Third whole-brain radiation therapy for multiple brain metastases. Should it be considered in selected patients?

Whole brain reirradiation for the treatment of multiple brain metastases has shown promising results. However, concerns remain over the possible neurotoxic effects of the cumulative dose as well as the questionable radiosensitivity of recurrent metastases. A second reirradiation of the whole brain is ordinarily performed in our department for palliative purposes in patients presenting with multiple metastatic brain progression. For this study, an investigational third whole brain reirradiation has been administered to highly selected patients to obtain disease control and delay progression. Clinical outcomes and neurological toxicity were also evaluated.

Facial approximation for identification purposes: soft tissue thickness in a Caucasian population. Sex and age-related variations.

The aim of this study was to collect soft tissue thickness (STT) values of an Italian population from 12 bone landmarks, to improve the facial approximation process for identification purposes. 100 Italian adults (50 males and 50 females), who had undergone head CT for clinical purposes, were analysed in order to expand the database of the Italian population. Average values, standard deviation and range were collected according to gender and age and the obtained values were statistically analysed in order to evaluate any possible significant difference. Only one landmark was statistically significant associated with sex, females showed significantly higher values for para-zygomaxillary. Two landmarks were statistically significant associated with age, upper incisor and pogonion. The obtained results were compared with the existing literature. Such information can be useful in the forensic craniofacial reconstruction process and can facilitate choosing the most suitable STT values according to osteological analysis of the human remains.

Nonvitamin K-dependent oral anticoagulants (NOACs) in chronic kidney disease patients with atrial fibrillation.

Atrial fibrillation (AF) represents the most common arrhythmia in patients with chronic kidney disease (CKD). As in the general population, in CKD patients AF is associated with an increased risk of thromboembolism and stroke. However, CKD patients, especially those on renal replacement therapy (RRT), also exhibit an increased risk of bleeding, especially from the gastrointestinal tract. Oral anticoagulation is the most effective form of thromboprophylaxis in patients with AF presenting increased risk of stroke. Limited evidence on efficacy, the increased risk of bleeding as well as some concern regarding the use of warfarin in CKD, has often resulted in the underuse of anticoagulation CKD patients. A large body of evidence suggests that non-vitamin K-dependent oral anticoagulant agents (NOACs) significantly reduce the risk of stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with vitamin K antagonist such as warfarin in normal renal function subjects. Hence, they are currently recommended for patients with atrial fibrillation at risk for stroke. However, NOACs metabolism is largely dependent on the kidneys for elimination and little is known in patients with creatinine clearance <25ml/min who were excluded from all pivotal phase 3 NOACs trials. This review focuses on the current pharmacokinetic, observational, and prospective data on NOACs in patients with moderate to advanced chronic kidney disease (creatinine clearance 15-49ml/min) and those on dialysis.

Pathophysiology of the cardio-renal syndromes types 1-5: An uptodate.

According to the recent definition proposed by the Consensus conference on Acute Dialysis Quality Initiative Group, the term cardio-renal syndrome (CRS) has been used to define different clinical conditions in which heart and kidney dysfunction overlap. Type 1 CRS (acute cardio- renal syndrome) is characterized by acute worsening of cardiac function leading to AKI (5, 6) in the setting of active cardiac disease such as ADHF, while type - 2 CRS occurs in a setting of chronic heart disease. Type 3 CRS is closely link to acute kidney injury (AKI), while type 4 represent cardiovascular involvement in chronic kidney disese (CKD) patients. Type 5 CRS represent cardiac and renal involvement in several diseases such as sepsis, hepato - renal syndrome and immune - mediated diseases.

Analysis of the main risk factors for gestational diabetes diagnosed with International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria in multiple pregnancies.

