Hypovitaminosis D, impaired bone turnover and low bone mass are common in patients with peripheral arterial disease

Hypovitaminosis D is common in patients with peripheral arterial disease (PAD). Subsequent secondary hyperparathyroidism and osteomalacia contribute to bone pain and myalgias, and so aggravate clinical symptoms of claudication. We evaluated 95 out of 297 patients with angiographically confirmed PAD stages II (pain in the calves and/or thighs only during exercise) or IV (history of, or presence of local ulcers) and compared them with 44 matched healthy controls regarding their medical history, bone density measurements of the femoral neck and calcaneal bone ultrasound. Bone pain, myalgias and mobility restriction as well as routine laboratory parameters, serum vitamin D [25(OH)D], crosslaps (CTX), parathyroid hormone (PTH), osteocalcin (OC) and alkaline phosphatase (AP) were recorded and analysed. 25(OH)D was significantly lower in PAD IV patients (9.6±4.6 ng/ml, P<0.0001) as compared to PAD II stages and controls (19.0±7.6 and 19.1±9.1 ng/ml), paralleled by lower serum calcium [2.24±0.02 mmol/l, P=0.0002 versus PAD II (2.36±0.02) and P<0.0001 versus controls (2.39±0.02)] and higher iPTH serum levels (66.3±3.6 pg/ml, P<0.0001) as compared to PAD II patients (45.3±3.5) and healthy controls (38.5±2.4). Alkaline phosphatase and serum crosslaps values were significantly higher and age-adjusted bone density and bone ultrasound measurements significantly lower in PAD IV patients, who were also twice as likely to have bone pain and myalgias as PAD II patients. Bone ultrasound measurements correlated significantly with both clinical severity and pain as well as serological parameters of bone metabolism. Underlying PAD has a significant impact on bone density and metabolism as well as on bone and muscular pain. Patients with PAD are at high risk for osteoporosis and osteomalacia and should be regularly monitored and treated for their vitamin D deficiencies.S. Kudlacek represents the Austrian Study Group on Normative Values of Bone Metabolism.     

Reduction in Fracture Rate and Back Pain and Increased Quality of Life in Postmenopausal Women Treated with Teriparatide: 18-Month Data from the European Forsteo Observational Study (EFOS)

The European Forsteo Observational Study was designed to examine the effectiveness of teriparatide in postmenopausal women with osteoporosis treated for up to 18 months in normal clinical practice in eight European countries. The incidence of clinical vertebral and nonvertebral fragility fractures, back pain, and health-related quality of life (HRQoL, EQ-5D) were assessed. Spontaneous reports of adverse events were collected. All 1,648 enrolled women were teriparatide treatment-naive, 91.0% of them had previously received other anti-osteoporosis drugs, and 72.8% completed the 18-month study. A total of 168 incident clinical fractures were sustained by 138 (8.8%) women (821 fractures/10,000 patient-years). A 47% decrease in the odds of fracture in the last 6-month period compared to the first 6-month period was observed (P < 0.005). Mean back pain VAS was reduced by 25.8 mm at end point (P < 0.001). Mean change from baseline in EQ-VAS was 13 mm by 18 months. The largest improvements were reported in the EQ-5D subdomains of usual activities and pain/discomfort. There were 365 adverse events spontaneously reported, of which 48.0% were considered related to teriparatide; adverse events were the reason for discontinuation for 79 (5.8%) patients. In conclusion, postmenopausal women with severe osteoporosis who were prescribed teriparatide in standard clinical practice had a significant reduction in the incidence of fragility fractures and a reduction in back pain over an 18-month treatment period. This was associated with a clinically significant improvement in HRQoL. Safety was consistent with current prescribing information. These results should be interpreted in the context of the open-label, noncontrolled design of the study.     

Anxiety, Depression and Health-Related Quality of Life after Jejunoileal Bypass: A 25-Year Follow-up Study of 20 Female Patients

Background: Jejunoileal (JI) bypass was a widely performed operation for morbid obesity in the 1970s.The aim of this study was to investigate the long-term status for mental and physical health after weight loss induced by this operation. Methods: 20 female patients (age 48-80 y, BMI 23-75 kg/m²) were interviewed 25 years after JI bypass. The Hospital Anxiety and Depression Scale (HAD) and Short Form 36 (SF-36) were used. Scores from the Norwegian female population, and published scores for morbidly obese patients were used for comparison. An assessment was made on whether present demographic and clinical factors influenced the scores. Results: Anxiety and depression scores, and scores for physical functioning, bodily pain, vitality and mental health on the SF-36 were similar to scores in the Norwegian female population used for comparison. The scores from the patient sample were much better than scores published for morbidly obese patients, and implies that weight loss induced by the operation has been of great benefit on mental health and health-related quality of life. Anxiety and depression symptoms improved; however, being socially handicapped by the stools had a negative impact on HAD and SF-36 scores. Conclusion: These results suggest that 25 years after the JI bypass most of these patients have a similar level of mental and physical health as the general Norwegian female population. For individuals with bothersome side-effect(s) of the operation, a negative impact is seen.     

