No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial

Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.     

Men's health in Europe

Background

In 2011 the European Commission launched the report ‘The State of Men's Health in Europe’ covering the health of 290 million men across 34 European countries. This is the first official statement on the health of men in Europe. The work was carried out by a team of writers from across Europe aided by a management advisory group, a reviewing group and a broader reference group.

Methods

Data from major international databases were used to compile a detailed analysis based on population data, lifestyle and preventable risk factors, use of health services and morbidity and mortality data based on the ICD-10, with the results focused on the “European shortlist” of 65 causes of death.

Results

Changes in male demographics are creating a reversal in the age distribution ratio, with a decreasing younger population but increasing numbers of elderly men. The data on morbidity and mortality are most striking in relation to the high levels of premature death in men across the disease spectrum with marked differences between countries.

Conclusions

The very large variations seen in the health of men across Europe demonstrates that much of men's higher risk of premature death is caused by socio-cultural factors and therefore avoidable. No country should be complacent about the health of its male population.     

Assessment of a portable device for the quantitative measurement of ankle joint stiffness in spastic individuals

ObjectiveSpasticity is a common complication with neurological diseases and CNS lesions. Instrumented systems to evaluate spasticity often cannot provide an immediate result, thus limiting their clinical usefulness. In this study we investigated the accuracy and reliability of the portable Neurokinetics RA1 Ridgidity Analyzer to measure stiffness of the ankle joint in 46 controls, 14 spinal cord injured (SCI) and 23 multiple sclerosis (MS) participants.MethodsAnkle stiffness measures were made twice by two raters, at speeds above and below the expected stretch reflex threshold. Ankle torque was measured with the portable device and a stationary torque motor. Inter- and intra-rater reliability was assessed with the intra-class correlation coefficient (ICC).ResultsStiffness measures with the portable and stationary devices were significantly correlated for controls and MS participants (p < 0.01). Intra-rater reliability for the portable device ranged from 0.60–0.89 (SCI) and 0.63–0.67 (control) and inter-rater reliability ranged from 0.70–0.73 (SCI) and 0.61–0.77 (control). Ankle stiffness measures in SCI and MS participants were significantly larger than in controls for both slow (p < 0.05) and fast movements (p < 0.01), with stiffness being larger for fast compared to slow movements in SCI and MS participants (p < 0.05), but not in controls (p = 0.5).ConclusionThe portable device correlated well with measures obtained by a torque motor in both controls and MS participants, showed high intra- and inter-rater reliability for the SCI participants, and could easily distinguish between stiff and control ankle joints. However, the device, in its current form, may be less accurate during rapid movements when inertia contributes to stiffness and the shape of the air-filled pads did not provide a good interface with the foot.SignificanceThis study demonstrates that a portable device can potentially be a useful diagnostic tool to obtain reliable information of stiffness for the ankle joint.     

Prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) in Danish patients with recurrent epithelial ovarian cancer (REOC)

The level of the soluble urokinase plasminogen activator receptor (suPAR) is elevated in tumour tissue from several types of cancer. This is the first study aiming to predict the prognosis for survival by the use of a pre-chemotherapeutic plasma suPAR value in 71 patients with recurrent epithelial ovarian cancer (REOC). For determination of suPAR, pre-chemotherapeutic blood samples from the patients with REOC were processed into plasma (EDTA) within one working day from venipuncture. The plasma suPAR level is not correlated with performance status (p=0.41), FIGO stage (p=0.09), treatment-free interval (TFI) of 12 months (p=0.26), site of recurrence (peritoneum, p=0.50 or pelvis, p=0.44), age (p=0.43), or serum CA125 (p=0.09). Univariate as well as multivariate analyses cannot demonstrate that high pre-chemotherapeutic levels of plasma suPAR (p=0.22, p=0.80) are associated with shorter survival of REOC patients. Multivariate analysis showed that only TFI of 12 months (p=0.001) and performance score status of 2 (p=0.02) were independent prognostic factors. Our study indicates that pre-chemotherapeutic measurement of plasma suPAR level in REOC patients may not be useful to identify a subgroup of patients with poor prognosis.     

Optimizing cost-efficiency in mean exposure assessment - cost functions reconsidered

Background

Reliable exposure data is a vital concern in medical epidemiology and intervention studies. The present study addresses the needs of the medical researcher to spend monetary resources devoted to exposure assessment with an optimal cost-efficiency, i.e. obtain the best possible statistical performance at a specified budget. A few previous studies have suggested mathematical optimization procedures based on very simple cost models; this study extends the methodology to cover even non-linear cost scenarios.

Methods

Statistical performance, i.e. efficiency, was assessed in terms of the precision of an exposure mean value, as determined in a hierarchical, nested measurement model with three stages. Total costs were assessed using a corresponding three-stage cost model, allowing costs at each stage to vary non-linearly with the number of measurements according to a power function. Using these models, procedures for identifying the optimally cost-efficient allocation of measurements under a constrained budget were developed, and applied on 225 scenarios combining different sizes of unit costs, cost function exponents, and exposure variance components.

Results

Explicit mathematical rules for identifying optimal allocation could be developed when cost functions were linear, while non-linear cost functions implied that parts of or the entire optimization procedure had to be carried out using numerical methods. For many of the 225 scenarios, the optimal strategy consisted in measuring on only one occasion from each of as many subjects as allowed by the budget. Significant deviations from this principle occurred if costs for recruiting subjects were large compared to costs for setting up measurement occasions, and, at the same time, the between-subjects to within-subject variance ratio was small. In these cases, non-linearities had a profound influence on the optimal allocation and on the eventual size of the exposure data set.

Conclusions

The analysis procedures developed in the present study can be used for informed design of exposure assessment strategies, provided that data are available on exposure variability and the costs of collecting and processing data. The present shortage of empirical evidence on costs and appropriate cost functions however impedes general conclusions on optimal exposure measurement strategies in different epidemiologic scenarios.     

PINK1 cleavage at position A103 by the mitochondrial protease PARL

Mutations in PTEN-induced kinase 1 (PINK1) cause early onset autosomal recessive Parkinson's disease (PD). PINK1 is a 63 kDa protein kinase, which exerts a neuroprotective function and is known to localize to mitochondria. Upon entry into the organelle, PINK1 is cleaved to produce a ～53 kDa protein (ΔN-PINK1). In this paper, we show that PINK1 is cleaved between amino acids Ala-103 and Phe-104 to generate ΔN-PINK1. We demonstrate that a reduced ability to cleave PINK1, and the consequent accumulation of full-length protein, results in mitochondrial abnormalities reminiscent of those observed in PINK1 knockout cells, including disruption of the mitochondrial network and a reduction in mitochondrial mass. Notably, we assessed three N-terminal PD-associated PINK1 mutations located close to the cleavage site and, while these do not prevent PINK1 cleavage, they alter the ratio of full-length to ΔN-PINK1 protein in cells, resulting in an altered mitochondrial phenotype. Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and that loss of PARL results in aberrant PINK1 cleavage in mammalian cells. These combined results suggest that PINK1 cleavage is important for basal mitochondrial health and that PARL cleaves PINK1 to produce the ΔN-PINK1 fragment.