INTRODUCTION: The aim is to investigate the proportion of multiple pregnancies with gestational diabetes mellitus (GDM) diagnosed using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria and to identify the impact of age, body mass index (BMI), and mode of conception on incidence of GDM. MATERIALS AND METHODS: This is a single center, retrospective cohort study on 656 multiple pregnancies screened for GDM with 75-g, 2-h oral glucose tolerance test at 24-28 weeks of gestation, between January 2010 and January 2016. The diagnosis of gestational diabetes mellitus (GDM) was reached through the IADPSG. RESULTS: The incidence of GDM in our population was 15.1%. When patients who conceived through heterologous assisted reproduction technology were compared with those who conceived spontaneously, there was a significant difference for GDM (31.1 vs 13.6%, p < 0.001, OR 2.86). A similar finding was also observed comparing egg donation IVF/ICSI patients with homologous IVF/ICSI patients (31.1 vs 14.8%, p = 0.006, OR 2.59). Incidence of GDM was significantly higher in obese than in non-obese patients (42.5 vs 14.8%, p < 0.001, OR 4.88) and in women over 35 compared to younger patients (18.4 vs 11.1%, p = 0.01, OR 1.81). Logistic regression comparing the diabetes onset with conception mode gave a p = 0.07. The calculation of the Chi-square and odds ratio for single mode of conception showed that homologous vs conceived spontaneously p = 0.90, OR 0.97, heterologous vs homologous p = 0.01 with OR 2.46, and heterologous vs conceived spontaneously p = 0.01 with OR 2.39. Logistic regression showed that age and BMI are risk factors for developing GDM, respectively, p = 0.03 with OR 1.4 and p < 0.01 and OR 1.09. DISCUSSION: The contribution our study can make is improved counseling about GDM risks for couples with multiple pregnancies. Our data support the role of age, BMI, and mode of conception as risk factors for GDM in multiple pregnancies.

Pilot Study on Epigenetic Response to A Mind-Body Treatment.

In the last years, epigenetics and functional genomics methods to evaluate the genomic effects and mechanisms of mind-body therapies have increasingly grown. DNA microarray technology has been used to show the involvement of the stress response pathways both in the case of disease and stress and as an effect of mind-body therapies. In the present research, the DNA samples obtained from 20 individuals who experienced a mind-body therapeutic protocol (MBT-T), were analysed from the bio-molecular point of view by means of an epigenetic marker (MSAP molecular tool), in order to estimate the different status of methylation. The subjects were compared at 3 different times: prior to, 1 hour after, and 24 hours after the treatment. The molecular data were processed through different biostatistics approaches: the Bayesian statistics approach, in order to estimate the clustering membership of the subjects (Structure), and the statistical estimation of the DNA methylation level (MSAP statistical tool). The structure analysis revealed that the clusters and their membership changed among the three time points moving from higher heterogeneous distribution to higher homogeneous clusters. Before the treatment, the subjects' epigenetic profiles were heterogeneous; after the mind-body treatment we found that epigenetic profiles converged to homogeneous DNA methylation status. DNA epigenetic status of the subjects was affected by the MBT-T treatment.

Pilot Study on Epigenetic Response to A Mind-Body Treatment.

In the last years, epigenetics and functional genomics methods to evaluate the genomic effects and mechanisms of mind-body therapies have increasingly grown. DNA microarray technology has been used to show the involvement of the stress response pathways both in the case of disease and stress and as an effect of mind-body therapies. In the present research, the DNA samples obtained from 20 individuals who experienced a mind-body therapeutic protocol (MBT-T), were analysed from the bio-molecular point of view by means of an epigenetic marker (MSAP molecular tool), in order to estimate the different status of methylation. The subjects were compared at 3 different times: prior to, 1 hour after, and 24 hours after the treatment. The molecular data were processed through different biostatistics approaches: the Bayesian statistics approach, in order to estimate the clustering membership of the subjects (Structure), and the statistical estimation of the DNA methylation level (MSAP statistical tool). The structure analysis revealed that the clusters and their membership changed among the three time points moving from higher heterogeneous distribution to higher homogeneous clusters. Before the treatment, the subjects' epigenetic profiles were heterogeneous; after the mind-body treatment we found that epigenetic profiles converged to homogeneous DNA methylation status. DNA epigenetic status of the subjects was affected by the MBT-T treatment.

Semen quality impairment is associated with sexual dysfunction according to its severity.

