Pathology skills lab: use of macroscopic tumor models in pathology teaching.

BACKGROUND: The shortage of pathologists in Germany, coupled with an aging workforce, requires innovative approaches to attract medical students to the field. Medical education must address different learning styles to ensure that all students are successful. METHODS: The pilot project "Practical Pathology" aims to enhance students' understanding of pathology by providing hands-on experience in macroscopic gross analysis through the use of tumor dummies built from scratch. RESULTS: An evaluation survey, completed by 63 participating students provided positive feedback on the course methodology, its relevance to understanding the pathology workflow, and its improvement over traditional teaching methods. The majority of students recognized the importance of hands-on training in medical education. Students with previous work experience rated the impact of the course on knowledge acquisition even more positively. CONCLUSION: The course improved students' understanding of pathological processes and potential sources of clinical-pathological misunderstanding. An increase in motivation for a potential career in the field of pathology was observed in a minority of students, although this exceeded the percentage of pathologists in the total medical workforce.

Effects of the Flying Start on Estimated Short Sprint Profiles Using Timing Gates.

Short sprints are predominantly assessed using timing gates and analyzed through parameters of the mono-exponential equation, including estimated maximal sprinting speed (MSS) and relative acceleration (TAU), derived maximum acceleration (MAC), and relative propulsive maximal power (PMAX), further referred to as the No Correction model. However, the frequently recommended flying start technique introduces a bias during parameter estimation. To correct this, two additional models (Estimated TC and Estimated FD) were proposed. To estimate model precision and sensitivity to detect the change, 31 basketball players executed multiple 30 m sprints. Athlete performance was simultaneously measured by a laser gun and timing gates positioned at 5, 10, 20, and 30 m. Short sprint parameters were estimated using a laser gun, representing the criterion measure, and five different timing gate models, representing the practical measures. Only the MSS parameter demonstrated a high agreement between the laser gun and timing gate models, using the percent mean absolute difference (%MAD) estimator (%MAD < 10%). The MSS parameter also showed the highest sensitivity, using the minimum detectable change estimator (%MDC95), with an estimated %MDC95 < 17%. Interestingly, sensitivity was the highest for the No Correction model (%MDC95 < 7%). All other parameters and models demonstrated an unsatisfying level of sensitivity. Thus, sports practitioners should be cautious when using timing gates to estimate maximum acceleration indices and changes in their respective levels.

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

A novel de novo truncating variant in a Hungarian patient with CTNNB1 neurodevelopmental disorder.

PURPOSE: We aimed to elucidate the underlying disease in a Hungarian family, with only one affected family member, a 16-year-old male Hungarian patient, who developed global developmental delay, cognitive impairment, behavioral problems, short stature, intermittent headaches, recurrent dizziness, strabismus, hypermetropia, complex movement disorder and partial pituitary dysfunction. After years of detailed clinical investigations and careful pediatric care, the exact diagnosis of the patient and the cause of the disease was still unknown. METHODS: We aimed to perform whole exome sequencing (WES) in order to investigate whether the affected patient is suffering from a rare monogenic disease. RESULTS: Using WES, we identified a novel, de novo frameshift variant (c.1902dupG, p.Ala636SerfsTer12) of the catenin beta-1 (CTNNB1) gene. Assessment of the novel CTNNB1 variant suggested that it is a likely pathogenic one and raised the diagnosis of CTNNB1 neurodevelopmental disorder (OMIM 615,075). CONCLUSIONS: Our manuscript may contribute to the better understanding of the genetic background of the recently discovered CTNNB1 neurodevelopmental disorder and raise awareness among clinicians and geneticists. The affected Hungarian family demonstrates that based on the results of the clinical workup is difficult to establish the diagnosis and high-throughput genetic screening may help to solve these complex cases.

Long-Term Follow-Up of a Family with Retinal Dystrophy Caused by RPE65 Mutation.

