Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials.

Ocrelizumab is a B cell-depleting drug widely used in relapsing-remitting multiple sclerosis (RRMS) and primary-progressive MS. In RRMS, it is becoming increasingly apparent that accumulation of disability not only manifests as relapse-associated worsening (RAW) but also as progression independent of relapse activity (PIRA) throughout the disease course. This study's objective was to investigate the role of PIRA in RRMS patients treated with ocrelizumab. We performed a single-center, retrospective, cross-sectional study of clinical data acquired at a German tertiary multiple sclerosis referral center from 2018 to 2022. All patients with RRMS treated with ocrelizumab for at least six months and complete datasets were analyzed. Confirmed disability accumulation (CDA) was defined as a ≥ 12-week confirmed increase from the previous expanded disability status scale (EDSS) score of ≥ 1.0 if the previous EDSS was ≤ 5.5 or a ≥ 0.5-point increase if the previous EDSS was > 5.5. PIRA was defined as CDA without relapse since the last EDSS measurement and at least for the preceding 12 weeks. RAW was defined as CDA in an interval of EDSS measurements with ≥ 1 relapses. Cox proportional hazard models were used to analyze the probability of developing PIRA depending on various factors, including disease duration, previous disease-modifying treatments (DMTs), and optical coherence tomography-assessed retinal degeneration parameters. 97 patients were included in the analysis. Mean follow-up time was 29 months (range 6 to 51 months). 23.5% developed CDA under ocrelizumab therapy (n = 23). Of those, the majority developed PIRA (87.0% of CDA, n = 20) rather than RAW (13.0% of CDA, n = 3). An exploratory investigation using Cox proportional hazards ratios revealed two possible factors associated with an increased probability of developing PIRA: a shorter disease duration prior to ocrelizumab (p = 0.02) and a lower number of previous DMTs prior to ocrelizumab (p = 0.04). Our data show that in ocrelizumab-treated RRMS patients, the main driver of disability accumulation is PIRA rather than RAW. Furthermore, these real-world data show remarkable consistency with data from phase 3 randomized controlled trials of ocrelizumab in RRMS, which may increase confidence in translating results from tightly controlled RCTs into the real-world clinical setting.

WHO informal consultation on revision of guidelines on evaluation of similar biotherapeutic products, virtual meeting, 30 June - 2 July 2021.

The WHO informal consultation was held to promote the revision of WHO guidelines on evaluation of similar biotherapeutic products (SBPs) adopted by the Expert Committee on Biological Standardization (ECBS) in 2009. It was agreed in the past consultations that the evaluation principles in the guidelines are still valid, but a review was recommended to provide more clarity and case-by-case flexibility. The opportunity was therefore taken to review the experience and identify areas where the current guidance could be more permissive without compromising its basic principles, and where additional explanation could be provided regarding the possibility of reducing the amount of data needed for regulatory approval. The meeting participants applauded the leading role taken by the WHO in providing a much-needed streamlined approach for development and evaluation of SBPs which will provide efficient and cost-effective product development and increase patient access to treatments. It was recognized that the principles as currently described in the draft WHO guidelines are based on sound science and experience gained over the last fifteen years of biosimilar approvals. However, since these guidelines when finalised will constitute the global standard for biosimilar evaluation and assist national regulatory authorities in establishing revised guidance and regulatory practice in this complex area, it was felt that further revision and clarity on certain perspectives in specific areas was necessary to dispel uncertainties arising in the current revised version. This report describes the principles in the draft guidelines, including topics discussed and consensus reached.

Dive behaviour and foraging effort of female Cape fur seals Arctocephalus pusillus pusillus.

While marine top predators can play a critical role in ecosystem structure and dynamics through their effects on prey populations, how the predators function in this role is often not well understood. In the Benguela region of southern Africa, the Cape fur seal (Arctocephalus pusillus pusillus) population constitutes the largest marine top predator biomass, but little is known of its foraging ecology other than its diet and some preliminary dive records. Dive information was obtained from 32 adult females instrumented with dive recorders at the Kleinsee colony (29°34.17' S, 16°59.80' E) in South Africa during 2006-2008. Most dives were in the depth range of epipelagic prey species (less than 50 m deep) and at night, reflecting the reliance of Cape fur seals on small, vertically migrating, schooling prey. However, most females also performed benthic dives, and benthic diving was prevalent in some individuals. Benthic diving was significantly associated with the frequency with which females exceeded their aerobic dive limit. The greater putative costs of benthic diving highlight the potential detrimental effects to Cape fur seals of well-documented changes in the availability of epipelagic prey species in the Benguela.

