Jonas Rutishauser

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial

IMPORTANCE International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE Time to next exacerbation within 180 days. RESULTS Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN19646069.

Functional Characterization of Pendrin in a Polarized Cell System EVIDENCE FOR PENDRIN-MEDIATED APICAL IODIDE EFFLUX

Pendreds syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS/SLC26A4 gene that encodes pendrin. Functionally, pendrin is a transporter of chloride and iodide in Xenopus oocytes and heterologous mammalian cells and a chloride/base exchanger in β-intercalated cells of the renal cortical collecting duct. The partially impaired thyroidal iodide organification in Pendreds syndrome suggests a possible role of pendrin in iodide transport at the apical membrane of thyroid follicular cells, but experimental evidence for this concept is lacking. The iodide transport properties of pendrin were determined in polarized Madin-Darby canine kidney cells expressing the sodium iodide symporter (NIS), pendrin, or NIS and pendrin using a bicameral system-permitting measurement of iodide content in the basal, intracellular, and apical compartments. Moreover, we determined the functional consequences of two naturally occurring mutations (L676Q and FS306>309X). In polarized Madin-Darby canine kidney cells, NIS mediates uptake at the basolateral membrane. Only minimal amounts of iodide reach the apical compartment in the absence of pendrin. In cells expressing NIS and pendrin, pendrin mediates transport of iodide into the apical chamber. Wild type pendrin also mediates iodide efflux in transiently transfected cells. In contrast, both pendrin mutants lose the ability to promote iodide efflux. These results provide evidence that pendrin mediates apical iodide efflux from polarized mammalian cells loaded with iodide. Consistent with the partial organification defect observed in patients with Pendreds syndrome, naturally occurring mutations of pendrin lead to impaired transport of iodide.

Correlation of plasma copeptin and vasopressin concentrations in hypo-, iso-, and hyperosmolar states

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 (Spearmans rank correlation coefficient 0.49 and 0.77, respectively). There was a close correlation of vasopressin and copeptin concentrations (Spearmans 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.

Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus.

Autosomal dominant neurohypophyseal diabetes insipidus is caused by mutations in the gene encoding the vasopressin precursor protein, prepro-vasopressin-neurophysin II. We analyzed the molecular consequences of a mutation (ΔG227) recently identified in a Swiss kindred that destroys the translation initiation codon. In COS-7 cells transfected with the mutant cDNA, translation was found to initiate at an alternative ATG, producing a truncated signal sequence that was functional for targeting and translocation but was not cleaved by signal peptidase. The mutant precursor was completely retained within the endoplasmic reticulum. The uncleaved signal did not affect folding of the neurophysin portion of the precursor, as determined by its protease resistance. However, formation of disulfide-linked aggregates indicated that it interfered with the formation of the disulfide bond in vasopressin, most likely by blocking its insertion into the hormone binding site of neurophysin. Preventing disulfide formation in the vasopressin nonapeptide by mutation of cysteine 6 to serine was shown to be sufficient to cause aggregation and retention. These results indicate that the ΔG227 mutation induces translation of a truncated signal sequence that cannot be cleaved but prevents correct folding and oxidation of vasopressin, thereby causing precursor aggregation and retention in the endoplasmic reticulum.

Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum

Autosomal dominant neurohypophyseal diabetes insipidus results from mutations in the precursor protein of the antidiuretic hormone arginine vasopressin. Mutant prohormone is retained in the endoplasmic reticulum of vasopressinergic neurons and causes their progressive degeneration by an unknown mechanism. Here, we show that several dominant pro-vasopressin mutants form disulfide-linked homo-oligomers and develop large aggregations visible by immunofluorescence and immunogold electron microscopy, both in a fibroblast and a neuronal cell line. Double-labeling showed the pro-vasopressin aggregates to colocalize with the chaperone calreticulin, indicating that they originated from the endoplasmic reticulum. The aggregates revealed a remarkable fibrillar substructure. Bacterially expressed and purified mutant pro-vasopressin spontaneously formed fibrils under oxidizing conditions. Mutagenesis experiments showed that the presence of cysteines, but no specific single cysteine, is essential for disulfide oligomerization and aggregation in vivo. Our findings assign autosomal dominant diabetes insipidus to the group of neurodegenerative diseases associated with the formation of fibrillar protein aggregates.

Growth retardation in untreated autosomal dominant familial neurohypophyseal diabetes insipidus caused by one recurring and two novel mutations in the vasopressin-neurophysin II gene

OBJECTIVE Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the vasopressin (AVP)-neurophysin II (NPII) gene, manifests gradually during early childhood with progressive polyuria and polydipsia. Patients are usually treated with synthetic AVP analog. If unlimited access to water is provided, prognosis is usually good even in the absence of specific treatment. In this study, we describe three families with adFNDI, in which growth failure was a prominent complaint, on the clinical and molecular level. DESIGN/METHODS Histories from affected and unaffected family members were taken. Height and weight of index patients were recorded longitudinally. Patients underwent water deprivation tests, magnetic resonance imaging, and genetic analysis. One mutant was studied by heterologous expression in cell culture. RESULTS A total of ten affected individuals were studied. In two of the three pedigrees, a novel mutation in the AVP-NPII gene was found. The index children in each pedigree showed growth retardation, which was the reason for referral in two. In these cases, water intake was tightly restricted by the parents in an attempt to overcome suspected psychogenic polydipsia and to improve appetite. Once the children were treated by hormone replacement, they rapidly caught up to normal weight and height. CONCLUSIONS Genetic testing and appropriate parent counseling should be enforced in adFNDI families to ensure adequate treatment and avoid chronic water deprivation, which causes failure to thrive.