We present here the case histories of two siblings, a boy and a girl, with Leber's congenital amaurosis (LCA). The diagnosis was based on non-recordable full-field electroretinogram (ffERG). The long-term ophthalmologic follow-up included kinetic perimetry (Goldmann), visual evoked potentials with flash stimulation, optical coherence tomography (OCT: B-scan images at the area of fovea), and multifocal ERG. The boy (sibling 1, born in 1986) was sent for electrophysiological examination at the age of four because he had nystagmus from birth. The diagnosis would be LCA based on non-recordable ffERG. Four years later, his visual acuity decreased rapidly due to vitreous opacification, caused by the autoimmune reaction of the retinal pigment epithelial cells. This was treated successfully with steroid injections, administered parabulbarly. Retinal autoimmune panel was not performed. Genetic testing became available only in 2019, and it revealed a RPE65 gene mutation: (NM_000329.2) c.{442G>A};{442G>A} (p.{Glu148Lys}; {Glu148Lys}). His sister (sibling 2, born in 1993) showed similar symptoms, caused by the same genetic mutation. Even though their parents were free of symptoms, it appeared that they were heterozygous carriers of the same mutation. Research of the family tree revealed a consanguineous marriage four generations before. Both siblings received successful gene therapy relatively late in their age: sibling 1 was 35 and sibling 2 was 28 years old, meaning that they were at an advanced stage of the disease. Nevertheless, follow-up examinations showed measurable improvements in their retinal function. The study shows that electrophysiological examinations, including flash-evoked responses, are useful in the objective evaluation of the progression in the central photoreceptor loss during the follow-up of LCA. The results also show that gene therapy can have beneficial effects even at an advanced stage of the disease.

Whole-Exome Sequencing Identified Two Novel Pathogenic Mutations in the PTCH1 Gene in BCNS.

Basal cell nevus syndrome (BCNS, OMIM 109400) is a familial cancer syndrome characterized by the development of numerous basal cell cancers and various other developmental abnormalities, including epidermal cysts of the skin, calcified dural folds, keratocysts of the jaw, palmar and plantar pits, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, and fetal rhabdomyomas. BCNS shows autosomal dominant inheritance and is caused by mutations in the patched 1 (PTCH1) gene and the suppressor of the fused homolog (SUFU) gene. In a few cases, variants of patched 2 (PTCH2) have been found in patients who met the criteria for BCNS. In an investigation of 11 Hungarian families who fulfilled the diagnostic criteria for BCNS, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) identified two novel pathogenic variants (c.2994C>A; p.Cys998Ter and c.814_818del; p.Asn272SerfsTer11), one recently identified variant (c.1737_1745del p.Val580_Val582del), and three recurrent disease-causing variants of the PTCH1 gene with a diagnosis rate of 63.6%. Disease-causing variants were not found for the SUFU and PTCH2 genes. These applied methods could not fully elucidate the genetic background of all the BCNS cases that we investigated. To uncover the missing heritability of BCNS, whole-genome sequencing or an epigenetic approach might be considered in the future.

Inflammatory fibroid polyp of the renal pelvis: first report at an extra-gastrointestinal site with molecular confirmation.

Inflammatory fibroid polyps (IFP) are rare and benign mesenchymal tumours of the gastrointestinal tract. They are submucosal spindle cell lesions with an eosinophilic-rich inflammatory infiltrate and mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. In this report, we present the case of a 74-year-old female with a solid tumour of the kidney, which presented as a bland proliferation of spindle cells with thin-walled blood vessels and an inflammatory infiltrate with eosinophilic granulocytes. Immunohistochemistry revealed a positivity for vimentin and a weak staining for CD99 and CD34 in the spindle cells. Because of the morphological similarity to IFPs of the gastrointestinal tract, a molecular pathology analysis was performed. This identified an oncogenic mutation in exon 18 of the PDGFRA gene, which is characteristic for inflammatory fibroid polyps of the gastrointestinal tract. To the best of our knowledge, this is the first case of an IFP in the urogenital tract.

Genetic Etiology of Nonsyndromic Hearing Loss in Hungarian Patients.

Hearing loss is the most prevalent sensory disorder worldwide. The majority of congenital nonsyndromic hearing loss (NSHL) cases are caused by hereditary factors. Previously, the majority of NSHL studies focused on the GJB2 gene; however, with the availability of next-generation sequencing (NGS) methods, the number of novel variants associated with NSHL has increased. The purpose of this study was to design effective genetic screening for a Hungarian population based on a pilot study with 139 NSHL patients. A stepwise, comprehensive genetic approach was developed, including bidirectional capillary sequencing, multiplex ligation-dependent probe amplification (MLPA), and an NGS panel of 108 hearing loss genes. With our results, a genetic diagnosis was possible for 92 patients. Sanger sequencing and MLPA identified the genetic background of 50% of these diagnosed cases, and the NGS panel identified another 16%. The vast majority (92%) of the diagnosed cases showed autosomal recessive inheritance and 76% were attributed to GJB2. The implementation of this stepwise analysis markedly increased our diagnostic yield and proved to be cost-effective as well.