Net reclassification improvement with serial biomarkers and bed-sided spirometry to early predict the need of organ support during the early post-transplantation in-hospital stay in allogeneic HCT recipients.

To predict the need of intensive care unit admission with organ support during the transplantation hospital stay in 101 consecutives allogeneic hematopoietic cell transplantation (allo-HCT) recipients the added predictive utility of three times per week Copeptin, MR-proADM, MR-proANP, NT-proBNP, IL-6, Procalcitonin, D-dimer and three times per week bed-sided pulmonary function test was determined in comparison with an index model. The index model was calculated by multivariate regression analysis out of the patients' routine laboratory parameters. To calculate the added predictive utility of the investigated markers the Δ-AUC and the continuous net reclassification improvement (cNRI + 2 to - 2), splitted for events and non-events were calculated for each marker in comparison with the index model. According to the Δ-AUC, none of the parameters improved risk prediction. In contrast, the cNRI was significantly improved for events and non-events by Copeptin (event 0.75, p value 0.0013; non-event 0.4, p value 0.000079) and for events by NT-proBNP (0.6, p value 0.018). D-dimer and PCT significantly predicted the non-event. Of the spirometry parameters, the FEF50% improved prediction of event and non-event according to the cNRI model. Our data support the additional serial analysis of Copeptin and NT-proBNP in allo-HCT recipients during the transplantation hospital stay.

Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: European regulators' perspective.

Progressive multifocal leukoencephalopathy (PML) has been associated with the use of a number of multiple sclerosis (MS) immunomodulatory therapies and has assumed a critical place in the evaluation of their benefit/risk. In this review, we discuss the European Union regulatory approach to drug-induced PML in MS, highlight a number of key issues related to the current knowledge on PML, and outline possible paths to help progress the risk management of patients with MS at risk of PML.

[Opportunities and challenges of extrapolation for biosimilars]. / Möglichkeiten und Herausforderungen der Extrapolation bei Biosimilars.

Although biosimilars approved in the European Union have proved to be safe and efficacious, their licensing requirements continue to be disputed by medical professionals. In particular, extrapolation to indications of the originator without one's own clinical data of the biosimilar is controversial. Conceptually, the development of biosimilars is derived from that of generics. However, due to their complexity and inherent variability, considerably more data are necessary for biosimilars to demonstrate comparability with the originator (the reference product) than for the usually low-molecular generics. Biosimilars increase competition and help contain healthcare, and they improve access for patients to valuable treatments with biologicals. However, biosimilar development is a laborious and lengthy process and requires major biotechnological know-how. The basis is comprehensive, structural, and functional characterization of the biosimilar and reference product as well as their comparison with suitable and sensitive methods. The clinical development programme is reduced and tailored to address remaining uncertainties and to confirm comparable clinical performance. Extrapolation of data to other indications of the reference product is the greatest cost advantage of biosimilar development, but must always be scientifically justified and, if necessary, substantiated by further data. The scientific principles underlying the comparability exercise for a biosimilar are the same as those applied to a change in the manufacturing process of an already licensed biological. In both cases, different versions of a biological substance are compared and the clinical relevance of observed differences is assessed. Competent authorities do have decades of experience in evaluating changes in the manufacturing process, which they can now apply to biosimilars. For approval of a biosimilar and extrapolation of data, the totality of the evidence from the complete comparability exercise is considered, as has been the case for the first biosimilar infliximab.

Clinical Relevance of Computed Tomography Pulmonary Venography.

BACKGROUND: In clinical routine, the pulmonary contrast-enhanced chest computer tomography (CT) is usually focussed on the pulmonary arteries. The purpose of this pictorial essay is to raise the clinicians' awareness for the clinical relevance of CT pulmonary venography. CASE PRESENTATION: A pictorial case series illustrates the clinical consequences of different pulmonary venous pathologies on systemic, pulmonary and bronchial circulation. CONCLUSION: Computed tomography pulmonary venography must be considered before atrial septal defect (ASD) closure and pulmonary lobectomy. Computed tomography pulmonary venography should be considered for patients with right ventricular overload and pulmonary hypertension, as well as for patients with unclear recurrent pulmonary infections, progressive dyspnoea, pleural effusions, haemoptysis, and for patients with respiratory distress after lung-transplantation.