Statins in clinical medicine.

Statins inhibit cholesterol biosynthesis. Their main effect is a decrease in circulating levels of LDL cholesterol, which translates into a ~ 20% relative reduction of major vascular events and coronary mortality per mmol/L LDL reduction achieved. Statins are efficient in preventing first cardiovascular events, but the cost-efficiency of primary prevention remains controversial. In primary prevention particularly, the pros and cons of statin therapy should be weighted by considering patient-specific life circumstances and assessing the individual cardiovascular risk, as provided by risk calculators. Since diabetes mellitus poses a high risk even in the absence of known coronary artery disease, statin treatment is generally indicated in these patients. There is no lower LDL threshold defining the limit of treatment benefit; rather, LDL target levels should be sought according to individual cardiovascular risk. If the necessary precautions are taken, e.g., by considering age, co-morbidities and co-medication when choosing the dose, statins are well tolerated and safe, as evidenced by many randomised controlled trials and meta-analyses. If a patient will not tolerate a statin dose necessary to achieve his or her LDL target level, ezetimibe may be added. There is no indication that statins alter cancer risk. Despite recent evidence that statin treatment is associated with a small risk of incident diabetes mellitus, this disadvantage is outweighed by the vascular benefits. Statins have pleiotropic effects, such as anti-inflammatory properties. It is still debated to what extent these effects translate into cardiovascular risk reduction beyond that conferred by LDL reduction.

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

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.

Medical care of type 2 diabetes mellitus in light of international and national recommendations: a retrospective analysis

QUESTION UNDER STUDY Type 2 diabetes mellitus (T2Dm) is a chronic disease with great economic impact. In 2009, the Swiss Society for Endocrinology and Diabetes (SSED) published recommendations for treatment of T2Dm. In Switzerland, few data are currently available on metabolic control and physician compliance with treatment guidelines. We aimed to investigate clinical care in T2Dm in the year after the publication of SSED recommendations. METHODS We retrospectively studied the charts of all patients with T2Dm admitted to our general internal medicine clinic during 2009. Metabolic control was judged from glycated haemoglobin A1c (HbA1c) levels. Antidiabetic therapy was analysed, and frequencies of screening for end-organ damage were investigated. A group with newly diagnosed T2Dm was analysed separately from patients with known T2Dm upon admission. RESULTS In patients with known T2Dm, the mean (± standard deviation) HbA1c level was 7.66% ± 1.73%. Only 44% of patients showed HbA1c levels at the target of ≤7%. Prior to admission and at discharge, 56% and 55% of patients, respectively, were treated with metformin. Among patients with HbA1c >8.5%, the proportion of those treated with insulin increased from 49% upon admission to 76% at discharge. Only half the patients received a lifestyle intervention in the year prior to admission or during hospital stay. Screening for diabetic retinopathy and nephropathy was performed in approximately one-third and two-thirds of patients, respectively. CONCLUSIONS In the majority of unselected T2Dm patients admitted to our hospital, metabolic control was suboptimal. Implementation of treatment recommendations by both general practitioners and hospitals should be improved.

Short versus conventional term glucocorticoid therapy in acute exacerbation of chronic obstructive pulmonary disease - THe \"REDUCE\" trial

BACKGROUND International guidelines advocate a 10 to 14-day course of systemic glucocorticoid therapy in the management of COPD exacerbations. The optimal duration of therapy is unknown and glucocorticoids have serious adverse effects. The aim of this trial is to demonstrate non-inferiority of a five-day compared to a 14-day course of systemic glucocorticoids with respect to COPD outcome, thereby significantly reducing steroid exposure and side effects in patients with COPD exacerbations. METHODS This is a randomised, placebo-controlled, non-inferiority multicentre trial. Patients with acute COPD exacerbation are randomised to receive 40 mg of prednisone-equivalent daily for 14 days (conventional arm) or glucocorticoid treatment for 5 days, followed by placebo for another 9 days (intervention arm). Follow-up is 180 days. The primary endpoint is time to next exacerbation. Secondary endpoints include cumulative glucocorticoid dose, time to open-label glucocorticoid therapy, glucocorticoid-associated side effects and complications, duration of hospital stay, death, change in FEV1, need for assisted ventilation, clinical outcome assessed by standardised questionnaires, and suppression of the hypothalamic-pituitary-adrenal axis. RESULTS Mean age (± SD) of patients who finished the study was 70 ± 11 years. 12% had mild or moderate disease, whereas severe and very severe stages were found in 30 and 58%, respectively. At the time of inclusion, 20% of patients were under treatment with systemic glucocorticoids. CONCLUSIONS If the strategy of significantly reducing cumulative exposure to glucocorticoids while taking advantage of their beneficial short-term effects proves to be successful, it will warrant a change in common glucocorticoid prescription practice, thereby improving the management of COPD.