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

PURPOSE: The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). EXPERIMENTAL DESIGN: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts. RESULTS: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001). CONCLUSIONS: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377.

Spontaneous reshaping of vertebral fractures in an adolescent with osteogenesis imperfecta.

Background: Vertebral compression fractures (VFs) are a common and severe finding in patients with osteoporosis. In children, VFs have the unique potential to reshape and regain their original configuration. Spontaneous vertebral body reshaping (i.e., medication-unassisted) has been reported in secondary osteoporosis. Here we describe a previously unreported spontaneous vertebral reshaping in an adolescent with osteogenesis imperfecta (OI) with multiple vertebral fractures. Case report: A 17-year-old female was diagnosed with OI type I at 5 years of age caused by a novel frameshift variant in COL1A1 (NM_000088.4: c.540delC; p.Met181TrpfsTer84). Due to parental reservations about medication, she had never received bisphosphonate or any other bone active therapy. A lateral spine X-ray demonstrated transparent bones and no VF. However, previous spine X-rays taken at age of 6 years at an external institution showed VFs in T5-7 (Genant semiquantitative method grade I-II). The two lateral spine x-rays, taken 11 years apart, demonstrate that substantial spontaneous vertebral reshaping occurred without bone active therapy during puberty. Discussion: Vertebral reshaping is explained by the stabilization of bone mineral density (BMD) and the remaining growth capacity the children. We hypothesize that spontaneous reshaping may occur in milder forms of OI, and that puberty may be a key mediator of the phenomenon. In all children with OI and vertebral fractures, we nevertheless recommend bisphosphonate therapy since it improves bone mass, BMD, vertebral shape, physical activity and reduces fracture rates.

Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring.

POGZ-related disorders (also known as White-Sutton syndrome) encompass a wide range of neurocognitive abnormalities and other accompanying anomalies. Disease severity varies widely among POGZ patients and studies investigating genotype-phenotype association are scarce. Therefore, our aim was to collect data on previously unreported POGZ patients and perform a large-scale phenotype-genotype comparison from published data. Overall, 117 POGZ patients' genotype and phenotype data were included in the analysis, including 12 novel patients. A severity scoring system was developed for the comparison. Mild and severe phenotypes were compared with the types and location of the variants and the predicted presence or absence of nonsense-mediated RNA decay (NMD). Missense variants were more often associated with mild phenotypes (p = 0.0421) and truncating variants predicted to escape NMD presented with more severe phenotypes (p < 0.0001). Within this group, variants in the prolin-rich region of the POGZ protein were associated with the most severe phenotypes (p = 0.0004). Our study suggests that gain-of-function or dominant negative effect through escaping NMD and the location of the variants in the prolin-rich domain of the protein may play an important role in the severity of manifestations of POGZ-associated neurodevelopmental disorders.

Comparison of Metabolic Characteristics of Physically Active Individuals with Different Training Habits during Incremental Treadmill Test.

The number of people engaging in self-conducted regular physical activity is increasing, but the effects of home fitness and individually planned workouts on health and metabolism are unknown. We aimed to examine the effects of regular training conducted without the supervision of professionals on exercise metabolism in our cross-sectional observational study. Forty-five physically active volunteers, classified into three groups, based on the type and frequency of their training (group 1 frequent long-term endurance, group 2 three times per week aerobic training, and group 3 two times per week short aerobic and resistance training), fulfilled a vita maxima incremental treadmill test. Aerobic capacity (VO2max), MET (metabolic equivalent of task), and metabolic responses were examined. The results were evaluated by ANOVA and Bonferroni and Scheffe multiple comparison analysis using Microsoft Excel and SPSS 23 programs. (p < 0.05). Significant differences were found between group 1 and 3 in VO2max (p = 0.46) and MET (p = 0.46) between group 1 and 2, in FatmaxHR (heart rate on maximum fat oxidation) (p= 0.04). We concluded self-conducted regular physical activity has positive effects on metabolism and health. Aerobic training performed four times per week showed the most beneficial effects on metabolism and health maintenance. In addition, based on our findings, strength training performed two times per week is recommended.

Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions.

Neurofibromatosis type 1 is a tumor predisposition syndrome inherited in autosomal dominant manner. Besides the intragenic loss-of-function mutations in NF1 gene, large deletions encompassing the NF1 gene and its flanking regions are responsible for the development of the variable clinical phenotype. These large deletions titled as NF1 microdeletions lead to a more severe clinical phenotype than those observed in patients with intragenic NF1 mutations. Around 5-10% of the cases harbor large deletion and four major types of NF1 microdeletions (type 1, 2, 3 and atypical) have been identified so far. They are distinguishable in term of their size and the location of the breakpoints, by the frequency of somatic mosaicism with normal cells not harboring the deletion and by the number of the affected genes within the deleted region. In our study genotype-phenotype analyses have been performed in 17 mostly pediatric patients with NF1 microdeletion syndrome identified by multiplex ligation-dependent probe amplification after systematic sequencing of the NF1 gene. Confirmation and classification of the NF1 large deletions were performed using array comparative genomic hybridization, where it was feasible. In our patient cohort 70% of the patients possess type-1 deletion, one patient harbors type-2 deletion and 23% of our cases have atypical NF1 deletion. All the atypical deletions identified in this study proved to be novel. One patient with atypical deletion displayed mosaicism. In our study NF1 microdeletion patients presented dysmorphic facial features, macrocephaly, large hands and feet, delayed cognitive development and/or learning difficulties, speech difficulties, overgrowth more often than patients with intragenic NF1 mutations. Moreover, neurobehavior problems, macrocephaly and overgrowth were less frequent in atypical cases compared to type-1 deletion. Proper diagnosis is challenging in certain patients since several clinical manifestations show age-dependency. Large tumor load exhibited more frequently in this type of disorder, therefore better understanding of genotype-phenotype correlations and progress of the disease is essential for individuals suffering from neurofibromatosis to improve the quality of their life. Our study presented additional clinical data related to NF1 microdeletion patients especially for pediatric cases and it contributes to the better understanding of this type of disorder.

Influencing Factors of Cardiac Adaptation in Adolescent Athletes.

Endurance training-induced changes in left ventricular diastolic function and right ventricular parameters have been investigated extensively in adolescent athletes. Our aim was to examine the parameters for adolescent athletes (n=121, 15.1±1.6 years) compared to adult athletes and age-matched non-athletes. We explored the effects of influencing factors on the echocardiographic parameters. Significantly higher E/A (p<0.05) and e' values (p<0.001) were detected in adolescent athletes compared to age-matched non-athletes' and also adult athletes' parameters. Significantly lower structural and functional right ventricular parameters (p<0.05) were detected in adult athletes. In adolescent athletes significantly higher right ventricular diameters, tricuspid S wave, right ventricular end-diastolic and end-systolic area values (p<0.05) were found compared to the matching parameters of non-athletes. We found significantly higher corrected tricuspid annular plane systolic excursion values (p<0.001) in athletes compared to the non-athletes. Based on multivariate analysis lean body mass, body surface area, age and cumulative training time were proved as strong predictive factors of both left ventricular diastolic and right ventricular parameters. Supernormal left ventricular diastolic function and significantly higher right ventricular parameters are indicative of cardiac adaptation. Well-defined cut-off values should be applied to discriminate pathological conditions in the relation of the influencing factors.

Systemic Screening for 22q11.2 Copy Number Variations in Hungarian Pediatric and Adult Patients With Congenital Heart Diseases Identified Rare Pathogenic Patterns in the Region.