STUDY QUESTION: Is sexual dysfunction associated with severity of semen quality impairment in men with couple infertility? SUMMARY ANSWER: In males of infertile couples the prevalence of erectile dysfunction (ED) increases as a function of semen quality impairment severity. WHAT IS KNOWN ALREADY: Infertile men are at a higher risk for sexual dysfunction, psychopathological and general health disorders. However, it has never been systematically investigated if these problems are associated with severity of semen quality impairment. STUDY DESIGN, SIZE, DURATION: Cross-sectional analysis of a first-time evaluation of 448 males of infertile couples attending an outpatient clinic from September 2010 to November 2015. In addition, 74 age-matched healthy, fertile men from an ultrasound study on male fertility were studied for comparison. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects underwent a complete physical, biochemical, scrotal and flaccid penile colour-Doppler ultrasound evaluation and semen analysis. Patients had already undergone at least one semen analysis; therefore, the majority were aware of their sperm quality before taking part in the study. Validated tools, such as the International Index of Sexual Function-15 (IIEF-15), Premature Ejaculation Diagnostic Tool (PEDT), Middlesex Hospital Questionnaire (MHQ), National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score and Chronic Disease Score (CDS), were used to evaluate, respectively, sexual dysfunction, premature ejaculation (PE), psychopathological traits, prostatitis-like symptoms, lower urinary tract symptoms and general health status. MAIN RESULTS AND THE ROLE OF CHANCE: Among men with couple infertility, 96 showed azoospermia (Group #1), 245 at least one sperm abnormality (Group #2) and 107 normozoospermia (Group #3). Fertile men were considered as a control group (Group #4). After adjusting for age, we observed a higher prevalence of ED (IIEF-15-erectile function domain score <26) (18.3% versus 0%; P = 0.006) and PE (PEDT score >8) (12.9% versus 4.1%; P = 0.036) in males of infertile couples compared with fertile men. The ED prevalence increases as a function of semen quality impairment severity (P < 0.0001), even after adjusting for confounders (age, CDS, MHQ and NIH-CPSI total score), despite similar hormonal, glyco-metabolic and penile vascular status. Compared to fertile men, all three groups of males with couple infertility showed a poorer erectile function, associated with an overall psychopathological burden (MHQ total score), particularly with somatized anxiety (MHQ-S). Azoospermic men showed the worst erectile function and general health: in this group, erectile function was negatively associated not only with psychopathological disturbances (MHQ total and MHQ-S scores; P < 0.0001) but also with a less healthy phenotype (higher CDS; P = 0.015). In addition, azoospermic men reported higher PE prevalence and lower sexual desire and orgasmic function when compared to fertile men (all P < 0.05), all of which were related to psychopathological symptoms. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional nature of the study represents its main limitation. A possible selection bias concerning the control group of healthy, fertile men recruited into an ultrasound study might have occurred. Finally, causality cannot be inferred in this type of study design and hence there should be some caution in interpreting the results. WIDER IMPLICATIONS OF THE FINDINGS: Investigation of male sexual function, general health and psychological status in infertile couples, especially if azoospermic, is advisable, in order to improve not only reproductive but also general and sexual health. STUDY FUNDING/COMPETING INTERESTS: Grants were received from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: None.

Hepatitis C virus outbreak in a haemodialysis unit: learning from failures.

The investigation of an outbreak of hepatitis C virus in an Italian haemodialysis (HD) centre showed that three patients acquired infection with the same strain, affecting a chronically hepatitis C virus (HCV)-infected patient receiving HD in the same room and during the same shifts. Through our observational analysis many possible modes of transmission were identified, but none could be definitively identified as the route of HCV spread in this small cluster. This outbreak confirms that repeated opportunities for nosocomial HCV transmission may occur among HD patients due to several breaches in the standard precautions for bloodborne infections by healthcare staff.

Structural insights into the multi-determinant aggregation of TDP-43 in motor neuron-like cells.

