Familiäre Kavernome des Zentralnervensystems

In 1928, Hugo Friedrich Kufs reported on a family with cerebral, retinal, and cutaneous cavernous malformations. Since then, more than 300 families with inherited cavernous malformations have been reported. Genetic studies showed three loci, on chromosomes 7q21-q22 (with the gene CCM1), 7p15-p13 (CCM2), and 3q25.2-q27 (CCM3). The gene product of CCM1 is Krit 1 (Krev interaction trapped 1), a protein interacting with angiogenesis by various mechanisms. Recently, CCM2 has also been identified; its product is a protein which might have a function similar to that of Krit 1. However, the CCM3 gene has still not been found. In this study, we present clinical and genetic findings on 15 German families.     

B cells in the pathophysiology of myasthenia gravis

Myasthenia gravis (MG) is an archetypal autoimmune disease. The pathology is characterized by autoantibodies to the acetylcholine receptor (AChR) in most patients or to muscle‐specific tyrosine kinase (MuSK) in others and to a growing number of other postsynaptic proteins in smaller subsets. A decrease in the number of functional AChRs or functional interruption of the AChR within the muscle end plate of the neuromuscular junction is caused by pathogenic autoantibodies. Although the molecular immunology underpinning the pathology is well understood, much remains to be learned about the cellular immunology contributing to the production of autoantibodies. This Review documents research concerning the immunopathology of MG, bringing together evidence principally from human studies with an emphasis on the role of adaptive immunity and B cells in particular. Proposed mechanisms for autoimmunity, which take into account that different types of MG may incorporate divergent immunopathology, are offered. Muscle Nerve 57 : 172–184, 2018     

Risk of recurrent venous thromboembolism among young women after a first event while exposed to combined oral contraception versus not exposed to: A cohort study

The risk of recurrent venous thromboembolism (VTE) in young women after a first oestrogen contraception associated VTE episode is unknown. This uncertainty has an impact on the decision whether to stop anticoagulant treatment. Our objective was to assess the risk of recurrent VTE in women after a first VTE episode on oestrogen contraception. This was a prospective cohort study in which we consecutively enrolled between 1992 and 2011 all women under 50 years with a first objectively confirmed VTE. The incidence of recurrent VTE during follow-up after stopping anticoagulation was compared between women users and non-users of combined oral contraception (COC) at the time of index VTE. Of the 241 women aged 50 or younger seen for a first VTE and followed-up after stopping anticoagulation, there were 180 COC-users and 61 non-users. Median duration of follow-up off-anticoagulants was 66 months (interquartile range: 33–103). There were 14 recurrences in COC-users and 5 cases in non-users. No significant association was found between exposure to COC and the incidence of recurrent VTE after adjustment for age or after restricting the analysis to major unprovoked VTE: incidence rate of recurrence 17.9/1,000/year (95% CI: 9.6-33.2) in women with COC as compared with 17.6/1,000/year (95% CI: 6.6-47) with an incidence ratio of 0.7 (95% CI: 0.2-2.4, p = 0.59). The risk of recurrent VTE is low in young women after a first VTE. However, this risk is not significantly lower in women after a first VTE while exposed to combined oral contraception.     

Antioxidant agents transiently inhibit aneuploidy progression in Li-Fraumeni cell strains

Cultured human fibroblasts from patients with the Li-Fraumeni syndrome (LFS) containing heterozygous germline p53 mutations develop genomic instability, loss of the wild-type p53 allele, and immortalize at a low frequency. Since genomic instability and phenotypic change are observed in presenescent cells without specific exposure to mutagens, we hypothesized that reactive oxygen species (ROS) produced during normal cell metabolism coupled with deficient p53 dependent DNA damage repair pathways make a significant contribution to immortalization related parameters. To test this hypothesis, three LFS cell strains (MDAH087, MDAH041, and MDAH172) were exposed to five compounds with demonstrated antioxidant properties for > or =85% of their proliferative lifetimes. Agent effectiveness was evaluated every five passages during subculturing by analyzing aberrant chromosome number, anchorage independent growth (AIG), and p16 expression. Cytogenetic analysis revealed that of the five antioxidants tested, only oltipraz was significantly effective in transiently delaying a shift to hyperdiploidy in all three cell strains. However, treated populations were not different from untreated controls when measured in the last 10% of their lifetimes. Additionally, no differences were observed in AIG and p16 expression in antioxidant treated or untreated control populations. Epidemiological studies, in vitro and in vivo experimentation and some clinical trials have suggested that antioxidants may inhibit the progression of cancer and other mutation related diseases. This data, however, does not support the hypothesis that the antioxidants tested have chemopreventive potential in cancers that develop genomic instability due to loss of p53.     

Carotenoids in Palliative Care—Is There Any Benefit from Carotenoid Supplementation in the Adjuvant Treatment of Cancer-Related Symptoms?