Congenital heart defects (CHD) are the most common developmental abnormalities, affecting approximately 0.9% of livebirths. Genetic factors, including copy number variations (CNVs), play an important role in their development. The most common CNVs are found on chromosome 22q11.2. The genomic instability of this region, caused by the eight low copy repeats (LCR A-H), may result in several recurrent and/or rare microdeletions and duplications, including the most common, ∼3 Mb large LCR A-D deletion (classical 22q.11.2 deletion syndrome). We aimed to screen 22q11.2 CNVs in a large Hungarian pediatric and adult CHD cohort, regardless of the type of their CHDs. All the enrolled participants were cardiologically diagnosed with non-syndromic CHDs. A combination of multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray analysis and droplet digital PCR methods were used to comprehensively assess the detected 22q11.2 CNVs in 212 CHD-patients. Additionally, capillary sequencing was performed to detect variants in the TBX1 gene, a cardinal gene located in 22q11.2. Pathogenic CNVs were detected in 5.2% (11/212), VUS in 0.9% and benign CNVs in 1.8% of the overall CHD cohort. In patients with tetralogy of Fallot the rate of pathogenic CNVs was 17% (5/30). Fifty-four percent of all CNVs were typical proximal deletions (LCR A-D). However, nested (LCR A-B) and central deletions (LCR C-D), proximal (LCR A-D) and distal duplications (LCR D-E, LCR D-H, LCR E-H, LCR F-H) and rare combinations of deletions and duplications were also identified. Segregation analysis detected familial occurrence in 18% (2/11) of the pathogenic variants. Based on in-depth clinical information, a detailed phenotype-genotype comparison was performed. No pathogenic variant was identified in the TBX1 gene. Our findings confirmed the previously described large phenotypic diversity in the 22q11.2 CNVs. MLPA proved to be a highly efficient genetic screening method for our CHD-cohort. Our results highlight the necessity for large-scale genetic screening of CHD-patients and the importance of early genetic diagnosis in their clinical management.

Genetic aspects of Gorlin‒Goltz syndrome / A Gorlin-Goltz-szindróma genetikai aspektusai.

Összefoglaló. A Gorlin-Goltz-szindróma - más néven naevoid basalsejtes carcinoma szindróma - egy ritka, viszont számos orvosi társszakmát érinto, rendkívül változatos megjelenésu és genetikailag is heterogén betegség. Bár a tudományos kutatások egyik kedvenc területe, az aránylag alacsony betegszám, valamint a genotípus és a fenotípus közötti, igen komplex összefüggések miatt a kórképrol meglévo ismereteink még nem teljesek. A témában megjelent nemzetközi és magyar nyelvu publikációk jelentos része esetközlésekre és a szindróma általános ismertetésére szorítkozik. A közlemény célja, hogy áttekintést adjon a szindróma genetikai vonatkozásairól. A nemzetközi és a magyar nyelvu szakirodalom áttanulmányozását végeztük. A naevoid basalsejtes carcinoma szindróma genetikai hátterének, az egyelore azonosítatlan örökletes tényezoknek pontos megismerése még várat magára. A genetikai vizsgálatok a szindróma pontosabb megértéséhez, könnyebb diagnosztizálásához, a pozitív családtervezéshez és a személyre szabott terápiákhoz is hozzájárulhatnak. Orv Hetil. 2020; 161(49): 2072-2077. Summary. Gorlin-Goltz syndrome, or nevoid basal cell carcinoma syndrome, is a rare disease that requires multidisciplinary approach in patient management. The disease is genetically heterogenous and has an extremely variable expressivity. Although the syndrome is in the focus of scientific research, our knowledge of it is still limited due to the relatively low number of recognised patients and the complexity of genotype-phenotype correlation. Several papers in this field have been published in the international and also in the Hungarian literature but most of these reports are single cases or small case series of families and outline general information about the disease. Authors aimed to review the literature of the syndrome and to report the genetic background and its role in the diagnosis and treatment. A review of the English and Hungarian literature was performed. The full genetic background of the syndrome is not yet discovered. Increasing the awareness of the syndrome, collecting and thoroughly analysing the medical records and performing genetic tests on the patients may lead to the better understanding of the disease; they may also help early diagnosis and treatment, positive family planning and may establish personalized medicine. Orv Hetil. 2020; 161(49): 2072-2077.

Associations between fitness levels and self-perceived health-related quality of life in community - dwelling for a group of older females.

