between scalp and muscle. Side- and age-dependence of the biomechanical properties were different between the tissue types. Strain at maximum force of fascia (r = -0.37) and elastic modulus of temporal muscle (r = 0.26) weakly correlated with post-mortem interval. Only strain at maximum force of scalp differed significantly between sexes. Uniaxial biomechanical properties of individual head tissue layers can thus not be estimated solely based on adjacent layers. Therefore, correlations between the tissues' biomechanical properties, anthropometric data and post-mortem interval need to be established independently for each layer. Sex seems not to be a relevant influencing factor for the passive tissue mechanics of the here investigated temporal head tissue layers.

CXCL13 chemokine in pediatric and adult neuroborreliosis.

OBJECTIVES: Diagnosis of Lyme neuroborreliosis (NB) depends on the proof of intrathecal antibody production against Borrelia burgdorferi. CXCL13 has been seen to be elevated early in NB, before antibody production has started. In this study, we determined the diagnostic role of the CXCL13 chemokine in cerebrospinal fluid (CSF) and serum for the first time in pediatric NB patients as well as in adults, compared to controls and blood donors (BD). MATERIAL AND METHODS: CXCL13 levels were measured in CSF and serum of 33 children and 42 adult patients. Serum CXCL13 was measured in 300 BD. RESULTS: CSF CXCL13 levels were significantly elevated in definite and probable acute NB in children and adults compared to seropositive and seronegative neurological controls (P < 0.001). Serum CXCL13 levels showed great fluctuations and were not significantly elevated in NB patients. CONCLUSIONS: Our study suggests that CSF CXCL13 can be used as a diagnostic marker for NB in children as well. In contrast, CXCL13 serum levels show great variance even in the healthy population and are not indicative of active NB.

Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review.

According to current guidelines, pulmonary arterial hypertension (PAH) is diagnosed when mean pulmonary arterial pressure (Ppa) exceeds 25 mmHg at rest or 30 mmHg during exercise. Issues that remain unclear are the classification of Ppa values <25 mmHg and whether Ppa >30 mmHg during exercise is always pathological. We performed a comprehensive literature review and analysed all accessible data obtained by right heart catheter studies from healthy individuals to determine normal Ppa at rest and during exercise. Data on 1,187 individuals from 47 studies in 13 countries were included. Data were stratified for sex, age, geographical origin, body position and exercise level. Ppa at rest was 14.0+/-3.3 mmHg and this value was independent of sex and ethnicity. Resting Ppa was slightly influenced by posture (supine 14.0+/-3.3 mmHg, upright 13.6+/-3.1 mmHg) and age (<30 yrs: 12.8+/- 3.1 mmHg; 30-50 yrs: 12.9+/-3.0 mmHg; > or = 50 yrs: 14.7+/-4.0 mmHg). Ppa during exercise was dependent on exercise level and age. During mild exercise, Ppa was 19.4+/-4.8 mmHg in subjects aged <50 yrs compared with 29.4+/-8.4 mmHg in subjects > or = 50 yrs (p<0.001). In conclusion, while Ppa at rest is virtually independent of age and rarely exceeds 20 mmHg, exercise Ppa is age-related and frequently exceeds 30 mmHg, especially in elderly individuals, which makes it difficult to define normal Ppa values during exercise.

IL10R1 loss-of-function alleles in rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVE: IL-10 is a pleiotropic cytokine involved in the regulation of innate and cell-mediated immunity and a key mediator within the disturbed SLE immune system. IL-10 binds to IL10R1, which is expressed on a variety of immune cells and activates the JAK-STAT pathway. Two (out of several known) genetic IL10R1 variants may alter IL-10 binding or signal transduction. Here we investigate the differential activity of these IL10R1 variants and their possible association with RA or SLE susceptibility. METHODS: IL10R1-wt, IL10R1-S138G, IL10R1-G330R, or IL10R1- S138G +G330R were cloned into pIRESpuro3 and transfected into HeLa cells. Single cell clones were tested for IL-10-induced SOCS3- and SLAM gene expression by real-time PCR. DNA from 182 RA patients, 222 SLE patients, and 250 healthy controls was genotyped by allele-specific PCR. RESULTS: A biphasic increase of SOCS3 mRNA was observed that peaked at 15 minutes and 4 hours after IL-10 stimulation. The presence of IL10R1 S138G and G330R showed a weaker induction of both SOCS3 and SLAM upon stimulation with IL-10. In RA a homozygous G330R genotype was more commonly present than in controls (15.4% vs. 7.6%; p<0.05). In SLE the G330R allele frequency was also increased (36.3% vs. 30.0%; p<0.05) without showing a gene-dose relationship at the genotype level. CONCLUSIONS: Based on these results, both variants of the IL10R1 gene are loss-of-function alleles. IL10R1 G330R may possibly contribute to RA or SLE disease susceptibility in Caucasian populations.

Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine.

OBJECTIVE: To study the feasibility of multimodal neuroimaging in mild to moderate Alzheimer disease (AD) and to estimate the size of possible treatment effects of memantine on potential functional, structural and metabolic biomarkers of disease progression. METHODS: In this randomised, double-blind, placebo-controlled pilot study, 36 patients with moderate AD received 52 weeks of memantine (20 mg/day) or placebo. Patients were re-evaluated after 26 and 52 weeks to measure the change from baseline in several outcome measures including global and regional glucose metabolism, total brain and hippocampal volumes, as well as chemical shift imaging-derived global and regional N-acetylaspartate and myoinositol concentrations. RESULTS: In the total population, global glucose metabolism decreased by 2.3% (p<0.01), total brain volume by 2.1% (p<0.001) and hippocampal volume by 2.7% (p<0.01) after 52 weeks. Chemical shift imaging (CSI) spectra were severely affected by patient-induced artefacts and highly variable. Patients receiving memantine showed less decline in glucose metabolism in all brain areas than patients on placebo. Their loss of hippocampal volume was substantially smaller (2.4% vs 4.0%). No between-group differences were seen for changes in total brain volume. CONCLUSIONS: The results support the use of multimodal imaging including MRI and positron emission tomography (PET) to monitor the progression of moderate AD. CSI yielded unreliable longitudinal results. The data suggest that memantine has potentially protective effects in AD and they can be used for planning larger confirmatory studies on the cerebral effects of memantine.

The Genome Austria Tissue Bank (GATiB).

In the context of the Austrian Genome Program, a tissue bank is being established (Genome Austria Tissue Bank, GATiB) which is based on a collection of diseased and corresponding normal tissues representing a great variety of diseases at their natural frequency of occurrence from a non-selected Central European population of more than 700,000 patients. Major emphasis is put on annotation of archival tissue with comprehensive clinical data, including follow-up data. A specific IT infrastructure supports sample annotation, tracking of sample usage as well as sample and data storage. Innovative data protection tools were developed which prevent sample donor re-identification, particularly if detailed medical and genetic data are combined. For quality control of old archival tissues, new techniques were established to check RNA quality and antigen stability. Since 2003, GATiB has changed from a population-based tissue bank to a disease-focused biobank comprising major cancers such as colon, breast, liver, as well as metabolic liver diseases and organs affected by the metabolic syndrome. Prospectively collected tissues are associated with blood samples and detailed data on the sample donor's disease, lifestyle and environmental exposure, following standard operating procedures. Major emphasis is also placed on ethical, legal and social issues (ELSI) related to biobanks. A specific research project and an international advisory board ensure the proper embedding of GATiB in society and facilitate international networking.

Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus.

BACKGROUND: Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer insulin analogues might result in fewer macrovascular and microvascular events. OBJECTIVES: To assess the effects of long-term treatment with long-acting insulin analogues (insulin glargine and insulin detemir) compared to NPH insulin in patients with type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as insulin producing companies. SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. MAIN RESULTS: Six studies comparing insulin glargine to NPH (Neutral Protamine Hagedorn) insulin and two studies comparing insulin detemir to NPH insulin were identified. In these trials, 1715 patients were randomised to insulin glargine and 578 patients to insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. AUTHORS' CONCLUSIONS: Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2 treated with "basal" insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with insulin glargine or detemir.

Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.

BACKGROUND: Short acting insulin analogue use for diabetic patients is still controversial, as reflected in many scientific debates. OBJECTIVES: To assess the effects of short acting insulin analogues versus regular human insulin. SEARCH STRATEGY: The Cochrane Library (Issue 3, 2005), MEDLINE, EMBASE until September 2005. SELECTION CRITERIA: Randomised controlled trials with an intervention duration of at least 4 weeks. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was done independently by two reviewers. MAIN RESULTS: Altogether 8274 participants took part in 49 randomised controlled studies. Most studies were of poor methodological quality. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was -0.1% (95% CI: -0.2 to -0.1) in favour of insulin analogue, whereas in patients with type 2 diabetes the WMD was 0.0% (95% CI: -0.1 to 0.0). In subgroup analyses of different types of interventions in type 1 diabetic patients, the WMD in HbA1c was -0.2% (95% CI: -0.3 to -0.1) in favour of insulin analogue in studies using continuous subcutaneous insulin injections (CSII), whereas for conventional intensified insulin therapy (IIT) studies the WMD in HbA1c was -0.1% (95% CI: -0.1 to 0.0). The WMD of the overall mean hypoglycaemic episodes per patient per month was -0.2 (95% CI: -1.1 to 0.7) and -0.2 (95% CI: -0.5 to 0.1) for analogues in comparison to regular insulin in patients with type 1 diabetes and type 2 diabetes, respectively. For studies in type 1 diabetes patients the incidence of severe hypoglycaemia ranged from 0 to 247.3 (median 21.8) episodes per 100 person-years for insulin analogues and from 0 to 544 (median 46.1) for regular insulin, in type 2 the incidence ranged from 0 to 30.3 (median 0.3) episodes per 100 person-years for insulin analogues and from 0 to 50.4 (median 1.4) for regular insulin. No study was designed to investigate possible long term effects (e.g. mortality, diabetic complications), in particular in patients with diabetes related complications. AUTHORS' CONCLUSIONS: Our analysis suggests only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin. Until long term efficacy and safety data are available we suggest a cautious response to the vigorous promotion of insulin analogues. For safety purposes, we need a long-term follow-up of large numbers of patients and well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child.

Serum sclerostin levels in renal cell carcinoma patients with bone metastases.

Sclerostin has been proposed as a potent inhibitor of bone formation. Sclerostin antibodies are under clinical development to treat osteoporosis and metastatic bone disease. Serum sclerostin level is elevated in multiple myeloma, an osteolytic malignancy, where it might serve as predictive marker for the use of sclerostin-directed antibodies. As renal cell carcinoma (RCC) patients often present with osteolytic metastases, we aimed to investigate serum sclerostin levels in RCC patients. Our study included 53 RCC patients (19 with bone metastases, 25 with visceral metastases and 9 with localized disease) and 53 age- and gender-matched non-osteoporotic controls. Frozen serum samples were subjected to sclerostin quantitative sandwich ELISA. The mean serum sclerostin levels of RCC patients and controls were 45.8 pmol/l and 45.1 pmol/l, respectively (p = 0.86). Analysis of variance showed no difference between the subgroups of RCC patients with regard to visceral or bone metastases or localized disease (p = 0.22). There was no significant association between eGFR (estimated glomerular filtration rate) and serum sclerostin levels in RCC patients (r = 0.05; p = 0.74) and controls (r = 0.06; p = 0.68). Our results indicate that serum sclerostin levels appear not to be a valuable biomarker to assess the occurrence of bone metastases in RCC patients.

Association of the vitamin D receptor genotype BB with low bone density in hyperthyroidism.

