Vitamin D deficiency remains very common in the general population. Adding to the importance of this issue is the discovery that vitamin D plays a role in many other tissues apart from the bone, ...including muscle, brain, prostate, breast and colon. In this study, we investigated the prevalence of vitamin D deficiency in a large group of patients hospitalised in the cantonal hospital Basel-Country, and analysed the dependence of serum vitamin D concentrations on gender, time of the year and age.
We retrospectively analysed anonymised data received from the central laboratory of the cantonal hospital Basel-Country. The pool of data contains values obtained between 2013 and 2017 from 8861 patients aged between 18 and 102 years. If sequential measurements were available from a patient, only the first was used for the analyses. Vitamin D deficiency was defined as a serum concentration of <50 nmol/l and severe deficiency as <25 nmol/l. Vitamin D values between 50 and 75 nmol/l are considered a grey zone. Optimal values are >75 nmol/l.
Mean ± standard deviation serum vitamin D concentration was 52.5 ± 30.5 nmol/l, with women having a higher mean of 55.5 ± 31.5 nmol/l as compared with 48.1 ± 28.6 nmol/l in men (p <10-5). Of the 8861 first measurements taken within the observation period, 4527 (51%) were vitamin D deficient with levels <50 nmol/l, including 1860 (21.0%) with levels <25 nmol/l. There was only a weak positive association of average vitamin D levels with age (p = 0.06). Women reached peak concentrations of 56.9 ± 35.4 nmol/l in the age group 90-102 years, whereas men reached peaks of 50.3 ± 31.9 nmol/l in 50-59-year-olds. Mean autumn and spring concentrations differed less (51.6 ± 29.6 vs 52.7 ± 30.7 nmol/l, respectively, p = 0.38) than mean summer and winter concentrations (57.1 ± 29.5 vs 48.0 ± 31.2 nmol/l, respectively, p <10-5).
Vitamin D deficiency was a common finding in our cohort, affecting all age groups and occurring in over half (51%) of the values measured. As current guidelines recommend vitamin D concentrations >75 nmol/l, only 22.1% of measured values indicated adequate vitamin D levels. This issue should be addressed in order to improve quality of life and reduce medical costs.  .
Symptom-checkers have become important tools for self-triage, assisting patients to determine the urgency of medical care. To be safe and effective, these tools must be validated, particularly to ...avoid potentially hazardous undertriage without leading to inefficient overtriage. Only limited safety data from studies including small sample sizes have been available so far. The objective of our study was to prospectively investigate the safety of patients’ self-triage in a large patient sample. We used SMASS (Swiss Medical Assessment System; in4medicine, Inc) pathfinder, a symptom-checker based on a computerized transparent neural network. We recruited 2543 patients into this single-center, prospective clinical trial conducted at the cantonal hospital of Baden, Switzerland. Patients with an Emergency Severity Index of 1-2 were treated by the team of the emergency department, while those with an index of 3-5 were seen at the walk-in clinic by general physicians. We compared the triage recommendation obtained by the patients’ self-triage with the assessment of clinical urgency made by 3 successive interdisciplinary panels of physicians (panels A, B, and C). Using the Clopper-Pearson CI, we assumed that to confirm the symptom-checkers’ safety, the upper confidence bound for the probability of a potentially hazardous undertriage should lie below 1%. A potentially hazardous undertriage was defined as a triage in which either all (consensus criterion) or the majority (majority criterion) of the experts of the last panel (panel C) rated the triage of the symptom-checker to be “rather likely” or “likely” life-threatening or harmful. Of the 2543 patients, 1227 (48.25%) were female and 1316 (51.75%) male. None of the patients reached the prespecified consensus criterion for a potentially hazardous undertriage. This resulted in an upper 95% confidence bound of 0.1184%. Further, 4 cases met the majority criterion. This resulted in an upper 95% confidence bound for the probability of a potentially hazardous undertriage of 0.3616%. The 2-sided 95% Clopper-Pearson CI for the probability of overtriage (n=450 cases,17.69%) was 16.23% to 19.24%, which is considerably lower than the figures reported in the literature. The symptom-checker proved to be a safe triage tool, avoiding potentially hazardous undertriage in a real-life clinical setting of emergency consultations at a walk-in clinic or emergency department without causing undesirable overtriage. Our data suggest the symptom-checker may be safely used in clinical routine.
Copeptin and vasopressin levels correlate closely over a wide range of osmolalities, and the copeptin assay may be a useful alternative to the arginine vasopressin measurement.