Clinical performance and radiation dosimetry of no-carrier-added vs carrier-added 123I-metaiodobenzylguanidine (MIBG) for the assessment of cardiac sympathetic nerve activity

Purpose We hypothesized that assessment of myocardial sympathetic activity with no-carrier-added (nca) ¹²³I-meta-iodobenzylguanidine (MIBG) compared to carrier-added (ca) ¹²³I-MIBG would lead to an improvement of clinical performance without major differences in radiation dosimetry. Methods In nine healthy volunteers, 15 min and 4 h planar thoracic scintigrams and conjugate whole-body scans were performed up to 48 h following intravenous injection of 185 MBq ¹²³I-MIBG. The subjects were given both nca and ca ¹²³I-MIBG. Early heart/mediastinal ratios (H/M), late H/M ratios and myocardial washout were calculated. The fraction of administered activity in ten source organs was quantified from the attenuation-corrected geometric mean counts in conjugate views. Radiation-absorbed doses were estimated with OLINDA/EXM software. Results Both early and late H/M were higher for nca ¹²³I-MIBG (ca ¹²³I-MIBG early H/M 2.46 ± 0.15 vs nca ¹²³I-MIBG 2.84 ± 0.15, p = 0.001 and ca ¹²³I-MIBG late H/M 2.69 ± 0.14 vs nca ¹²³I-MIBG 3.34 ± 0.18, p = 0.002). Myocardial washout showed a longer retention time for nca ¹²³I-MIBG (p < 0.001). The effective dose equivalent (adult male model) for nca ¹²³I-MIBG was similar to that for ca ¹²³I-MIBG (0.025 ± 0.002 mSv/MBq vs 0.026 ± 0.002 mSv/MBq, p = 0.055, respectively). Conclusion No-carrier-added ¹²³I-MIBG yields a higher relative myocardial uptake and is associated with a higher myocardial retention. This difference between nca ¹²³I-MIBG and ca ¹²³I-MIBG in myocardial uptake did not result in major differences in estimated absorbed doses. Therefore, nca ¹²³I-MIBG is to be preferred over ca ¹²³I-MIBG for the assessment of cardiac sympathetic activity.     

Selective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival in rats with C6 gliomas

OBJECT: The response of brain tumors to systemic chemotherapy is limited by the blood-tumor barrier (BTB). Nitric oxide (NO) has been implicated in the regulation of vascular permeability and blood flow. The authors evaluated the effects of exogenous NO, which was released from a short-acting NO donor (Proli/NO), and those of NO metabolites on the capillary permeability of tumors and normal brain tissue by using quantitative autoradiography in a C6 glioma model in rats. METHODS: The Proli/NO was infused at a wide dose range (10(-2) to 10(-12) M) either intravenously or into the internal carotid artery (ICA) and demonstrated substantial tumor-selective increases in blood-brain barrier (BBB) permeability in response to various-sized tracers ([14C]aminoisobutyric acid, [14C]sucrose, [14C]dextran). Internal carotid artery or intravenous administration of sodium nitrite had a comparable effect on BTB permeability. The NO effect on microvascular permeability could be obtained without causing hemodynamic side effects. The effect of NO on the efficacy of carboplatin chemotherapy was investigated in intracerebral C6 gliomas. Simultaneous intravenous infusions of Proli/NO (10(-6) M) and carboplatin (20 mg/kg) led to long-term survival in 40% of rats harboring intracerebral C6 gliomas compared with control animals receiving ICA or intravenous infusions of carboplatin, Proli/NO, or vehicle alone. No residual tumor was demonstrated on histological or magnetic resonance imaging studies performed in rats treated with Proli/NO and carboplatin, and no toxicity was observed. CONCLUSIONS: This new approach demonstrated the in vivo efficacy and safety of NO and nitrite in enhancing the delivery of systemically delivered radiolabeled tracers and carboplatin into rat gliomas. The NO-induced tumor-selective BBB disruption and intravenous carboplatin chemotherapy may be more efficacious than current chemotherapy strategies against brain tumors.     

S-Classification of Sentinel Lymph Node Predicts Axillary Nonsentinel Lymph Node Status in Patients with Breast Cancer

Background One-half of breast cancer patients with positive sentinel lymph node (SN) have no further metastases in the axillary lymph node basin. The aim of the present study was to identify patients with positive SN who are unlikely to have further metastases in the axillary lymph node basin, using a new classification of SN, namely the S-classification. Methods Specimens of positive SN were subjected to a pathological review according to the previously published S-classification. S-stages of positive SN were correlated with the status of further metastases in the axillary lymph node basin after axillary lymph node dissection (ALND). Results Of 117 patients who underwent sentinel lymph node biopsy, 36 (30.8%) had a positive SN and were subjected to level I and II ALND. The occurrence of positive nonsentinel nodes was significantly related to the S-stage of SN. No patient with stage SI had additional metastases in the nonsentinel lymph nodes, while 14.3% of patients with SII stage disease and 60.9 % of patients with SIII disease had other non-SN that were metastatic. Conclusion S-stages of positive SN are highly predictive for axillary nonsentinel node status. Especially patients with SI sentinel node metastases appear to be at low risk for further nonsentinel node metastases.     

