GWAS links variants in neuronal development and actin remodeling related loci with pseudoexfoliation syndrome without glaucoma

Pseudoexfoliation syndrome (PEXS) is an age-related elastosis, strongly associated with the development of secondary glaucoma. It is clearly suggested that PEXS has a genetic component, but this has not been extensively studied. Here, a genome-wide association study (GWAS) using a DNA-pooling approach was conducted to explore the potential association of genetic variants with PEXS in a Polish population, including 103 PEXS patients without glaucoma and 106 perfectly (age- and gender-) matched controls. Individual sample TaqMan genotyping was used to validate GWAS-selected single-nucleotide polymorphism (SNP) associations. Multivariate binary logistic regression analysis was applied to develop a prediction model for PEXS. In total, 15 SNPs representing independent PEXS susceptibility loci were selected for further validation in individual samples. For 14 of these variants, significant differences in the allele and genotype frequencies between cases and controls were identified, of which 12 remained significant after Benjamini-Hochberg adjustment. The minor allele of five SNPs was associated with an increased risk of PEXS development, while for nine SNPs, it showed a protective effect. Beyond the known LOXL1 variant rs2165241, nine other SNPs were located within gene regions, including in OR11L1, CD80, TNIK, CADM2, SORBS2, RNF180, FGF14, FMN1, and RBFOX1 genes. None of these associations with PEXS has previously been reported. Selected SNPs were found to explain nearly 69% of the total risk of PEXS development. The overall risk prediction accuracy for PEXS, expressed by the area under the ROC curve (AUC) value, increased by 0.218, from 0.672 for LOXL1 rs2165241 alone to 0.89 when seven additional SNPs were included in the proposed 8-SNP prediction model. In conclusion, several new susceptibility loci for PEXS without glaucoma suggested that neuronal development and actin remodeling are potentially involved in either PEXS onset or inhibition or delay of its conversion to glaucoma

Practical considerations for in vivo MRI with higher dimensional spatial encoding

Object: This work seeks to examine practical aspects of in vivo imaging when spatial encoding is performed with three or more encoding channels for a 2D image. Materials and methods: The recently developed 4-Dimensional Radial In/Out (4D-RIO) trajectory is compared in simulations to an alternative higher-order encoding scheme referred to as O-space imaging. Direct comparison of local k-space representations leads to the proposal of a modification to the O-space imaging trajectory based on a scheme of prephasing to improve the reconstructed image quality. Data were collected using a 4D-RIO acquisition in vivo in the human brain and several image reconstructions were compared, exploiting the property that the dense encoding matrix, after a 1D or 2D Fourier transform, can be approximated by a sparse matrix by discarding entries below a chosen magnitude. Results: The proposed prephasing scheme for the O-space trajectory shows a marked improvement in quality in the simulated image reconstruction. In experiments, 4D-RIO data acquired in vivo in the human brain can be reconstructed to a reasonable quality using only 5% of the encoding matrix—massively reducing computer memory requirements for a practical reconstruction. Conclusion: Trajectory design and reconstruction techniques such as these may prove especially useful when extending generalized higher-order encoding methods to 3D image

NO-degradation by alfalfa class 1 hemoglobin (Mhb1): a possible link to PR-1a gene expression in Mhb1-overproducing tobacco plants

AbstractTobacco plants overproducing alfalfa class 1 hemoglobin (HOT plants) have been shown to have reduced necrotic symptom development. Here, we show that this altered pathogenic response is linked to a significant increase in the nitric oxide (NO)-affected pathogenesis-related (PR-1a) transcript accumulation in the transgenic plants. Homogenates of HOT transgenic seedlings were also found to have higher NO-scavenging activity than non-transformed ones. The NO-scavenging properties of recombinant alfalfa class1 hemoglobin have been examined. Recombinant Mhb1 (rMhb1) was produced in bacteria and purified using polyethylene glycol (10–25%) fractionation, chromatography on DEAE–Sephacel, and Phenyl Superose columns. After the final purification step, the obtained preparations were near homogeneous and had a molecular weight of 44 kDa determined by size-exclusion chromatography and 23 kDa by SDS–PAGE, indicating that rMhb1 is a dimer. The protein participated in NO-degradation activity with NAD(P)H as a cofactor. After ion-exchange columns, addition of FAD was necessary for exhibiting maximal NO-degradation activity. The NAD(P)H-dependent NO-scavenging activity of rMhb1, which is similar to that of barley hemoglobin, supports a conclusion that both monocot and dicot class 1 hemoglobins can affect cellular NO levels by scavenging NO formed during hypoxia, pathogen attack and other stresses

