Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1)

We report a 21-year-old male with symptomatic optic glioma who does not fulfill the diagnosis of neurofibromatosis 1 (NF1) according to standard NIH criteria. Analysis of the NF1 gene revealed a recurrent mutation in exon 37 (C6792A or Y2264X). This nonsense mutation causes skipping of exon 37 during the splicing process and is predicted to result in a protein shortened by 34 amino acid residues. The mutation was detected in all tissues examined (blood lymphocytes, oral mucosa, and dermal fibroblasts). The same mutation was previously found in 3 patients with clinically confirmed NF1. To our knowledge, this is the first report of an adult patient carrying a putative (non-mosaic) NF1 gene mutation in multiple tissues but not fulfilling the NIH criteria for the clinical diagnosis of NF1. Am. J. Med. Genet. 86:328–330, 1999.     

A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years

Hereditary non-polyposis colorectal cancer (HNPCC) syndrome is caused by heterozygous germline mutations in DNA mismatch repair genes (MMR), (MSH2, MLH1, MSH6, and PMS2) and it is inherited in an autosomal dominant pattern with high penetrance. Several patients have been reported carrying bi-allelic MMR gene mutations and whose phenotype resembled a syndrome with childhood malignancies including hematological malignancies, brain, and colorectal tumors. This phenotype is similar to the tumor spectrum of MMR knockout mice. Herein we describe two brothers of healthy consanguineous parents from Pakistan, who had developed two and three colorectal cancers at the ages of 11 and 12 years, respectively, and less than 30 polyps. Tumor specimens were microsatellite instable (MSI-H), and expression of MSH2 and MSH6 was lost. Mutation analyses of DNA samples from both patients revealed a novel homozygous c.2006-5T > A mutation in intron 12 of the MSH2 gene. This phenotype of the brothers is unusual as they neither develop hematological malignancies nor brain tumors at an older age of presentation than other patients with homozygous MSH2 mutations. The milder phenotype may be due to the expression of low amounts of MSH2 protein with reduced activity.     

Split-face-study using two different light sources for topical PDT of actinic keratoses:non-inferiority of the LED system

Background: Photodynamic therapy (PDT) with 5-amino-4-oxo-pentanoate (methylaminolevulinate, MAL) is an effective and safe treatment option for actinic keratoses. Light-emitting diodes (LED) are suitable light sources for topical PDT. To evaluate the efficacy, painfulness, patient satisfaction and cosmesis of LED-based PDT a prospective, randomized and controlled split-face study was performed. Methods: Topical ALA-PDT was administered to 17 patients whose actinic ker-atoses (n = 131) were symmetrically distributed and suitable for a two-side comparison. After incubation with MAL (16%), irradiation was performed with the incoherent lamp (160 mW cm⁻²; 100 J cm⁻², PDT 1200L, Waldmann Medizintechnik, Villingen-Schwenningen, Germany) on one side and the LED system (120 mW cm⁻²; 40 J cm⁻², LEDA, WaveLight AG, Erlangen, Germany) on the other side. The patients were followed by re-evaluation up to 6 months. Results: Six months following treatment there was no significant difference between the infiltration and keratosis scores in both treatment regimes (p = 0.812). The remission rate was 78.5% (LED system) vs.80.3% (incoherent lamp). There was no significant difference between both light sources regarding the pain during therapy (p = 0.988). There was no significant difference between both treatment regimes regarding patient satisfaction (p = 1). Conclusions: LEDA-based MAL-PDT is an effective alternative for the treatment of atinic keratoses. The remission rates and cosmetic results are not inferior to PDT using incoherent light systems. Both treatment regimes are similarly painful.     

Dizziness: Anxiety, health care utilization and health behavior—: Results from a representative German community survey

Background

Due to the lack of epidemiological data on the relation of dizziness and anxiety, we investigated the prevalence of dizziness and anxiety in a representative sample of the German population. We explored the consequences of comorbid anxiety for emotional distress, functional impairment, health care utilization, and health behavior in dizziness.

Methods

By the end of 2006, we surveyed a total of 1287 persons between 14 and 90 years of age in their homes by trained interviewers with standardized self-rating questionnaires on anxiety (Patient Health Questionnaire, Generalized Anxiety Disorder Scale, Mini-Social Phobia Inventory) and dizziness (Vertigo Symptom Scale). The sample was representative for the German population in terms of age, sex, and education.

Results

Symptoms of dizziness were reported by 15.8% of the participants. Of the participants with dizziness, 28.3% reported symptoms of at least one anxiety disorder (generalized anxiety, social phobia, panic). Persons with dizziness reported more somatic problems such as hypertension, migraine, diabetes, etc. Comorbid anxiety was associated with increased health care use and impairment.

Conclusion

Dizziness is a highly prevalent symptom in the general population. A subgroup with comorbid anxiety is characterized by an increased subjective impairment and health care utilization due to their dizziness. Because treatment options for distinct neurotologic disorders are also known to reduce psychological symptoms, and in order to avoid unnecessary medical treatment, early neurologic and psychiatric/psychotherapeutic referral may be indicated.     

