The molecular immunology of human susceptibility to fungal diseases: lessons from single gene defects of immunity

Introduction: Fungal diseases are a threat to human health. Therapies targeting the fungus continue to lead to disappointing results. Strategies targeting the host response represent unexplored opportunities for innovative treatments. To do so rationally requires the identification and neat delineation of critical mechanistic pathways that underpin human antifungal immunity. The study of humans with single-gene defects of the immune system, i.e. inborn errors of immunity (IEIs), provides a foundation for these paradigms.

Areas covered: A systematic literature search in PubMed, Scopus, and abstracts of international congresses was performed to review the history of genetic resistance/susceptibility to fungi and identify IEIs associated with fungal diseases. Immunologic mechanisms from relevant IEIs were integrated with current definitions and understandings of mycoses to establish a framework to map out critical immunobiological pathways of human antifungal immunity.

Expert opinion: Specific immune responses non-redundantly govern susceptibility to their corresponding mycoses. Defining these molecular pathways will guide the development of host-directed immunotherapies that precisely target distinct fungal diseases. These findings will pave the way for novel strategies in the treatment of these devastating infections.     

Diagnostische Bedeutung von Muskelbiopsien bei metabolischen Myopathien

Summary In the diagnosis of metabolic myopathies the use of biochemical methods, in addition to morphological examination of muscle biopsies, is often necessary in order to identify a specific metabolic defect. In order to narrow down the spectrum of biochemical methods, extensive clinical investigation and morphological examination, including histology, enzyme histochemistry and electromicroscopy if necessary have to be done beforehand. Patients are classified in the following groups: 1) progressive muscular weakness and/or muscle wasting with storage of a) glycogen, b) lipid or c) mitochondrial alterations; 2) recurrent rhabdomyolysis induced by fasting or exercise a) with glycogen storage or b) without any specific morphological alterations. The spectrum of metabolic defects comprises disorders of glycogen and glucose metabolism (deficiency of acid maltase, debranching and branching enzyme, phosphorylase, phosphofructokinase and other glycolytic enzymes), lipid metabolism (carnitine deficiency, carnitine palmitoyl transferase deficiency), mitochondria (respiratory chain disorders, pyruvate dehydrogenase deficiency) and others such as adenylate deaminase deficiency. In some of these e.g. infantile acid maltase deficiency and mitochondriopathies, it is clinically more important when organs other than muscle are affected; however, muscle biopsy is a useful substrate for diagnosis of these metabolic disorders.

Mit Unterstützung durch die DFG und die Friedrich Baur Stiftung, München     

The Effect of Medication Reconciliation via a Patient Portal on Medication Discrepancies: A Randomized Noninferiority Study

BackgroundMedication reconciliation has become standard care to prevent medication transfer errors. However, this process is time-consuming but could be more efficient when patients are engaged in medication reconciliation via a patient portal.ObjectivesTo explore whether medication reconciliation by the patient via a patient portal is noninferior to medication reconciliation by a pharmacy technician.Design (including intervention)Open randomized controlled noninferiority trial. Patients were randomized between medication reconciliation via a patient portal (intervention) or medication reconciliation by a pharmacy technician at the preoperative screening (usual care).Setting and ParticipantsPatients scheduled for elective surgery using at least 1 chronic medication were included.MeasuresThe primary endpoint was the number of medication discrepancies compared to the electronic nationwide medication record system (NMRS). For the secondary endpoint, time investment of the pharmacy technician for the medication reconciliation interview and patient satisfaction were studied. Noninferiority was analyzed with an independent t test, and the margin was set at 20%.ResultsA total of 499 patients were included. The patient portal group contained 241 patients; the usual care group contained 258 patients. The number of medication discrepancies was 2.6 ± 2.5 in the patient portal group and 2.8 ± 2.7 in the usual care group. This was not statistically different and within the predefined noninferiority margin. Patients were satisfied with the use of the patient portal tool. Also, the use of the portal can save on average 6.8 minutes per patient compared with usual care.Conclusions and ImplicationsMedication reconciliation using a patient portal is noninferior to medication reconciliation by a pharmacy technician with respect to medication discrepancies, and saves time in the medication reconciliation process. Future studies should focus on identifying patient characteristics for successful implementation of patient portal medication reconciliation.     