[Regulatory aspects of biosimilars. Myths and facts]. / Regulatorische Aspekte zu Biosimilars. Mythen und Fakten.

BACKGROUND: Biosimilars are currently a hot topic and there are many unsolved questions, misunderstandings and sometimes considerable uncertainty, especially among clinicians and patients. Regulatory agencies, such as the European Medicines Agency (EMA) issue guidelines for the development and approval of biosimilars, which are based on scientific principles. OBJECTIVE: This article addresses some of the frequently noted misunderstandings and misperceptions. For example, why biosimilars are (or can only be) "similar" but not "identical" compared to the original pharmaceutical product, and aspects, such as the pharmaceutical quality of biosimilars, immunogenicity and the approval process for biosimilars are highlighted.

Poor sleep quality is associated with impaired glucose tolerance in women after gestational diabetes.

We analyzed the association of sleep quality and glucose metabolism in women after gestational diabetes (pGDM) and in women after normoglycemic pregnancy (controls). Data during pregnancy and a visit within the first 15 months after delivery were collected from 61 pGDM and 30 controls in a prospective cohort study. This included a medical history, physical examination, questionnaires (Pittsburgh Sleep Quality Index (PSQI), and Perceived Stress Scale (PSS)), and 5-point oral glucose tolerance test with insulin measurements to determine indices of insulin sensitivity and insulin secretion. We used Spearman correlation coefficients and multivariate regression models for analysis.9.3 ± 3.2 months after delivery, pGDM had significantly higher fasting and 2 h glucose levels and lower insulin sensitivity than controls. There was no significant difference in age, BMI and sleep quality as assessed with the PSQI between the two groups. The PSQI score correlated with the ogtt-2 h plasma glucose in pGDM (δ = 0.41; p = 0.0012), but not in controls. This association was confirmed with a multivariate linear regression model with adjustment for age, BMI and months post-delivery. Perceived stress was an independent risk factor (OR 1.12; 95% CI 1.02-1.23) for impaired sleep. Our findings suggest that post-delivery sleep quality significantly influences glucose tolerance in women after GDM and that impaired sleep is associated with increased stress perception. Measures to improve of sleep quality and reduce perceived stress should therefore be tested as additional strategies to prevent progression to type 2 diabetes after GDM.

Efficacy and patient satisfaction of breast conserving therapy for central breast cancer by the B technique.

PURPOSE: To evaluate the oncologic safety and cosmetic results after breast cancer surgery for central breast cancer by the B technique. METHODS: Seventy women with operable breast cancer located in the central portion of the breast that had received resection surgery with the B technique were recruited. The primary outcome was the oncological safety, quantified as rate of positive resection margins and the cosmetic outcome evaluated by postsurgical self-assessment of the cosmetic outcome via questionnaire. The median follow-up period was 61.4 months (range 7.9-142.6 months). RESULTS: With one exception all patients had T1-2 tumors less than 5 cm in diameter. Most patients had invasive ductal breast cancers (57.1 %), followed by ductal carcinoma-in situ (27.1 %) and invasive lobular breast cancers (8.6 %). The incidence of positive resection margins was 17.1 %. No local tumor recurrence occurred during follow-up; one patient had distant metastases. In total, 80 % of the patients reported that the cosmetic results met or exceeded their expectations. CONCLUSIONS: The B technique is a safe breast conservation surgery for the excision of tumors located in the central portion of the breast and yields a high rate of satisfactory cosmetic results.

Suppression of the nuclear factor Eny2 increases insulin secretion in poorly functioning INS-1E insulinoma cells.

Eny2, the mammalian ortholog of yeast Sus1 and drosophila E(y)2, is a nuclear factor that participates in several steps of gene transcription and in mRNA export. We had previously found that Eny2 expression changes in mouse pancreatic islets during the metabolic adaptation to pregnancy. We therefore hypothesized that the protein contributes to the regulation of islet endocrine cell function and tested this hypothesis in rat INS-1E insulinoma cells. Overexpression of Eny2 had no effect but siRNA-mediated knockdown of Eny2 resulted in markedly increased glucose and exendin-4-induced insulin secretion from otherwise poorly glucose-responsive INS-1E cells. Insulin content, cellular viability, and the expression levels of several key components of glucose sensing remained unchanged; however glucose-dependent cellular metabolism was higher after Eny2 knockdown. Suppression of Eny2 enhanced the intracellular incretin signal downstream of cAMP. The use of specific cAMP analogues and pathway inhibitors primarily implicated the PKA and to a lesser extent the EPAC pathway. In summary, we identified a potential link between the nuclear protein Eny2 and insulin secretion. Suppression of Eny2 resulted in increased glucose and incretin-induced insulin release from a poorly glucose-responsive INS-1E subline. Whether these findings extend to other experimental conditions or to in vivo physiology needs to be determined in further studies.