Bone mineral density (BMD) is modulated by genetic and environmental factors or certain diseases. In several conditions such as low calcium intake, an influence of vitamin D receptor (VDR) polymorphisms on BMD has been suggested. In the present study, we investigated the relationship of Bsm I and Fok I polymorphisms of the VDR gene and BMD in patients with hyperthyroidism, a disease that often results in low BMD. Bsm I and Fok I genotypes were determined in 76 postmenopausal hyperthyroid patients and 62 healthy postmenopausal women as controls. Patients and controls were matched for age, time since menopause, and lifestyle factors and were free of estrogen medication. BMD evaluation included axial dual X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (PQCT). Low BMD was defined as -2.5 STD below the young adult mean value. Biochemical parameters investigated were thyroid hormones, osteocalcin, and 25-(OH)-vitamin D3 as well as routine laboratory data. Low BMD was found in 61% of hyperthyroid patients and in only 23% of euthyroid controls. In the group of hyperthyroid patients with low bone density, the BB genotype (VDR Bsm I polymorphisms) was significantly more frequent (39%) than in controls (13%; p = 0.003) and hyperthyroid patients with normal BMD (6%; p = 0.013). The odds ratio (OR) for low BMD in patients with BB genotype was 5.7 (95% CI, 1.7-19.1; p < 0.005) as compared with the Bb and bb genotypes and 5.5 (95% CI, 2.3-13.2; p < 0.0001) for hyperthyroidism alone. The cumulative risk for low BMD in patients with hyperthyroidism and BB genotype was 31.4 (95% CI, 3.9-256; p < 0.0003). VDR Fok I genotypes showed no significant relationship with BMD or other general or bone-specific parameters. Thus, hyperthyroidism and the genetic background of a BB genotype may promote synergistically the development of low BMD in hyperthyroid patients. Screening for the BB genotype in these patients therefore could help to identify those with particularly high risk for the development of low BMD and allow early treatment.

Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation.

Osteoprotegerin (OPG) is an antiresorptive cytokine and a key regulator of osteoclastogenesis and activity. Since OPG is downregulated by glucocorticoids and cyclosporine A in vitro we examined whether immunosuppressive therapy would play a role in the development of transplantation osteoporosis. We enrolled 57 cardiac transplant recipients (median time since transplantation, 3.2 years (1.1-11.5 years)) in this cross-sectional study. Standardized spinal X-rays as well as hip bone density measurements were performed in all patients. Serum OPG was determined using a commercially available ELISA. Vertebral fractures were present in 56% of the patients. Bone densities of all femoral neck subregions were correlated to serum OPG concentrations (r values between 0.40 and 0.48, all P < 0.005). Multiple regression analysis revealed OPG levels to be independently correlated to femoral neck Z scores (r = 0.49, P = 0.002). After adjustment for age, BMI, neck Z score, renal function, and months since transplantation, serum OPG was the only significant predictor of prevalent vertebral fractures (P = 0.001). In a separate 6-month prospective study of 14 heart transplant recipients receiving calcium and vitamin D serum OPG levels fell by 41% (P = 0.0004) after 3 months and 47% (P = 0.0001) after 6 months following cardiac transplantation. Bone loss at the lumbar spine and femoral neck after 6 months was correlated to the decrease in serum OPG at 6 months (r = 0.82, P < 0.0001, and r = 0.60, P = 0.02, respectively) as well as 3 months after cardiac transplantation (r = 0.65, P = 0.01, and r = 0.69, P = 0.006, respectively). Serum OPG alone accounted for 67% of the variance of lumbar spine bone density changes over the first 6 months posttransplantation. We conclude that serum OPG levels decline consistently in all patients following initiation of immunosuppressive therapy and are independently correlated with changes in bone density. We hypothesize that OPG plays a major role in the development of transplantation osteoporosis.

Longitudinal change of white matter abnormalities.

A three year follow-up of 273 participants (mean age 60+/-6.1 years) of the Austrian Stroke Prevention Study provides first information on the rate, clinical predictors, and cognitive consequences of MRI white matter hyperintensity in elderly individuals without neuropsychiatric disease. Lesion progression was found in a total of 49 (17.9%) individuals. It was minor in 27 (9.9%) and marked in 22 (8.1%) participants. Diastolic blood pressure (odds ratio 1.07/mmHg) and early confluent or confluent white matter hyperintensities at baseline (odds ratio 2.62) were the only significant predictors of white matter hyperintensity progression. Lesion progression had no influence on the course of neuropsychologic test performance over the observational period.