312例儿童屈光不正性斜视分析

目的：探讨儿童屈光不正与伤痛视的关系。方法：将共同性斜视312例分为两组,3-6岁为学龄前组,7-12岁为学龄组进行比较。结果：237例内斜中,远视227例,占95.78%;近视10例,占4.22%。75例外斜中,远视42例,占56%;近视33例,上44%。结论：屈光不正性斜视的发病率。内斜视多于外斜视,学龄前组高于学龄组,内外伤痛视中,远视明显多于近视,将对斜视弱视治疗防治有一定参考价值。     

以痛性眼肌麻痹为首发症状的鼻咽癌4例分析

目的：研究以痛性眼肌为首发症状的鼻咽癌临床特点及误诊原因。方法：回顾分析４例鼻咽癌患者首发临床症状。结果：痛性眼肌麻痹可以是鼻咽癌的首发症状,可有第Ⅲ,Ⅳ,Ⅴ,Ⅵ对颅神经损害。结论：神经系统症状可以是促使鼻咽癌患者的就诊的原发症状,应及时进行鼻咽部颁标准检查,ＣＴ,ＭＲＴ检查有助于确诊。     

41例卵巢黄体破裂临床分析

[背景 ]卵巢黄体破裂是妇科急腹症之一 ,误诊率较高 .[病例报告 ]对 41例经手术及病理检查确定诊断的卵巢黄体破裂进行了临床分析 ,发病年龄为 2 0～ 41岁 ,平均 2 9岁 ;多在月经周期后半期发病 ,占 6 5 % ;发生于左侧卵巢 2 1例 ,右侧卵巢 2 0例 ;腹腔内出血为 15 0～ 2 5 0 0mL ,其中少于 5 0 0mL者2 5例 ,占 6 1% ;休克 7例 ,占 17% .黄体破裂出血量的多少与破口大小无关 .[讨论 ]本病因有腹痛、月经周期延长、不同程度的腹腔内出血及不规则阴道流血 ,易误诊为异位妊娠     

Diagnosing,discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests

PurposeFor patients with inherited metabolic disorders (IMDs), any diagnostic delay should be avoided because early initiation of personalized treatment could prevent irreversible health damage. To improve diagnostic interpretation of genetic data, gene function tests can be valuable assets. For IMDs, variant-transcending functional tests are readily available through (un)targeted metabolomics assays. To support the application of metabolomics for this purpose, we developed a gene-based guide to select functional tests to either confirm or exclude an IMD diagnosis.MethodsUsing information from a diagnostic IMD exome panel, Kyoto Encyclopedia of Genes and Genomes, and Inborn Errors of Metabolism Knowledgebase, we compiled a guide for metabolomics-based gene function tests. From our practical experience with this guide, we retrospectively selected illustrative cases for whom combined metabolomic/genomic testing improved diagnostic success and evaluated the effect hereof on clinical management.ResultsThe guide contains 2047 metabolism-associated genes for which a validated or putative variant-transcending gene function test is available. We present 16 patients for whom metabolomic testing either confirmed or ruled out the presence of a second pathogenic variant, validated or ruled out pathogenicity of variants of uncertain significance, or identified a diagnosis initially missed by genetic analysis.ConclusionMetabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.     

Plasma ionized magnesium in tubular disorders with and without total hypomagnesemia

 Selective electrodes have been designed for determining plasma ionized magnesium. In kidney disease the relationship between ionized and total circulating magnesium is often altered. Hence plasma ionized magnesium (ETH 7025 membrane) was determined in 25 patients with primary renal tubular disorders; 6 patients had total hypomagnesemia. Total plasma magnesium was never reduced in the remaining 19 patients. Plasma ionized magnesium values were low in the 6 patients with total hypomagnesemia. In 18 of the 19 patients without total hypomagnesemia plasma ionized magnesium values were not reduced. Ionized hypomagnesemia was noted in a patient with normal total plasma magnesium in the context of hypercalciuric nephrocalcinosis of unknown origin. The study demonstrates an excellent concordance between plasma total and ionized magnesium in tubular disorders associated with total hypomagnesemia and a good concordance in tubular disorders that are not linked with total hypomagnesemia. The determination of circulating ionized magnesium is of little value in the diagnostic work-up of the vast majority of renal tubular disorders. The determination might perhaps disclose latent hypomagnesemia in nephrocalcinosis of unknown cause. Received: 20 March 1998 / Revised: 28 May 1998 / Accepted: 29 May 1998     

A new case of malonyl coenzyme A decarboxylase deficiency presenting with cardiomyopathy

A new case of mitochondrial malonyl coenzyme A decarboxylase deficiency is described. The patient presented with an initial episode of metabolic acidosis, seizures, hypoglycemia, and cardiac failure at 2 months of age which slowly resolved. Subsequent evaluations at 4 years of age for developmental delay revealed a prominent elevation of malonic acid in urine. Malonyl carnitine was also elevated. The activity of malonyl CoA decarboxylase in cultured fibroblasts was 7% of normal. Conclusion Malonyl CoA decarboxylase deficiency may result in inhibition of fatty acid oxidation, which may account for the cardiomyopathy. Received: 12 April 1996 / Accepted: 24 September 1996