Deadly diving? Physiological and behavioural management of decompression stress in diving mammals.

Decompression sickness (DCS; 'the bends') is a disease associated with gas uptake at pressure. The basic pathology and cause are relatively well known to human divers. Breath-hold diving marine mammals were thought to be relatively immune to DCS owing to multiple anatomical, physiological and behavioural adaptations that reduce nitrogen gas (N(2)) loading during dives. However, recent observations have shown that gas bubbles may form and tissue injury may occur in marine mammals under certain circumstances. Gas kinetic models based on measured time-depth profiles further suggest the potential occurrence of high blood and tissue N(2) tensions. We review evidence for gas-bubble incidence in marine mammal tissues and discuss the theory behind gas loading and bubble formation. We suggest that diving mammals vary their physiological responses according to multiple stressors, and that the perspective on marine mammal diving physiology should change from simply minimizing N(2) loading to management of the N(2) load. This suggests several avenues for further study, ranging from the effects of gas bubbles at molecular, cellular and organ function levels, to comparative studies relating the presence/absence of gas bubbles to diving behaviour. Technological advances in imaging and remote instrumentation are likely to advance this field in coming years.

Tracking apex marine predator movements in a dynamic ocean.

Pelagic marine predators face unprecedented challenges and uncertain futures. Overexploitation and climate variability impact the abundance and distribution of top predators in ocean ecosystems. Improved understanding of ecological patterns, evolutionary constraints and ecosystem function is critical for preventing extinctions, loss of biodiversity and disruption of ecosystem services. Recent advances in electronic tagging techniques have provided the capacity to observe the movements and long-distance migrations of animals in relation to ocean processes across a range of ecological scales. Tagging of Pacific Predators, a field programme of the Census of Marine Life, deployed 4,306 tags on 23 species in the North Pacific Ocean, resulting in a tracking data set of unprecedented scale and species diversity that covers 265,386 tracking days from 2000 to 2009. Here we report migration pathways, link ocean features to multispecies hotspots and illustrate niche partitioning within and among congener guilds. Our results indicate that the California Current large marine ecosystem and the North Pacific transition zone attract and retain a diverse assemblage of marine vertebrates. Within the California Current large marine ecosystem, several predator guilds seasonally undertake north-south migrations that may be driven by oceanic processes, species-specific thermal tolerances and shifts in prey distributions. We identify critical habitats across multinational boundaries and show that top predators exploit their environment in predictable ways, providing the foundation for spatial management of large marine ecosystems.

Características dos componentes não integrantes da carcaça de novilhos superjovens da raça Devon, terminados em diferentes sistemas de alimentação / Characteristics of non-integrant components of carcass of Devon young steers, finished in different feeding systems

O objetivo do estudo foi avaliar as características dos componentes não integrantes da carcaça de novilhos Devon terminados em confinamento (CONF), em pastagem de clima temperado (pastagem de azevém - Lolium multiflorum Lam - PTEM) ou em pastagem de clima tropical (associação de pastagem de milheto - Pennisetum americanum (L.) Leeke - e capim-papuã - Bracharia plantaginea - PTRO). Os novilhos, ao início da terminação, estavam com 320kg e 15 meses de idade. Os animais confinados foram alimentados com relação volumoso:concentrado de 60:40; o volumoso era constituído de silagem de milho, e o concentrado de farelo de trigo, milho e minerais. Os animais foram abatidos com pesos semelhantes de 388,3; 386,7 e 375,8kg no CONF, na PTEM e na PTRO, respectivamente. Os animais da PTRO apresentaram maior (P<0,10) rendimento de carcaça quente (RCQ) relativo a 100kg de peso corporal vazio (RCQPCV) do que os da PTEM, 64,6 versus 62,6 por cento, e os do CONF apresentaram RCQPCV intermediário, 63,7 por cento. Os pesos absolutos do fígado, 5,22; 4,43 e 3,87kg, do conjunto dos órgãos internos, 12,81; 11,37 e 10,83kg, do rúmen-retículo, 7,62; 6,54 e 6,06kg, da gordura do coração, 1,26; 0,65 e 0,30kg, e dos intestinos, 9,97; 7,13 e 7,49kg, foram mais altos (P<0,05) nos animais da PTEM, em relação aos do CONF e da PTRO, respectivamente. A mesma ordem de grandeza ocorreu com os pesos relativos desses órgãos. A PTRO e o CONF originaram animais com maior (P<0,05) peso de conteúdo gastrintestinal em relação à PTEM, respectivamente, 60,27; 55,32 e 41,21kg. O CONF proporcionou animais com pesos absolutos mais elevados (P<0,05) do omaso, 5,17kg, em relação aos da PTEM, 3,70kg, e este peso foi intermediário nos animais da PTRO, 4,77kg. A mesma ordem de grandeza ocorreu com os pesos relativos do omaso, 1,61; 1,12 e 1,54 por cento.