Photoprovocation in cutaneous lupus erythematosus: a multicenter study evaluating a standardized protocol

Photosensitivity is an important and distinguishing sign in various subtypes of cutaneous lupus erythematosus (CLE); however, it remains poorly defined. The purpose of this study was to evaluate whether standardized photoprovocation is a reproducible method to assess photosensitivity in subjects with CLE. A total of 47 subjects with CLE (subacute cutaneous lupus erythematosus (SCLE), n=14; discoid lupus erythematosus (DLE), n=20; lupus erythematosus tumidus (LET), n=13) and 13 healthy volunteers underwent photoprovocation at seven European sites. Of these, 22 (47%) subjects (57% SCLE, 35% DLE, and 54% LET) and none of the healthy volunteers developed photoprovoked lesions according to clinical analysis. Of these 22 subjects, 19 (86%) developed lesions that were histopathologically confirmed as specific for lupus erythematosus (LE). In CLE subjects who developed UV-induced lesions, 86% had Fitzpatrick's phototypes I or II, and the mean minimal erythema dose (MED) was significantly lower compared with subjects without UV-induced lesions (P=0.004). No significant differences in photoprovocation results were observed between study sites. Safety parameters showed no clinically meaningful differences between CLE subjects and healthy volunteers after photoprovocation. In conclusion, a standardized, safe, and reproducible protocol for photoprovocation using UVA and UVB radiation induced skin lesions in approximately half of all CLE subjects and showed comparable results across multiple sites. This method may therefore be used for future diagnostic testing and clinical trials.     

Sensitivity of serum concentration of cartilage biomarkers to 21‐days of bed rest

The objective of the study was to test the hypothesis that serum levels of cartilage oligomeric matrix protein (COMP) would decrease and serum levels of tumor‐necrosis factor alpha (TNF‐α) and selected matrix metalloproteinases (MMPs) would increase in response to bed rest (BR) and that these changes are unaffected by the intake of potassium bicarbonate or whey protein. Seven and nine healthy male subjects participated in two 21‐day 6° head down tilt crossover BR‐studies with nutrition interventions. Serum samples were taken before, during, and after BR and biomarker concentrations were measured using commercial enzyme‐linked immunosorbent assays. MMP‐3 during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP‐3 increased significantly from 14 to 21 days of BR (+7%; p = 0.049). COMP during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP‐3 and COMP returned to baseline within 1 day after BR. MMP‐9 on day 3 of BR was significantly lower than at baseline (?31%; p < 0.033) and on days 3, 5, and 14 of BR significantly lower than at the end of and after BR (reduction greater 35%; p < 0.030). The nutritional countermeasures did not affect these results. The observed changes in cartilage biomarkers may be caused by altered cartilage metabolism in response to the lack of mechanical stimulus during BR and inflammatory biomarkers may play a role in changes in biomarker levels. Clinical relevance: Immobilization independently from injury can cause altered cartilage biomarker concentration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1465–1471, 2018.

     

Comparison of volumetric bone mineral density in the operated and contralateral knee after anterior cruciate ligament and reconstruction: A 1‐year follow‐up study using peripheral quantitative computed tomography

The purpose of this study was to quantify changes in volumetric bone mineral density (vBMD) in the tibial plateau of the operated and contralateral leg measured using peripheral quantitative computed tomography (pQCT) before and 3, 6, and 12 months after anterior cruciate ligament (ACL) reconstruction. The ACL was reconstructed with a hamstring tendon autograft using press‐fit fixation. pQCT measurements of the proximal tibia were obtained in 61 patients after ACL reconstruction, and total, cortical, and trabecular vBMD were calculated. vBMD in the operated leg decreased from baseline to 3 months (?12% [total], ?11% [cortical], and ?12.6% [trabecular]; p < 0.001) and remained below baseline for 12 months after surgery (6 months: ?9.5%, ?9.4%, and ?9.6%, p < 0.001; 12 months: ?8%, ?5%, and ?11%, p < 0.001). vBMD in the contralateral leg was slightly reduced only 6 months after surgery. Including age and sex as covariates into the analysis did not affect the results. ACL reconstruction contributed to loss in bone mineral density within the first year after surgery. The role of factors such as time of weight‐bearing, joint mechanics, post‐traumatic inflammatory reactions, or genetic predisposition in modulating the development of posttraumatic knee osteoarthritis after ACL injury should be further elucidated. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1804–1810, 2015.

     

Genetically encoded Ca2+-sensor reveals details of porcine endothelial cell activation upon contact with human serum

The activation of the endothelial surface in xenografts is still a poorly understood process and the consequences are unpredictable. The role of Ca²⁺-messaging during the activation of endothelial cells is well recognized and routinely measured by synthetic Ca²⁺-sensitive fluorophors. However, these compounds require fresh loading immediately before each experiment and in particular when grown in state-of-the-art 3D cell culture systems, endothelial cells are difficult to access with such sensors. Therefore, we developed transgenic pigs expressing a Ca²⁺-sensitive protein and examined its principal characteristics. Primary transgenic endothelial cells stimulated by ATP showed a definite and short influx of Ca²⁺ into the cytosol, whereas exposure to human serum resulted in a more intense and sustained response. Surprisingly, not all endothelial cells reacted identically to a stimulus, rather activation took place in adjacent cells in a timely decelerated way and with distinct intensities. This effect was again more pronounced when cells were stimulated with human serum. Finally, we show clear evidence that antibody binding alone significantly activated endothelial cells, whereas antibody depletion dramatically reduced the stimulatory potential of serum. Transgenic porcine endothelial cells expressing a Ca²⁺-sensor represent an interesting tool to dissect factors inducing activation of porcine endothelial cells after exposure to human blood or serum.