Acute rejection after paediatric heart transplantation: far less common and less severe

Despite improved immunosuppression, rejection accounts for significant morbidity and mortality in children after heart transplantation. We report the incidence and outcome of rejection of 105 children (male = 50; mean age of 8.3 ± 5.8 years) following heart transplantation between January 2002 and August 2007. A multi-variant model was constructed for risk factors associated with significant rejection. In 271.9 patient-years of follow-up, there were 23 episodes of significant rejection (≥3A) in 21 patients (20%). Five presented in haemodynamic collapse requiring extracorporeal membrane oxygenation support 1.6–35.9 months after transplantation; four of five survived the rejection episode. Overall rejection episodes were more common in older children, boys and those treated with sirolimus. Whereas the risk for rejection in patients on an immunosuppression regime containing tacrolimus was significantly lower. The latter finding persisted on multivariate analysis ( P  < 0.002). Interestingly, none of the patients who presented with haemodynamic collapse was on mycophenolate mofetil. While our experience is of a far lower incidence of rejection than registry data, rejection remains a serious problem after paediatric heart transplantation. Sirolimus without a calcineurin inhibitor was associated with more rejection episodes, whereas tacrolimus and mycophenolate appeared to provide the best protective profile.     

Patients undergoing surgery for lumbar degenerative spinal disorders favor smartphone-based objective self-assessment over paper-based patient-reported outcome measures

Background ContextSmartphone-based applications enable new prospects to monitor symptoms and assess functional outcome in patients with lumbar degenerative spinal disorders. However, little is known regarding patient acceptance and preference towards new modes of digital objective outcome assessment.PurposeTo assess patient preference of an objective smartphone-based outcome measure compared to conventional paper-based subjective methods of outcome assessment.Study designProspective observational cohort study.Patient sampleFourty-nine consecutive patients undergoing surgery for lumbar degenerative spinal disorder.Outcome measuresPatients completed a preference survey to assess different methods of outcome assessment. A 5-level Likert scale ranged from strong disagreement (2 points) over neutral (6 points) to strong agreement (10 points) was used.MethodsPatients self-determined their objective functional impairment using the 6-minute Walking Test application (6WT-app) and completed a set of paper-based patient-reported outcome measures (PROMs) before and 6 weeks after surgery. Patients were then asked to rate the methods of outcome assessment in terms of suitability, convenience, and responsiveness to their symptoms.ResultsThe majority of patients considered the 6WT-app a suitable instrument (median 8.0, interquartile range [IQR] 4.0). Patients found the 6WT more convenient (median 10.0, IQR 2.0) than the Zurich Claudication Questionnaire (ZCQ; median 8.0, IQR 4.0, p=.019) and Core Outcome Measure Index (COMI; median 8.0, IQR 4.0, p=.007). There was good agreement that the 6WT-app detects change in physical performance (8.0, IQR 4.0). 78 % of patients considered the 6WT superior in detecting differences in symptoms (vs. 22% for PROMs). Seventy-six percent of patients would select the 6WT over the other, 18% the ZCQ and 6% the COMI. Eighty-two percent of patients indicated their preference to use a smartphone app for the assessment and monitoring of their spine-related symptoms in the future.ConclusionsPatients included in this study favored the smartphone-based evaluation of objective functional impairment over paper-based PROMs. Involving patients more actively by means of digital technology may increase patient compliance and satisfaction as well as diagnostic accuracy.     

Effects of denosumab on bone histomorphometry: The FREEDOM and STAND studies

Denosumab, a human monoclonal antibody against RANKL, reversibly inhibits osteoclast‐mediated bone resorption and has been developed for use in osteoporosis. Its effects on bone histomorphometry have not been described previously. Iliac crest bone biopsies were collected at 24 and/or 36 months from osteoporotic postmenopausal women in the FREEDOM study (45 women receiving placebo and 47 denosumab) and at 12 months from postmenopausal women previously treated with alendronate in the STAND study (21 continuing alendronate and 15 changed to denosumab at trial entry). Qualitative histologic evaluation of biopsies was unremarkable. In the FREEDOM study, median eroded surface was reduced by more than 80% and osteoclasts were absent from more than 50% of biopsies in the denosumab group. Double labeling in trabecular bone was observed in 94% of placebo bones and in 19% of those treated with denosumab. Median bone‐formation rate was reduced by 97%. Among denosumab‐treated subjects, those with double labels and those with absent labels had similar levels of biochemical markers of bone turnover. In the STAND trial, indices of bone turnover tended to be lower in the denosumab group than in the alendronate group. Double labeling in trabecular bone was seen in 20% of the denosumab biopsies and in 90% of the alendronate samples. Denosumab markedly reduces bone turnover and also reduces fracture numbers. Longer follow‐up is necessary to determine how long such low turnover is safe. © 2010 American Society for Bone and Mineral Research.