The non-integrant components of carcass of Devon steers were evaluated. Animals were finished in feedlot (CONF), winter pasture (pasture of ryegrass - Lolium multiflorum Lam -PTEM), or tropical pasture (association of millet pasture - Pennisetum americanum (L.) Leeke - and Alexander Grass - Brachiaria plantaginea - PTRO). At the beginning of finishing, the average weight of steers was 320kg and age was 15 months. The roughage:concentrate ratio of CONF was 60:40. The animals were slaughtered at similar weights of 388.3, 386,7, and 375.8 for CONF, PTEM, and PTRO, respectively. The PTRO animals showed higher hot carcass dressing (HCD) percentage relative to 100kg of empty body weight (HCDEBW) in comparison to PTEM (64.6 versus 62.6 percent), and CONF animals showed intermediary value for HCDEBW (63.7 percent). The absolute weights of liver, 5.22, 4.43, and 3.87kg; total weights of all internal organs, 12.81, 11.37, and 10.83kg; rumen-reticulum, 7.62, 6.54, and 6.06kg; heart fat, 1.26, 0.65, and 0.30kg; and intestines, 9.97, 7.13, and 7.49kg, were higher (P<0.05) in PTEM animals than in CONF and PTRO animals, respectively. The same differences were observed concerning relative weights of the same organs. PTRO and CONF animals showed higher (P<0.05) gastrointestinal content than PTEM animals, 60.27, 55.32, and 41.21kg, respectively. Feedlot finished animals exhibited higher absolute weight of omasum, 5.17kg, than PTEM animals, 3.70kg, and PTRO animals presented intermediary value, 4,77kg. The same order was observed concerning relative weigh of the omasum, 1.61, 1.12, and 1.54 percent.

Reduced proliferation and a high apoptotic frequency of pancreatic beta cells contribute to genetically-determined diabetes susceptibility of db/db BKS mice.

Leptin receptor-deficient db/db mice are a commonly used research model and it is known that the genetic background, on which the mutation is bred, modulates the phenotype. While diabetes-resistant strains sustain near normal glycemia and hyperinsulinemia, susceptible backgrounds develop overt hyperglycemia and islet involution. We hypothesized that genetically-determined differences in the proliferative capacity and the apoptotic frequency of pancreatic beta cells contribute to this phenotypic disparity. We studied C57BLKS/J (BKS; diabetes-susceptible) and C57BL/6 (B6; diabetes-resistant) db/db mice and heterozygous controls from 5 to 12 weeks of age. Body weight, fasting blood glucose, plasma insulin, HOMA-IR, alpha cell mass, beta cell mass, proliferation and apoptosis were measured. Comparable insulin resistance developed in the 2 db/db strains, which was well compensated for on both genetic backgrounds until 7 weeks of age. As expected, the BKS mice became hyperglycemic at 9 weeks. Beta cell proliferation was initially increased in both db/db strains but decreased rapidly in the BKS mice with advancing age. The rate of beta cell apoptosis was already higher in prediabetic BKS mice than in their B6 counterparts. Beta cell mass increased continuously in the B6 strain until 12 weeks of age, but declined from 7 weeks onwards in BKS. An age-dependent decline of beta cell proliferation and an increased rate of beta cell apoptosis already in the prediabetic state probably contribute to the diabetes susceptibility of db/db BKS mice. These factors could also play a role in the genetic predisposition for type 2 diabetes in humans.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.