TDP-43 is aggregated in patients with ALS and FLTD through mechanisms still incompletely understood. Since aggregation in the cytosol is most probably responsible for the delocalization and loss of proper RNA-binding function of TDP-43 in the nucleus, interception of the formation of aggregates may represent a useful therapeutic option. In this study, we investigated the relative importance of the N-terminal and C-terminal moieties of TDP-43 in the aggregation process and the weight of each of the six cysteine residues in determining unfolding and aggregation of the different domains. We report that cytoplasmic inclusions formed by WT and mutant TDP-43 in motor neuron-like NSC34 cells are redox-sensitive only in part, and contain at least two components, i.e. oligomers and large aggregates, that are made of different molecular species. The two N-terminal cysteine residues contribute to the seeding for the first step in oligomerization, which is then accomplished by mechanisms depending on the four cysteines in the RNA-recognition motifs. Cysteine-independent large aggregates contain unfolded isoforms of the protein, held together by unspecific hydrophobic interactions. Interestingly, truncated isoforms are entrapped exclusively in oligomers. Ab initio modeling of TDP-43 structure, molecular dynamics and molecular docking analysis indicate a differential accessibility of cysteine residues that contributes to aggregation propensity. We propose a model of TDP-43 aggregation involving cysteine-dependent and cysteine-independent stages that may constitute a starting point to devise strategies counteracting the formation of inclusions in TDP-43 proteinopathies.

Sudden cardiac death and chronic kidney disease: From pathophysiology to treatment strategies.

Chronic kidney disease (CKD) patients demonstrate higher rates of cardiovascular mortality and morbidity; and increased incidence of sudden cardiac death (SCD) with declining kidney failure. Coronary artery disease (CAD) associated risk factors are the major determinants of SCD in the general population. However, current evidence suggests that in CKD patients, traditional cardiovascular risk factors may play a lesser role. Complex relationships between CKD-specific risk factors, structural heart disease, and ventricular arrhythmias (VA) contribute to the high risk of SCD. In dialysis patients, the occurrence of VA and SCD could be exacerbated by electrolyte shifts, divalent ion abnormalities, sympathetic overactivity, inflammation and iron toxicity. As outcomes in CKD patients after cardiac arrest are poor, primary and secondary prevention of SCD and cardiac arrest could reduce cardiovascular mortality in patients with CKD.

Pur-alpha functionally interacts with FUS carrying ALS-associated mutations.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to motor neuron loss. Fused in sarcoma (FUS) protein carrying ALS-associated mutations localizes to stress granules and causes their coalescence into larger aggregates. Here we show that Pur-alpha physically interacts with mutated FUS in an RNA-dependent manner. Pur-alpha colocalizes with FUS carrying mutations in stress granules of motoneuronal cells differentiated from induced pluripotent stem cells and that are derived from ALS patients. We observe that both Pur-alpha and mutated FUS upregulate phosphorylation of the translation initiation factor eukaryotic translation initiation factor 2 alpha and consistently inhibit global protein synthesis. In vivo expression of Pur-alpha in different Drosophila tissues significatively exacerbates the neurodegeneration caused by mutated FUS. Conversely, the downregulation of Pur-alpha in neurons expressing mutated FUS significatively improves fly climbing activity. All these findings suggest that Pur-alpha, through the control of mRNA translation, might be involved in the pathogenesis of ALS associated with the mutation of FUS, and that an alteration of protein synthesis may be directly implicated in the disease. Finally, in vivo RNAi-mediated ablation of Pur-alpha produced locomotion defects in Drosophila, indicating a pivotal role for this protein in the motoneuronal function.

Yttrium and aluminium complexes bearing dithiodiolate ligands: synthesis and application in cyclic ester polymerization.

Yttrium and aluminium complexes of two dithiodiolate ligands that feature different bridges (CF3)2C(OH)CH2SRSCH2C(OH)(CF3)2 (L(1)-H2, R = CH2CH2 and L(2)-H2, R = C6H4) were synthesized in good yields by reacting tris(silylamide)yttrium or trimethylaluminium with one equivalent of the proligand. All complexes were characterized by NMR and elemental analysis, and single-crystal X-ray structural analysis was also performed for one of the yttrium complexes. The catalytic activities of the four complexes in the ring-opening polymerization of ε-caprolactone and rac-lactide have been investigated. Furthermore, DOSY experiment and DFT calculations have been carried out to determine the structure of the isopropoxo derivative of the complex L(2)Y amide.