BACKGROUND: For older adults perceived quality of life has been linked to the ability to accomplish everyday tasks, a functional capacity which is thought to be based upon physical fitness. Although there is a relationship between physical activity and quality of life in older adults, the fitness of older adults and its relationship to quality of life needs more investigation. Therefore, the purpose of this study was to examine the associations between self-reported health-related quality of life and physical fitness in community-dwelling older females. METHODS: A cross-sectional study between four different age groups in retirement villages from two different places of the southern and western region of Hungary, among 173 women between the ages of 58 and 94 years old. We measured physical fitness using the Fullerton Test protocol and self-perceived health quality of life using the Short-Form Health Survey. RESULTS: Group means were different in six-minute walk distance, handgrip strength, and arm curls. The youngest group of females had higher scores of fitness in these categories as compared to the oldest grouping of women. Quality of Life were also difference across age groupings although not linear across the four age categories. Moderate level positive relationship was evident between perceived physical function and certain categories of physical fitness. CONCLUSIONS: Sociability and self-motivation has a leading role in quality of life in elder population. It is worth putting a lot more emphasis into continuous cultural, social and most importantly into physical activity programs for elderly.

Skin wipe test: A simple, inexpensive, and fast approach in the diagnosis of cystic fibrosis.

OBJECTIVE: To assess the performance of a newly developed skin wipe test (SWT) for the diagnosis of cystic fibrosis (CF). STUDY DESIGN: Spontaneously formed sweat from the forearm was wiped by a cotton swab moistened with 100 µL of deionized (DI) water and extracted into 400 µL of DI water (SWT). The conventional Macroduct sweat test (ST) was performed simultaneously. SWT samples of 114 CF patients, 76 healthy carriers, and 58 controls were analyzed by capillary electrophoresis with contactless conductivity detection and Cl- /K+ and (Cl- + Na+ )/K+ ion ratios were evaluated. Chloride concentrations from Macroduct ST were analyzed coulometrically. RESULTS: Analysis of 248 SWT samples and simultaneous Macroduct ST samples showed comparable method performance. Two ion ratios, Cl- /K+ and (Cl- + Na+ )/K+ , from the SWT samples and Cl- values from the ST samples were evaluated to diagnose CF. Sensitivity of the SWT method using the Cl- /K+ ratio (cutoff value 3.9) was 93.9%, compared to 99.1% when using the (Cl- + Na+ )/K+ ratio (cutoff value 5.0) and 98.3% in using Macroduct Cl- (cutoff value higher or equal to 60 mmol/L). The methods' specificities were 97.8%, 94.0%, and 100.0%, respectively. CONCLUSIONS: The developed SWT method with capillary electrophoretic analysis for CF diagnosis performs comparably to the conventional Macroduct ST. The SWT method is simple, fast, inexpensive, and completely noninvasive. Use of an ion ratio in obtained SWT samples is proposed as a new diagnostic parameter that shows significant promise in CF diagnostics.

Comprehensive Genetic Analysis of a Hungarian Amyotrophic Lateral Sclerosis Cohort.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Genetic factors play a key role in ALS, and identifying variants that contribute to ALS susceptibility is an important step toward understanding the etiology of the disease. The frequency of protein altering variants in ALS patients has been extensively investigated in populations of different ethnic origin. To further delineate the genetic architecture of the Hungarian ALS patients, we aimed to detect potentially damaging variants in major and minor ALS genes and in genes related to other neurogenetic disorders. A combination of repeat-sizing of C9orf72 and next-generation sequencing (NGS) was used to comprehensively assess genetic variations in 107 Hungarian patients with ALS. Variants in major ALS genes were detected in 36.45% of patients. As a result of repeat sizing, pathogenic repeat expansions in the C9orf72 gene were detected in 10 patients (9.3%). According to the NGS results, the most frequently mutated genes were NEK1 (5.6%), NEFH, SQSTM1 (3.7%), KIF5A, SPG11 (2.8%), ALS2, CCNF, FUS, MATR3, TBK1, and UBQLN2 (1.9%). Furthermore, potentially pathogenic variants were found in GRN and SIGMAR1 genes in single patients. Additional 33 novel or rare known variants were detected in minor ALS genes, as well as 48 variants in genes previously linked to other neurogenetic disorders. The latter finding supports the hypothesis that common pathways in different neurodegenerative diseases may contribute to the development of ALS. While the disease-causing role of several variants identified in this study has previously been established, other variants may show reduced penetrance or may be rare benign variants. Our findings highlight the necessity for large-scale multicenter studies on ALS patients to gain a more accurate view of the genetic pattern of ALS.