[Hemoptysis because of pulmonary vein stenosis and occlusion after pulmonary vein isolation for atrial fibrillation]. / Hämoptysen infolge Pulmonalvenenstenose und -verschluss nach Pulmonalvenen-Isolation bei Vorhofflimmern.

HISTORY AND ADMISSION FINDINGS: A 49-year-old woman was admitted because of hemoptysis for four months. Several bronchoscopies and thoracic computed tomographies at other hospitals had not revealed the cause of the sustained hemoptysis. Eight months before admission she had undergone pulmonary vein ablation (PVA) for paroxysmal atrial fibrillation. After the PVA she had initially received oral anticoagulation, but this had been stopped because of the hemoptysis. Physical examination at admission to our hospital was unremarkable except for moderate obesity and arterial hypertension INVESTIGATIONS: Ventilation/perfusion scintigraphy demonstrated combined ventilation and perfusion deficits in the left lower lobe. Transesophageal echocardiography strongly suggested stenoses of the left pulmonary veins. 3-D reconstruction of previously recorded computed tomographic images showed absence of the left inferior pulmonary vein (LIPV) and marked stenosis of the left superior pulmonary vein (LSPV). DIAGNOSIS: It was confirmed that the hemoptysis was caused by stenosis of the left pulmonary veins, resulting from the previous PVA. TREATMENT AND COURSE: Percutaneous transseptal balloon dilatation of the upper and lower pulmonary veins was successfully performed. The patient was put on oral anticoagulation and discharged home free of symptoms. CONCLUSION: Pulmonary vein stenosis must be considered as the most likely cause of hemoptysis and respiratory symptoms after pulmonary vein ablation for atrial fibrillation. Because of ever more frequent interventions to treat atrial fibrillation and other atrial arrhythmias, great clinical vigilance and an interdisciplinary approach is mandatory to assure optimal assessment of patients with acquired pulmonary vein stenosis.

Adrenomedullary function in patients with nonclassic congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is classified into three types based on disease severity: classic salt-wasting, classic simple virilizing, and nonclassic. Adrenomedullary dysplasia and epinephrine deficiency have been described in classic CAH, resulting in glucose dysregulation. Our objective was to investigate adrenomedullary function in nonclassic CAH and to evaluate adrenomedullary function according to disease severity. Adrenomedullary function was evaluated in response to a standardized cycle ergonometer test in 23 CAH patients (14 females, age 9-38 years; 6 salt-wasting, 7 simple virilizing, 5 nonclassic receiving glucocorticoid treatment, 5 nonclassic not receiving glucocorticoid), and 14 controls (7 females, age 12-38 years). Epinephrine, glucose, and cortisol were measured at baseline and peak exercise. CAH patients and controls were similar in age and anthropometric measures. Patients with nonclassic CAH who were not receiving glucocorticoid and controls experienced the expected stress-induced rise in epinephrine, glucose, and cortisol. Compared to controls, patients with all types of CAH receiving glucocorticoid had impaired exercise-induced changes in epinephrine (salt-wasting: p=0.01;simple virilizing: p=0.01; nonclassic: p=0.03), and cortisol (salt-wasting: p=0.004; simple virilizing: p=0.006; nonclassic: p=0.03). Salt-wasting patients displayed the most significant impairment, including impairment in glucose response relative to controls (p=0.03). Hydrocortisone dose was negatively correlated with epinephrine response (r=-0.58; p=0.007) and glucose response (r=-0.60; p=0.002). The present study demonstrates that untreated patients with nonclassic CAH have normal adrenomedullary function. The degree of epinephrine deficiency in patients with CAH is associated with the severity of adrenocortical dysfunction, as well as glucocorticoid therapy.

[Persistent cough and bronchiectasis]. / Persistierender Husten und Bronchiektasen.

A 68 yr. old lady suffered from chronic cough. Bronchiectasis was diagnosed and treated with physiotherapy. Coughing persisted over years, although an asthma disease was controlled by inhalation, a carcinoid tumor was surgically removed, and a coronary artery disease was treated by revasculating surgery. Antibiotics and systemic corticosteroids did not relieve symptoms either. After all, diagnosis and treatment of obstructive sleep apnea led to symptom free life. We assume micro-aspiration during periods of apnea being the cause of the coughing.