Phosphate balance in ESRD: diet, dialysis and binders against the low evident masked pool.

Phosphate metabolism is crucial in the pathophysiology of secondary hyperparathyroidism and vascular calcification. High phosphate levels have been consistently associated with unfavorable outcomes in dialysis patients, but several limitations are still hampering a resolutive definition of the optimal targets of phosphate serum levels to be achieved in this cohort. Nonetheless, hyperphosphatemia is a late marker of phosphate overload in humans. Clinical nephrologists routinely counteract the positive phosphate balance in dialysis patients through nutritional counseling, stronger phosphate removal by dialysis and prescription of phosphate binders. However, the superiority against placebo of phosphate control by diet, dialysis or binders in terms of survival has never been tested in dedicated randomized controlled trials. The present review discusses this conundrum with particular emphasis on the rationale supporting the value of a simultaneous intervention against phosphate overload in dialysis patients via the improvement of dietary intakes, dialysis efficiency and an individualized choice of phosphate binders.

Clinically relevant quality assurance (QA) for prostate RapidArc plans: gamma maps and DVH-based evaluation.

The aim of this paper is to evaluate clinically relevant quality assurance (QA) tests for RapidArc prostate patients. 26 plans were verified by the COMPASS system that provides an independent angle response and a reconstruction of dose distribution in patient CT model. Plan data were imported from treatment planning system via DICOM. The fluencies, measured by a 2D detector, were used by COMPASS to forward calculate dose in CT patients and reconstruct dose-volume-histogram (DVH). The gamma analysis was performed, using both the criteria 3%-3-mm and 2%-2 mm, for the whole grid patient and the per-structure volume. A DVH-based analysis was accomplished for target and organs-at-risk (OAR). The correlation between gamma passing rates and DVH discrepancies was performed using Pearson's test. Sensitivity, specificity and accuracy of whole and per-structure gamma method were calculated. No significant DVH deviation was observed for target and OAR. Weak correlation between gamma passing rates and dosimetric deviations was observed, all significant r-values were negative. The whole gamma method shows lack of sensitivity to detect dosimetric deviations >5%. Instead, a better balance between sensitivity and specificity was obtained employing per structure gamma both with 3%-3 mm and 2%-2 mm criteria. Because of the poor correlation between DVH goals and gamma passing rates, we encourage the DVH-based gamma passing rates, when it is possible. At least, a gamma method specific for structure was strongly suggested.

Clinically relevant quality assurance for intensity modulated radiotherapy plans: gamma maps and DVH-based evaluation.

PURPOSE: To explore a novel patient-dose DVH-based method for pretreatment dose quality assurance tests. METHODS: 20 IMRT plans for head-and-neck cancer patients were used. A comparison was performed between the planned dose distributions, the computed, and the reconstructed ones using the gamma-index (GI) method. The GI analysis was performed using both the 3%/3 mm and the 2%/2 mm criteria. RESULTS: No significant DVH-deviation was observed. Considering the 3%/3 mm criteria the mean GI% < 1 for the body and structures was significantly higher compared to 2%/2 mm criteria. CONCLUSIONS: Our results underline the importance of QA-methods based on DVH-metrics to predict the impact of delivered dose.

Impaired bone metabolism in glycogen storage disease type 1 is associated with poor metabolic control in type 1a and with granulocyte colony-stimulating factor therapy in type 1b.