Carotenoids are organic, liposoluble pigments found in nature, which are responsible for the characteristic colors of ripe tomatoes, carrots, peppers, and crustaceans, among others. Palliative care provided to patients with an incurable disease is aimed at improving the patient’s quality of life through appropriate treatment of symptoms accompanying the disease. Palliative care patients with burdensome symptoms related to advanced-stage cancers are especially interested in the use of natural dietary supplements and herbal remedies to reduce symptoms’ intensity and ameliorate the quality of life. Carotenoids seem to be a group of natural compounds with particularly promising properties in relieving symptoms, mainly due to their strong antioxidant, anti-inflammatory, and neuroprotective properties. Moreover, carotenoids have been used in folk medicine to treat various diseases and alleviate the accompanying symptoms. In this narrative review, the authors decided to determine whether there is any scientific evidence supporting the rationale for carotenoid supplementation in advanced-stage cancer patients, with particular emphasis on the adjuvant treatment of cancer-related symptoms, such as neuropathic pain and cancer-related cachexia.     

Mutations and polymorphisms of the skeletal muscle α‐actin gene (ACTA1)

The ACTA1 gene encodes skeletal muscle α‐actin, which is the predominant actin isoform in the sarcomeric thin filaments of adult skeletal muscle, and essential, along with myosin, for muscle contraction. ACTA1 disease‐causing mutations were first described in 1999, when a total of 15 mutations were known. In this article we describe 177 different disease‐causing ACTA1 mutations, including 85 that have not been described before. ACTA1 mutations result in five overlapping congenital myopathies: nemaline myopathy; intranuclear rod myopathy; actin filament aggregate myopathy; congenital fiber type disproportion; and myopathy with core‐like areas. Mixtures of these histopathological phenotypes may be seen in a single biopsy from one patient. Irrespective of the histopathology, the disease is frequently clinically severe, with many patients dying within the first year of life. Most mutations are dominant and most patients have de novo mutations not present in the peripheral blood DNA of either parent. Only 10% of mutations are recessive and they are genetic or functional null mutations. To aid molecular diagnosis and establishing genotype–phenotype correlations, we have developed a locus‐specific database for ACTA1 variations ( http://waimr.uwa.edu.au ). Hum Mutat 30:1–11, 2009. © 2009 Wiley‐Liss, Inc.     

Effects of leptin and leptin fragments on steroid secretion and proliferative activity of regenerating rat adrenal cortex

Leptin, an adipose tissue-secreted hormone, acts via several isoforms of specific receptors (Ob-Rs), which may variously interact with the native leptin molecule and its fragments. Evidence has been provided that leptin affects rat adrenal functions, but the results were rather conflicting depending on the experimental condition examined (e.g. regenerating vs. mature or immature adrenal gland). Hence, we investigated the effects of three subcutaneous injections of murine leptin(1-147) and several leptin fragments (3 nmol/100 g body weight; 28, 16 and 4 h before the sacrifice) on the secretory activity and growth of regenerating rat adrenal cortex. The following leptin fragments were tested: murine leptin(116-130), and human leptin fragments 150-167, 138-167, 93-105, 22-56 and [Tyr]26-39. Leptin(1-147) enhanced plasma concentration of both aldosterone and corticosterone. The blood level of aldosterone was raised by leptin(116-130), leptin(138-167) and leptin(93-105), and that of corticosterone by leptin(93-105) and Tyr-leptin(26-39). Metaphase index (stachmokinetic method with vincristine) was unaffected by leptin(1-147), and lowered by leptin(116-130), leptin(150-167) and leptin(138-167). Collectively, our findings allow us to conclude that leptin and leptin fragments enhance the secretory activity and inhibit the growth of regenerating rat adrenal cortex, the biological activity of leptin being located in the C-terminal segment of its molecule.     

Tumor‐infiltrating dendritic cells exhibit defective cross‐presentation of tumor antigens,but is reversed by chemotherapy

Cross‐presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8⁺ T cells. DCs are specialized cross‐presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross‐presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross‐presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1‐HA. We found that tumors were infiltrated by predominantly CD11b⁺ DCs with a semimature phenotype that could not cross‐present tumor Ag, and therefore, were unable to induce tumor‐specific T‐cell activation or proliferation. Although tumor‐infiltrating DCs were able to take up, process, and cross‐present exogenous cell‐bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross‐presentation of tumor DCs. These data demonstrate that DC cross‐presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.     

Short length of stay and the discharge process: Preparing breast cancer patients appropriately

ObjectiveBreast cancer is the most common cancer among women worldwide, increasing the relevance of an efficient and successful care process. As length of stay (LOS) in the hospital decreases, patients’ satisfaction with the LOS varies. We hypothesize that successful discharge planning can improve this evaluation.MethodsData of 4,390 female breast cancer patients from a cross-sectional survey was analyzed. The data was collected in 2017 in 86 German hospitals. Logistic regressions were used to test hypotheses.ResultsThe majority of included patients rated their LOS as appropriate. However, patients who felt better prepared for discharge were less likely to rate their stay as too short. A longer stay in the hospital further decreased this likelihood. The effect of LOS was moderated by patient experiences with preparation for discharge.ConclusionAs hospital LOS decreases, one challenge in allowing patients to feel sufficiently informed and ready to go home is the reduced time for face-to-face consultations. Our results indicate, however, that a strong and thorough discharge planning makes the actual number of days for LOS irrelevant for patient’s rating of LOS.Practice ImplicationsThe study results underscore the importance of ensuring the quality and thoroughness of the discharge process.