Background:
Copeptin, ...the C-terminal moiety of provasopressin, is cosecreted with vasopressin. Copeptin may be a useful parameter to characterize disorders of water homeostasis and can be readily measured in plasma or serum. However, it is unknown to date how circulating copeptin and vasopressin levels correlate at different plasma osmolalites.
Objective:
To correlate plasma copeptin with plasma osmolality and vasopressin concentrations in healthy subjects during iso-, hypo-, and hyperosmolar states.
Methods:
Plasma osmolalities, copeptin, and vasopressin levels were measured in 20 volunteers at baseline, after an oral water load, and during and after iv infusion of 3% saline. Correlation coefficients were determined between plasma osmolalites and copeptin and vasopressin concentrations, as well as between vasopressin and copeptin concentrations.
Results:
Median plasma osmolalities decreased from 290 mOsm/kg (range, 284–302) at baseline to 281 (273–288) mOsm/kg after water load and rose to 301 (298–307) mOsm/kg after hypertonic saline. Median plasma copeptin concentrations decreased from 3.3 (1.1–36.4) pm at baseline to 2.0 (0.9–10.4) pm after water load and increased to 13.6 (3.7–43.3) pm after hypertonic saline. Vasopressin and copeptin concentrations correlated with plasma osmolality (Spearman's rank correlation coefficient 0.49 and 0.77, respectively). There was a close correlation of vasopressin and copeptin concentrations (Spearman's rank correlation coefficient 0.8).
Conclusion:
Plasma vasopressin and copeptin correlate strongly over a wide range of osmolalities in healthy individuals. Therefore, the measurement of copeptin, which remains stable for several days, is a useful alternative to vasopressin measurements and will likely facilitate the differential diagnosis of disorders of water metabolism.
Context:
The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, given that ...inadequate treatment causes serious complications. The diagnostic “gold standard” is the water deprivation test with assessment of arginine vasopressin (AVP) activity. However, test interpretation and AVP measurement are challenging.
Objective:
The objective was to evaluate the accuracy of copeptin, a stable peptide stoichiometrically cosecreted with AVP, in the differential diagnosis of polyuria-polydipsia syndrome.
Design, Setting, and Patients:
This was a prospective multicenter observational cohort study from four Swiss or German tertiary referral centers of adults >18 years old with the history of polyuria and polydipsia.
Measurements:
A standardized combined water deprivation/3% saline infusion test was performed and terminated when serum sodium exceeded 147 mmol/L. Circulating copeptin and AVP levels were measured regularly throughout the test. Final diagnosis was based on the water deprivation/saline infusion test results, clinical information, and the treatment response.
Results:
Fifty-five patients were enrolled (11 with complete central DI, 16 with partial central DI, 18 with PP, and 10 with nephrogenic DI). Without prior thirsting, a single baseline copeptin level >21.4 pmol/L differentiated nephrogenic DI from other etiologies with a 100% sensitivity and specificity, rendering a water deprivation testing unnecessary in such cases. A stimulated copeptin >4.9 pmol/L (at sodium levels >147 mmol/L) differentiated between patients with PP and patients with partial central DI with a 94.0% specificity and a 94.4% sensitivity. A stimulated AVP >1.8 pg/mL differentiated between the same categories with a 93.0% specificity and a 83.0% sensitivity.
Limitation:
This study was limited by incorporation bias from including AVP levels as a diagnostic criterion.
Conclusion:
Copeptin is a promising new tool in the differential diagnosis of the polyuria-polydipsia syndrome, and a valid surrogate marker for AVP.
Primary Funding Sources:
Swiss National Science Foundation, University of Basel.
Comparison of several regimens of oral vitamin D including an individually calculated loading regimen with the aim of achieving serum values > 75 nmol/l. Interventional, randomized, 3-arm study in ...vitamin D-deficient outpatients. Participants were allocated to supplementation of 24,000 IU vitamin D monthly over three months, using either a monthly drinking solution (Vi-De 3) or capsule (D
VitaCaps), or an individualized loading regimen with the capsules taken weekly. For the loading regimen, the cumulative dose was calculated according to baseline 25-hydroxy-vitamin D (25(OH)D) serum value and body weight. Main inclusion criteria were age ≥ 18 years and 25(OH)D serum concentration < 50 nmol/l. The primary outcome was 25(OH)D serum concentration one week after treatment termination. Secondary endpoints were patient's preferences and adverse events. Full datasets were obtained from 52 patients. Mean 25(OH)D values were statistically significant higher after a loading regimen compared to a monthly administration of 24,000 IU vitamin D (76.4 ± 15.8 vs 61.4 ± 10.8 nmol/l; p < 0.01). All patients treated with the loading regimen reached sufficient 25(OH)D values > 50 nmol/l. Serum 25(OH)D values > 75 nmol/l were observed more frequently in patients taking the loading regimen (47% vs 11% drinking solution vs 12% capsules). Vitamin D-related adverse effects did not occur in any treatment groups. Capsules were preferred by 88.5% of the patients. Compared to treatments with monthly intake of 24,000 IU vitamin D, the intake of an individually calculated weekly loading regimen was able to raise serum concentrations > 50 nmol/l in all cases within a safe range.
Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. ...However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER-associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex. Serum hyperosmolality induces expression of both ERAD components and proAVP in AVP-producing neurons. Mice with global or AVP neuron-specific ablation of Se1L-Hrd1 ERAD progressively developed polyuria and polydipsia, characteristics of diabetes insipidus. Mechanistically, we found that ERAD deficiency causes marked ER retention and aggregation of a large proportion of all proAVP protein. Further, we show that proAVP is an endogenous substrate of Sel1L-Hrd1 ERAD. The inability to clear misfolded proAVP with highly reactive cysteine thiols in the absence of Sel1L-Hrd1 ERAD causes proAVP to accumulate and participate in inappropriate intermolecular disulfide-bonded aggregates, promoted by the enzymatic activity of protein disulfide isomerase (PDI). This study highlights a pathway linking ERAD to prohormone conformational maturation in neuroendocrine cells, expanding the role of ERAD in providing a conducive ER environment for nascent proteins to reach proper conformation.
Genetic forms of neurohypophyseal diabetes insipidus Rutishauser, Jonas, Prof; Spiess, Martin, Prof; Kopp, Peter, Prof
Baillière's best practice and research in clinical endocrinology and metabolism/Baillière's best practice & research. Clinical endocrinology & metabolism,
03/2016, Letnik:
30, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Neurohypophyseal diabetes insipidus is characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although in most ...patients non-hereditary causes underlie the disorder, genetic forms have long been recognized and studied both in vivo and in vitro . In most affected families, the disease is transmitted in an autosomal dominant manner, whereas autosomal recessive forms are much less frequent. Both phenotypes can be caused by mutations in the vasopressin-neurophysin II ( AVP ) gene. In transfected cells expressing dominant mutations, the mutated hormone precursor is retained in the endoplasmic reticulum, where it forms fibrillar aggregates. Autopsy studies in humans and a murine knock-in model suggest that the dominant phenotype results from toxicity to vasopressinergic neurons, but the mechanisms leading to cell death remain unclear. Recessive transmission results from AVP with reduced biologic activity or the deletion of the locus. Genetic neurohypophyseal diabetes insipidus occurring in the context of diabetes mellitus, optic atrophy, and deafness is termed DIDMOAD or Wolfram syndrome, a genetically and phenotypically heterogeneous autosomal recessive disorder caused by mutations in the wolframin ( WFS 1 ) gene.
Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials ...are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects.
We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis.
This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease.
ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.
The innate and adaptive immune system is involved in the airway inflammation associated with acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). We evaluated the ...association of mannose-binding lectin (MBL), immunoglobulin (Ig) and ficolin-2 concentrations with COPD exacerbations and according to the glucocorticoid treatment duration for an index exacerbation.
Post-hoc analysis of the randomized, double-blind, placebo-controlled REDUCE trial of 5 vs. 14 days of glucocorticoid treatment for an index exacerbation. MBL, ficolin-2 and total IgG/IgA and subclass concentrations were determined in stored samples drawn (n = 178) 30 days after the index exacerbation and associated with the risk of re-exacerbation during a 180-day follow-up period.
IgG and subclass concentrations were significantly lower after 14 days vs. 5 days of glucocorticoid treatment. Patients with higher MBL concentrations were more likely to suffer from a future exacerbation (multivariable hazard ratio 1.03 per 200 ng/ml increase (95% confidence interval (CI) 1.00-1.06), p = 0.048), whereas ficolin-2 and IgG deficiency were not associated. The risk was most pronounced in patients with high MBL concentrations, IgG deficiency and 14 days of glucocorticoid treatment pointing towards an interactive effect of MBL and IgG deficiency in the presence of prolonged glucocorticoid treatment duration Relative excess risk due to interaction 2.13 (95% CI - 0.41-4.66, p = 0.10). IgG concentrations were significantly lower in patients with frequent re-exacerbations (IgG, 7.81 g/L vs. 9.53 g/L, p = 0.03).
MBL modified the short-term exacerbation risk after a recent acute exacerbation of COPD, particularly in the setting of concurrent IgG deficiency and recent prolonged systemic glucocorticoid treatment. Ficolin-2 did not emerge as a predictor of a future exacerbation risk.
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