BACKGROUND: Glycogen storage disease type 1 (GSD1) is a rare and genetically heterogeneous metabolic defect of gluconeogenesis due to mutations of either the G6PC gene (GSD1a) or the SLC37A4 gene (GSD1b). Osteopenia is a known complication of GSD1. OBJECTIVES: The aim of this study was to investigate the effects of poor metabolic control and/or use of GSD1-specific treatments on bone mineral density (BMD) and metabolism in GSD1 patients. METHODS: In a multicenter, cross-sectional case-control study, we studied 38 GSD1 (29 GSD1a and 9 GSD1b) patients. Clinical, biochemical and instrumental parameters indicative of bone metabolism were analyzed; BMD was evaluated by dual-emission X-ray absorptiometry and quantitative ultrasound. RESULTS: Both GSD1a and GSD1b patients showed reduced BMD compared with age-matched controls. In GSD1a patients, these abnormalities correlated with compliance to diet and biochemical indicators of metabolic control. In GSD1b patients, BMD correlated with the age at first administration and the duration of granulocyte colony-stimulating factor (G-CSF) therapy. CONCLUSIONS: Our data indicate that good metabolic control and compliance with diet are highly recommended to improve bone metabolism in GSD1a patients. GSD1b patients on G-CSF treatment should be carefully monitored for the risk of osteopenia/osteoporosis.

Vitamin D metabolites and/or analogs: which D for which patient?

Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual patient. In this paper we review the main characteristics of the available drugs and provide evidence about any potential specific clinical indications, with special emphasis on renal patients, in order to facilitate the optimal choice. Natural vitamin D products (i.e. those identical to natural metabolites) are first examined, followed by the most frequently used synthetic molecules (i.e. bioengineered molecules not-existing in nature), which are generally indicated as " analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with normal renal function and in CKD stage 3-5 patients to correct vitamin D deficiency and improve, respectively, age- or growth-related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin D, has the most potent hypercalcemic effect in both normal and renal failure patients. In renal patients calcitriol is a potent inhibitor of parathyroid activity, but the risk of hypercalcemia, now regarded as harmful, is evident whenever pharmacologic doses are used. Alfacalcidol, requiring 25-hydroxylation to become the active hormonal form of vitamin D3, is prescribed in normal subjects to treat osteoporosis and in renal patients to cure hyperparathyroidism and renal bone disease. Doxercalciferol, transformed into the active hormonal form of vitamin D2 following 25-hydroxylation, is mostly studied in renal patients in whom it cures secondary hyperparathyroidism, possibly with a lower calcemic effect than calcitriol. Paricalcitol, a vitamin D2 analog not requiring activation, has been specifically developed to suppress PTH in renal patients with a limited calcemic effect. As such it is now regarded as a powerful drug useful to treat even severe cases of secondary hyperparathyroidism. Importantly, reno-protective and cardio-protective effects of this analog have been recently evaluated by means of randomized clinical trials in renal patients with partially positive renal effects and negative cardiac results, thus additional studies are needed for confirmation. 22-oxacalcitriol, a vitamin D3 analog with a limited calcemic effect available in Japan, is mostly used in renal patients affected by secondary hyperparathyroidism. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. In summary, available drugs with vitamin D like activity are not all the same either in terms of pharmacological actions, and side-effects. They have specific characteristics that may be useful to know in order to operate the best choice in the individual patient.

Clinical Uses of 1,25-dihydroxy-19-nor-vitamin D(2) (Paricalcitol).

The activation of vitamin D receptors (VDR) - (including activation by 25-hydroxyvitamin D) - seems to have not only mineral-metabolism beneficial effects but also important extra-skeletal actions. Paricalcitol is a synthetic vitamin D2 agonist of the VDR approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD). As a result of its selectivity, paricalcitol provides a wider therapeutic window for PTH suppression, minimizing deleterious effects of high serum calcium and/or phosphate concentrations. Paricalcitol also shares, and sometimes improves pleiotropic vitamin-D related systemic effects. For instance, paricalcitol has been repeatedly shown to decrease calcium and phosphate deposition in vessels and to decrease the expression of osteogenic factors preventing the active transformation of smooth muscle vascular cells into osteoblast-like cells in experimental models. In patients, paricalcitol has been associated with improved survival of dialysis patients and it may improve residual albuminuria in diabetic patients. Consequently, paricalcitol may enhance the standard of care in these high-risk patients. Although it seems reasonable to use these potential advantages to guide the individual and integral management of the complex CKD-mineral and bone disorder, it is necessary to recognize that many of these observations have not been proven nor confirmed in prospective clinical trials.