Hypertriglyceridemia associated with anticancer therapy based on asparaginase and steroids: a retrospective single center study of children with acute lymphoblastic leukemia and lymphoblastic lymphoma

Introduction: Hypertriglyceridemia (HTG) is one of the common complications of the regimens based on steroids and asparaginase used in the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in children. The aim of this cross-sectional retrospective study was the analysis of the prevalence, clinical course and management of hypertriglyceridemia following the administration of asparaginase and steroids according to the binding protocols. Material and methods: A cohort of 75 children with ALL or LBL was analyzed with reference to anthropometric and laboratory parameters, clinical symptoms, implemented treatment, and complications. Results: The prevalence of HTG in the analyzed cohort was 29.3%. Risk factors for HTG development were older age, cachexia and lower body mass index, but there was no correlation with high risk group. Patients with HTG presented with elevated lipase acivity and total cholesterol concentration and decreased antithrombin, albumin, sodium and high-density lipoprotein cholesterol. Reported symptoms were unspecific. Management of HTG included: omega 3 fatty acids, fibrates, insulin and plasmapheresis. Conclusions: Hypertriglyceridemia is a significant complication of ALL and LBL treatment, and can lead to acute and late complications and cause unwelcome interruptions to therapy that can lead to poorer outcomes of treatment. As the course of HTG is oligosymptomatic, but can have undesirable repercussions, every patient receiving asparaginase with steroids should be monitored for HTG. It is also noteworthy that HTG can occur three or more weeks after asparaginase administration

Relationship of 5-HTTLPR Polymorphism with Various Factors of Pain Processing:Subjective Experience, Motor Responsiveness and Catastrophizing

Although serotonin is known to play an important role in pain processing, the relationship between the polymorphism in 5-HTTLPR and pain processing is not well understood. To examine the relationship more comprehensively, various factors of pain processing having putative associations with 5-HT functioning were studied, namely the subjective pain experience (pain threshold, rating of experimental pain), catastrophizing about pain (Pain Catastrophizing Scale = PCS) and motor responsiveness (facial expression of pain). In 60 female and 67 male participants, heat pain stimuli were applied by a contact thermode to assess pain thresholds, supra-threshold ratings and a composite score of pain-relevant facial responses. Participants also completed the PCS and were grouped based on their 5-HTTLPR genotype (bi-allelic evaluation) into a group with s-allele carriers (ss, sl) and a second group without (ll). S-allele carriers proved to have lower pain thresholds and higher PCS scores. These two positive findings were unrelated to each other. No other difference between genotype groups became significant. In all analyses, "age" and "gender" were controlled for. In s-allele carriers the subjective pain experience and the tendency to catastrophize about pain was enhanced, suggesting that the s-allele might be a risk factor for the development and maintenance of pain. This risk factor seems to act via two independent routes, namely via the sensory processes of subjective pain experiences and via the booster effects of pain catastrophizing

Standing wave instabilities in a chain of nonlinear coupled oscillators

We consider existence and stability properties of nonlinear spatially periodic or quasiperiodic standing waves (SWs) in one-dimensional lattices of coupled anharmonic oscillators. Specifically, we consider Klein-Gordon (KG) chains with either soft (e.g., Morse) or hard (e.g., quartic) on-site potentials, as well as discrete nonlinear Schroedinger (DNLS) chains approximating the small-amplitude dynamics of KG chains with weak inter-site coupling. The SWs are constructed as exact time-periodic multibreather solutions from the anticontinuous limit of uncoupled oscillators. In the validity regime of the DNLS approximation these solutions can be continued into the linear phonon band, where they merge into standard harmonic SWs. For SWs with incommensurate wave vectors, this continuation is associated with an inverse transition by breaking of analyticity. When the DNLS approximation is not valid, the continuation may be interrupted by bifurcations associated with resonances with higher harmonics of the SW. Concerning the stability, we identify one class of SWs which are always linearly stable close to the anticontinuous limit. However, approaching the linear limit all SWs with nontrivial wave vectors become unstable through oscillatory instabilities, persisting for arbitrarily small amplitudes in infinite lattices. Investigating the dynamics resulting from these instabilities, we find two qualitatively different regimes for wave vectors smaller than or larger than pi/2, respectively. In one regime persisting breathers are found, while in the other regime the system rapidly thermalizes.Comment: 57 pages, 21 figures, to be published in Physica D. Revised version: Figs. 5 and 12 (f) replaced, some new results added to Sec. 5, Sec.7 (Conclusions) extended, 3 references adde

Oscillatory Instabilities of Standing Waves in One-Dimensional Nonlinear Lattices

In one-dimensional anharmonic lattices, we construct nonlinear standing waves (SWs) reducing to harmonic SWs at small amplitude. For SWs with spatial periodicity incommensurate with the lattice period, a transition by breaking of analyticity versus wave amplitude is observed. As a consequence of the discreteness, oscillatory linear instabilities, persisting for arbitrarily small amplitude in infinite lattices, appear for all wave numbers Q not equal to zero or \pi. Incommensurate analytic SWs with |Q|>\pi/2 may however appear as 'quasi-stable', as their instability growth rate is of higher order.Comment: 4 pages, 6 figures, to appear in Phys. Rev. Let

Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer

Background Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy. Methods Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Results In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r 2  = 0.23; p < 10 −16 ) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10 −16 ) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10 −43 ). Conclusions The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment

Female sex and burden of depressive symptoms predict insufficient response to telemedical treatment in adult attention-deficit/hyperactivity disorder: results from a naturalistic patient cohort during the COVID-19 pandemic

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder, that typically manifests itself during childhood and persists in a majority of the affected individuals into adulthood, negatively affecting physical and mental health. Previous studies have shown detrimental effects of the COVID-19 pandemic on mental health in individuals with ADHD. Thus, telemedicine could be a useful tool for optimizing treatment-outcomes in adult ADHD by improving treatment adherence and persistence. However, data on telemedical treatment outcomes in adult patients with ADHD is scarce.MethodsWe report here the sub-cohort analysis of a naturalistic cohort of adult patients (N = 254) recruited between April 2020–April 2021, comparing the effects of telemedical treatment on participants either clinically diagnosed with depression (N = 54) or ADHD (N = 67). Participants were asked to fill out the WHO-5 repetitively during &gt;12 weeks of telemedical treatment. Furthermore scores of WHO-5, SCL-90R and BDI-II, psychopathology, psychosocial functioning, sociodemographic data, medical records and a feedback survey were analyzed for both groups and compared. Participants with ADHD were further stratified according to the development of well-being during the study period in order to identify factors associated with a satisfactory treatment outcome.ResultsParticipants with depression reported a significant improvement of well-being during the course of the study, while no such effect could be seen in participants with ADHD on a group level. Despite the good outcome, participants with depression were more severely affected at baseline, with significantly worse psychopathology and a more precarious labor and financial situation. A detailed analysis of ADHD participants without clinical improvement revealed significantly higher BDI-II scores than for ADHD participants with a satisfactory outcome (p = 0.03, Mann–Whitney-U-Test), suggesting successful treatment was hampered by the combination of ADHD and depressive symptoms. Furthermore, female sex among ADHD patients was correlated with an unfavorable treatment outcome during the course of the study (p = 0.001, Spearman correlation) as well as living with children (p = 0.02, Spearman correlation).ConclusionBesides screening for depressive symptoms before telemedical treatment, future research should address the specific needs of female ADHD patients as these patients may be at a particularly high risk of being overburdened with family work

Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation

Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34-year-old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast-rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio-based exome sequencing. The novel homozygous splice-site mutation c.261G>A in the gene LRRK1 was found and co-segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L-plastin at position Ser5 was strongly reduced in patient-derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1-related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis