Phenotypic Polymorphism Research Articles

Синдром Шпринтцзена-Гольдберга: клиническое наблюдение

Authors represent bibliographical review and a clinical case report of Shprintzen-Goldberg syndrome (SGS) in an infant. SGS is a rare genetic disease that has been poorly studied and is of a practical and scientific interest due to the difficulty of its diagnosis, a fairly complex description of the phenotype and clinical polymorphism of manifestations. The purpose for publishing of this particular case report was to familiarize pediatric practitioners with this rare hereditary syndrome since there are no consensual clinical guidelines for the management of patients with SGS as yet. Identification of hereditary diseases accompanied by disruption of the structure and function of the musculoskeletal, cardiovascular and nervous systems would allow determining a more accurate plan for managing of a pediatric patient as well as establishing a possible prognosis for the patient’s further development, which is the number one problem considered by both parents/caregivers and physicians.

Seasonal changes in activity of hypothalamic thyroid hormone system in different winter phenotypes of Djungarian hamster (Phodopus sungorus).

Although the Djungarian hamster (Phodopus sungorus) is a seasonality model, it presents substantial variability in winter acclimation. In response to short photoperiod, some individuals express a suite of winter traits such as low body mass, regressed gonads, white fur, and daily torpor, while others develop only some adjustments or maintain a summer phenotype. Despite comprehensive research, the mechanisms underlying polymorphism of winter phenotype are still unknown. We compared key elements of the hypothalamic thyroid hormone system, as well as the tanycyte architecture in hamsters of both sexes. Individuals presented different responses to short photoperiod characterized either as phenotypes (non-responder, partial-responder and full-responder) or photoresponsive index. We measured the expression of genes coding iodothyronine deiodinase 2 and 3, monocarboxylate transporter 8, thyrotropin-releasing hormone, and somatostatin in 40 individuals and counted the number of immunolabeled tanycyte processes in standardized regions of interest around the third ventricle in 30 individuals. Animals acclimated to short photoperiod presented a downregulation of diodinase 2 and somatostatin and an upregulation of deiodinase 3, as well as a decreased number of tanycyte processes, compared to long photoperiod-exposed individuals. Although phenotypes did not differ in gene expression, the higher the photoresponsive index, the lower was the deiodinase 2 expression and the higher the deiodinase 3 expression. Partial-responders and full-responders had less tanycyte processes than non-responders, and the number of tanycyte processes correlated with the photoresponsive index. Sexes differed neither in their seasonal response, nor hypothalamic gene expression, but females had more tanycyte processes. Our results are in accordance with studies emphasizing the pivotal role of thyroid hormones in seasonal response. We suggest that the whole spectrum of winter phenotypes exists within the population of Djungarian hamsters and that it is reflected also at the level of neuroendocrine regulation. However, the neuroendocrine underpinnings of winter phenotype polymorphism require further investigation.

Cytokine gene polymorphisms and suicide risk in an Indian ancestral population: A case-control study

Background India currently accounts for a majority of global suicide deaths. Research in European ancestry has established that suicide mortality has a significant genetic component, and suggests that inflammation may play a crucial role in the pathophysiology of suicide. Inflammation is also highly relevant in regions of increased pollution exposure, such as the megacities of India. To address the existing gaps in genetic research on suicide and possible association with inflammatory biomarkers, we examined genetic polymorphism and clinical risk phenotypes in a population-based suicide-death cohort, India. Material and methods Genotyping of IL-1β(rs16944) & (rs1143627), IL-4(rs2070874), IL-6(rs1800795) and IL-10(rs1800896) was done in 234 post-mortem suicide-death cases and 256 post-mortem controls (N = 490) using PCR RFLP method. Results Our analyses identified three significant (p < 0.001) associations of cytokine variants with suicide death, including IL-1β(rs16944), OR = 0.627; IL-4(rs2070874), OR = 0.524; and IL-6(rs1800795), OR = 2.509. Cases were more likely female and were more likely to have a history of psychiatric illness, though rate of psychiatric illness was low in suicide cases(9%). Conclusion Our genetic results are generally consistent with previous research on risk for depression and suicidal behaviour, and both genetic and phenotypic results provide new insights into risk factors that may contribute to suicide in India.

Genomic and phenotypic polymorphism of Clostridium botulinum Group II strain Beluga through laboratory domestication

Laboratory domestication is the result of genetic and physiological changes of organisms acquired during numerous passages in vitro. This phenomenon has been observed in bacteria as well as in higher organisms. In an effort to understand the impact of laboratory domestication on the foodborne pathogen Clostridium botulinum and related microbial food safety research, we investigated multiple spore stocks of C. botulinum Group II Beluga from our collection, as that is a widely applied model strain used in laboratories over decades. An acquired nutrient auxotrophy was confirmed as thymidine dependency using phenotypic microarrays. In parallel, whole-genome re-sequencing of all stocks revealed a mutation in thyA encoding thymidylate synthase essential for de-novo synthesis of dTMP from dUMP in the auxotrophic stocks. A thyA-deficient Beluga variant stock was successfully complemented by introducing an intact variant of thyA and thymidine prototrophy was restored, indicating that the thymidine auxotrophy was solely due to the presence of a SNP in thyA. Our data suggested that this mutation, deleterious under nutrient-poor growth conditions in a chemically defined medium, has been present and maintained in laboratory stocks for nearly 30 years. Yet, the mutation remained unidentified since receiving the strain, most likely due to routine use of culture conditions optimized for growth performance. This work pinpoints the need for careful monitoring of model strains extensively used in laboratory settings at both phenotypic and genomic level. In applications like food safety challenge tests, compromised strains could cause incorrect predictions and thereby have deleterious consequences. To mitigate the risk of acquiring mutations, we recommend keeping passage numbers of laboratory strains low and to avoid single-colony passaging. In addition, relevant strains should be subjected to regular WGS checks and physiological validation to exclude DNA mutations with potential negative impacts on research data integrity and reproducibility.

Biogeography confounds the signal of cospeciation in Batesian mimicry.

Since the inception of the field of evolution, mimicry has yielded insights into foundational evolutionary processes, including adaptive peak shifts, speciation, and the emergence and maintenance of phenotypic polymorphisms.1,2,3 In recent years, the coevolutionary processes generating mimicry have gained increasing attention from researchers. Despite significant advances in understanding Batesian and Müllerian mimicry in Lepidopteran systems, few other mimetic systems have received similar detailed research. Here, we present a Batesian mimicry complex involving flightless, armored Pachyrhynchus weevils and their winged Doliops longhorn beetle mimics and examine their coevolutionary patterns within the Philippine archipelagos. Pachyrhynchus weevils are primarily found in the Philippines, where distinct species radiations have occurred on different islands, each with unique color patterns serving as a warning to predators. This defensive trait and mimicry between unrelated species were first described by Wallace in 1889. Notably, the distantly related longhorn beetle Doliops, despite being soft-bodied and ostensibly palatable, mimics the heavily armored, flightless Pachyrhynchus. To address mimicry in this system, we reconstructed the phylogeny of Doliops using a probe set consisting of 38,000 ultraconserved elements. Our study examines the following questions central to understanding the Pachyrhynchus-Doliops mimicry system: (1) to what extent are coevolutionary interactions conserved (i.e., lineage-constrained) and (2) are the codiversification patterns primarily driven by biotic or abiotic factors?4,5,6 To assess color mimicry and cospeciation, we examined the evolution of nanostructure-based warning colors and the effect of island biogeography on cospeciation. Our findings demonstrate the beetle's ability to repeatedly evolve multiple solutions to similar evolutionary challenges, evolving similar color patterns using different types of photonic crystals with varying degrees of order. We revealed that the observed pattern of cospeciation is driven mainly by abiotic factors from their biogeographic history. Unlike the patterns of coevolution seen between angiosperms and insect lineages,7 most ecological interactions do not persist longer than a few million years, leading to patterns of modularity rather than ecological nestedness.4,6,7.

Structural genomic variation and behavioral interactions underpin a balanced sexual mimicry polymorphism

How phenotypic diversity originates and persists within populations are classic puzzles in evolutionary biology. While balanced polymorphisms segregate within many species, it remains rare for both the genetic basis and the selective forces to be known, leading to an incomplete understanding of many classes of traits under balancing selection. Here, we uncover the genetic architecture of a balanced sexual mimicry polymorphism and identify behavioral mechanisms that may be involved in its maintenance in the swordtail fish Xiphophorus birchmanni. We find that ∼40% of X.birchmanni males develop a "false gravid spot," a melanic pigmentation pattern that mimics the "pregnancy spot" associated with sexual maturity in female live-bearing fish. Using genome-wide association mapping, we detect a single intergenic region associated with variation in the false gravid spot phenotype, which is upstream of kitlga, a melanophore patterning gene. By performing long-read sequencing within and across populations, we identify complex structural rearrangements between alternate alleles at this locus. The false gravid spot haplotype drives increased allele-specific expression of kitlga, which provides a mechanistic explanation for the increased melanophore abundance that causes the spot. By studying social interactions in the laboratory and in nature, we find that males with the false gravid spot experience less aggression; however, they also receive increased attention from other males and are disdained by females. These behavioral interactions may contribute to the maintenance of this phenotypic polymorphism in natural populations. We speculate that structural variants affecting gene regulation may be an underappreciated driver of balanced polymorphisms across diverse species.

A clinical case of multilocus imprinting disturbances: the first description in the Russian Federation

Multilocus imprinting disturbances (MLID) is a molecular subtype of imprinting disorders (IDs), in which multiple methylation abnormalities of imprinted regions and genes are observed in combination with polymorphic clinical manifestations, including overlapping phenotypic features of individual imprinting disorders. The causes of MLID are mutations in genes encoding oocyte and zygotic factors of embryo development, which increases the risk of recurrent birth of children with imprinting disorders in mothers carrying such mutations. Due to the need to understand the exact risk for repeated childbirth, it is advisable to diagnose MLID in patients with an ambiguous phenotype and a negative result of studies on individual imprinting disorders, followed by a search for mutations in MLID-associated genes. The purpose of the work is to describe the clinical and epigenetic characteristics of a patient with MLID. A clinical case of a comorbid patient aged 12 years with an established molecular genetic diagnosis of MLID by the method of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is presented. The features of the patient’s phenotype allow us to demonstrate the effect of hypomethylation of several differentially methylated regions of imprinted genes on the formation of a polymorphic phenotype, including overlapping signs of individual imprinting disorders, and to assess the difficulty of making an unambiguous clinical diagnosis for this patient. Pronounced clinical polymorphism, negative results of previously conducted molecular genetic studies on certain forms of imprinting disorders allow us to consider the MLID study as a first-line test for the diagnosis of methylation abnormalities in MLID and imprinting disorders.

Association between TIMP1 polymorphism and female neuromyelitis optica spectrum disorder in Chinese population

AimsEarlier studies have indicated an association between the TIMP1 polymorphism and the risk of certain autoimmune diseases, as well as a link between higher TIMP1 levels and blood-brain barrier (BBB) disruption in neuromyelitis optica spectrum disorders (NMOSD). This study aimed to explore the correlation between TIMP1 polymorphism and NMOSD phenotypes. MethodsGenotyping of three loci (rs4898, rs2070584, rs6609533) in the TIMP1 gene was performed in 126 NMOSD patients and 213 healthy controls (HCs) from North China using the SNaPshot sequencing technique, and a correlation analysis was done between phenotypes and TIMP1 genotype. ResultsThe frequency of the rs4898-T, rs2070584-T, and rs6609533-G alleles was significantly higher in NMOSD patients than those in HCs (p < 0.05). Accordingly, the rs4898-TT, rs2070584-TT, and rs6609533-GG genotypes were found at a higher frequency in patients than in controls (p < 0.05). Haplotype analysis showed TIMP1 T-T-G (rs4898-rs2070584-rs6609533) frequency was higher in female NMOSD patients (p = 0.019), and the frequency of T-T-G haplotypes in the BBB disrupted group was higher compared with that in the BBB normal group (p = 0.04). ConclusionsTIMP1 rs4898-T, rs2070584-T, and rs6609533 polymorphism may contribute to the susceptibility of Female NMOSD patients in the Chinese Population. TIMP1 T-T-G (rs4898-rs2070584-rs6609533) haplotype is more common among female NMOSD patients and is linked to heightened disruption of the BBB.

One Genome, Multiple Phenotypes: Would Rhodnius milesi Carcavallo, Rocha, Galvão &amp; Jurberg, 2001 (Hemiptera, Triatominae) Be a Valid Species or a Phenotypic Polymorphism of R. neglectus Lent, 1954?

Species of the Rhodnius genus have a complex taxonomy because the events of phenotypic plasticity and cryptic speciation make it difficult to correctly classify these vectors. During the taxonomic history of the genus, five synonymization events occurred. Additionally, some authors suggest that R. milesi possibly represent only phenotypic polymorphisms of R. neglectus. Thus, we analyzed the specific status of R. milesi in relation to R. neglectus using phylogenetic studies with the mitochondrial gene cytochrome B and the study of reproductive barriers. The phylogenetic reconstruction grouped R. milesi together with R. neglectus from different localities, demonstrating that these taxa represent the same species based on the phylogenetic species concept. Experimental crosses demonstrate the absence of pre- and postzygotic barriers under laboratory conditions. Additionally, when the hatch rates of crosses are compared to intraspecific crosses, it can be noted that they are high and very similar. Finally, the mortality rate of the hybrids does not indicate hybrid inviability, the absence of chromosome pairing errors does not indicate hybrid sterility, and the proportion between male and female hybrids demonstrates that Haldane’s rule was not acting. Therefore, we perform the formal synonymization of R. milesi with R. neglectus.

Plumage polymorphism in raptors

ABSTRACT Trait polymorphisms are a perennially popular topic of study in ecology and evolutionary biology. Plumage polymorphisms occur broadly in birds, with a particularly high rate among the raptors. The regularity of this heritable, melanin-based trait in raptors has prompted research into its potential connections to aspects of life history such as immune response, foraging ecology, and mating systems. Because raptors are a non-monophyletic grouping of multiple orders, they can further be leveraged to explore the eco-evolutionary drivers of recurrent plumage polymorphism phenotypes. Here we characterize plumage polymorphism throughout the raptors and review the existing literature on factors involved in its development and maintenance. We identify patterns and trends in this past body of research and discuss the opportunity to strengthen our understanding of plumage polymorphism through a holistic research approach. Specifically, we detail the likely benefits of applying genomic tools to plumage polymorphism research in raptors while encouraging both a focus on unstudied polymorphic species and on the potential interactions among multiple hypotheses that might promote plumage polymorphism.

Carry-over effects of seasonal migration on reproductive success through breeding site retention in a partially migratory bird.

Understanding the maintenance and dynamics of phenotypic polymorphisms requires unpicking key ecological mechanisms shaping the fitness costs and benefits of expressing alternative phenotypes, generating selection. Seasonal migration versus year-round residence expressed in partially migratory populations represents one common polymorphism that can experience strong selection through differential reproductive success. Yet, key hypothesised pathways that could generate such selection remain to be empirically tested. One hypothesis is that migratory tactics affect subsequent reproductive success through carry-over effects on breeding site retention and resulting breeding dispersal. By remaining in breeding areas all year round, residents could retain their preferred breeding site between years, and consequently have higher reproductive success. Conversely, migrants that escape harsh non-breeding season conditions could return in better condition, with high resource holding potential, and outcompete residents to retain their site. Such effects could further depend on migration timing and vary between years. Yet, such pathways have not been quantified, precluding empirical parameterisation of partial migration theory. We used 4 years of breeding and non-breeding season data from partially migratory European shags (Gulosus aristotelis) to test whether the three most frequent migratory tactics in this population (full resident, early migrant departing soon after breeding, and late migrant departing in late autumn) differed in their breeding site retention; whether site retention predicted reproductive success; and hence whether effects of migratory tactic on reproductive success were explicable through site retention. Overall, residents were much more likely to retain their breeding site between years than both early and late migrants, and site retention was associated with increased reproductive success. Yet, these effects varied somewhat among years: late migrants were always least likely to retain their site but had variable relative reproductive success. Path analyses revealed that effects of migratory tactic on reproductive success were only partly attributable to breeding site retention. These results indicate that multiple mechanisms underlie reproductive selection on migratory tactics, potentially contributing to maintaining behavioural polymorphisms. Yet, the clear associations between migratory tactics and local breeding dispersal reveal that these movements can be strongly interlinked across seasons, shaping overall spatioseasonal dynamics in partially migratory systems.

Population Pharmacokinetics of Sertraline in Psychiatric and Substance Use Disorders.

This study aimed to characterize the population pharmacokinetics of sertraline in Mexican patients with psychiatric and substance use disorders. Fifty-nine patients (13 to 76 years old) treated with doses of sertraline between 12.5 and 100 mg/day were included. Plasma sertraline concentrations were determined in blood samples and five of the main substances of abuse were determined by rapid tests in urine samples. Demographic, clinical, and pharmacogenetic factors were also evaluated. Population pharmacokinetic analysis was performed using NONMEM software with first-order conditional estimation method. A one-compartment model with proportional residual error adequately described the sertraline concentrations versus time. CYP2D6*2 polymorphism and CYP2C19 phenotypes significantly influenced sertraline clearance, which had a population mean value of 66 L/h in the final model. The absorption constant and volume of distribution were fixed at 0.855 1/h and 20.2 L/kg, respectively. The model explained 11.3% of the interindividual variability in sertraline clearance. The presence of the CYP2D6*2 polymorphism caused a 23.1% decrease in sertraline clearance, whereas patients with intermediate and poor phenotype of CYP2C19 showed 19.06% and 48.26% decreases in sertraline clearance, respectively. The model was internally validated by bootstrap and visual predictive check. Finally, stochastic simulations were performed to propose dosing regimens to achieve therapeutic levels that contribute to improving treatment response.

Absence of long-term balancing selection on variation in EuMYB3, an R2R3-MYB gene responsible for the anther-color polymorphism in Erythronium umbilicatum

Balancing selection has been shown to be common in plants for several different types of traits, such as self-incompatibility and heterostyly. Generally, for these traits balancing selection is generated by interactions among individuals or between individuals and other species (e.g., pathogens or pollinators). However, there are phenotypic polymorphisms in plants that do not obviously involve types of interactions that generate balancing selection. Little is known about the extent to which balancing selection also acts to preserve these polymorphisms. Here we ask whether balancing selection preserves an anther-color polymorphism in Erythronium umbilicatum (Liliaceae). We identified a major gene underlying this polymorphism. We then attempted to detect signatures of balancing selection on that gene by developing a new coalescence test for balancing selection. We found that variation in anther color is in large part caused by variation in a paralog of EuMYB3, an anthocyanin-regulating R2R3-MYB transcription factor. However, we found little evidence for balancing selection having acted historically on EuMYB3. Our results thus suggest that plant polymorphisms, especially those not involved in interactions that are likely to generate negative frequency-dependent selection, may reflect a transient state in which one morph will eventually be fixed by either genetic drift or directional selection. Our results also suggest that regulation of the anthocyanin pathway is more evolutionarily labile than is generally believed.

Ultrastructural features of tumor-associated mast cells in parasympathetic paragangliomas (chemodectomas) of the neck.

The mechanisms of the pathogenesis of neck paraganglioma (PGL) and the possible role of mast cells (MCs) in its development and metastasis are still poorly understood. We analyzed MCs' morphologic characterization, activation, and the properties of their cytoplasmic/released granules in PGLs, using light and transmission electron microscopy. Paragangliomas showed a large tumor-associated MC population both in the connective tissue layers of the tumor and between the tumor cells. Notably, MCs were presented by a high expression of specific proteases, size variation, polymorphism, and variable ultrastructural phenotype of granules. A massive number of granules were released surrounding the degranulated MCs while the integrity of MC membrane was maintained. Granules were electron-dense with or without a membrane, ranging from 0.2 to 0.8 μm in diameter. MC plasmalemma was not found at the site of MC-collagen fibrils contact, whereas the secretome and fibrils were directly contacted. We observed direct and mediator-based interactions between MCs and paraganglioma cells. The latter preserved their membrane integrity when MC granules were not in proximity. The effects of the MC secretome on the paraganglioma microenvironment demonstrated its pathogenetic role in tumor progression and allow its application to new diagnostic criteria and the development of protocols for personalized therapy. RESEARCH HIGHLIGHTS: Ultrastructural analysis reveals novel regulatory effects of mast cells via diverse secretory pathways on the pathogenesis of parasympathetic paraganglioma, including fibrous extracellular matrix remodeling and mediator-based interactions between MCs and cells of the tumor microenvironment.

Putative SNPs in Ovar-DRB1 and GALNTL6 Genes Conferring Susceptibility to Natural Infection of Haemonchus Contortus in Southern Indian Sheep.

To explore associations between phenotypic traits and polymorphisms in the DRB1 and GALNT6 gene in Nellore, Deccani and Kenguri sheep naturally infected with Haemonchus contortus. Blood and faecal samples were collected to evaluate fecal worm egg counts (FEC), packed cell volume (PCV), hemoglobin (Hb), eosinophilia and for DNA isolation. Animals were grouped into susceptible and resistant groups based on EPG counts. FEC and circulating eosinophilia were higher in a susceptible group. Log FEC was negatively correlated (P < 0.01) with PCV, and Hb estimates. The second exon of DRB1 and intron variant of GALNTL6 genes were amplified from DNA samples of resistant and susceptible sheep. Characterization of Ovar-DRB1 amplicon by RFLP revealed two genotypes ('bb' and 'ab'). The genotype frequencies differed significantly between both groups (P < 0.05). The 'bb' genotypes had higher (P < 0.05) log FEC value than 'ab' genotypes and 'b' allele was linked with susceptibility to haemonchosis in sheep. The mean FEC of Nellore sheep was high indicating susceptibility of the breed and also in which the frequency of 'b' allele was more compared to the other two breeds. OVAR-DRB1 genotypes associated with FEC did not affect PCV and Hb. PCR-RFLP assay developed to determine the genotypes with respect to SNP rs424521894 of GALNTL6 revealed monomorphic nature at the locus in the breeds studied. MHC polymorphism could be used as a genetic marker for the selection of sheep resistant to H. contortus. However, a more intensive study, involving controlled infections and other GALNTL6 SNPs may be enforced to make any decisive assertion.

Evaluation of genomic prediction considering non-additive genetic effects on fatty acid traits of Japanese Black cattle.

Genomic prediction was conducted using 2494 Japanese Black cattle from Hiroshima Prefecture and both single-nucleotide polymorphism information and phenotype data on monounsaturated fatty acid (MUFA) and oleic acid (C18:1) analyzed with gas chromatography. We compared the prediction accuracy for four models (A, additive genetic effects; AD, as for A with dominance genetic effects; ADR, as for AD with the runs of homozygosity (ROH) effects calculated by ROH-based relationship matrix; and ADF, as for AD with the ROH-based inbreeding coefficient of the linear regression). Bayesian methods were used to estimate variance components. The narrow-sense heritability estimates for MUFA and C18:1 were 0.52-0.53 and 0.57, respectively; the corresponding proportions of dominance genetic variance were 0.04-0.07 and 0.04-0.05, and the proportion of ROH variance was 0.02. The deviance information criterion values showed slight differences among the models, and the models provided similar prediction accuracy.

Epilepsy and MELAS syndrome: literature review and clinical observation

MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) belongs to the group of mitochondrial diseases. Most MELAS syndrome cases are associated with the A3243G mutation in the MTTL1 gene. A common clinical manifestation of the syndrome is presented by epileptic seizures (ES) characterized by phenotypic polymorphism and resistance to antiepileptic therapy. Diagnosis and treatment of epilepsy in patients with MELAS syndrome often poses difficulties. We present a clinical case of adult patient with MELAS syndrome with identified A3243G mutation and epilepsy. The disease course developed to severe cognitive impairment. The first focal ES occurred during stroke-like episode. Further seizures were observed spontaneously, with high frequency, often manifested as a series. Focal ES often had blurred polymorphic manifestations. The choice of drug therapy took into account the side effects of antiepileptic drugs (AEDs) including potentially mitochondria-related negative effects. While diagnosing EP in MELAS syndrome, it should be considered that seizures often occur during stroke-like episodes and may have blurred polymorphic clinical manifestations. Cognitive impairment in patients complicates ES detection. First-line drugs should be presented by AEDs with low mitochondrial toxicity.

Mercurial risk from dental amalgam use in a population of Moroccan dentists: A latent class regression approach.

Dentists using dental amalgam are chronically exposed to low doses of elemental mercury. The complex toxico-kinetics of this systemic toxicant results in polymorphic and variable clinical phenotypes. In this context, adapted statistical methods are required to highlight potential adverse effects of occupational mercury exposure on dentists' health. The present study aims to analyze the distribution of self-reported subjective symptoms, commonly associated with chronic mercury poisoning, according to occupational mercury exposure in a population of Moroccan liberal dentists. In order to achieve the defined objectives, a three-step latent class regression was fitted. First a latent class analysis was performed to cluster the studied population according to their declared symptoms. Dentists were then classified in the defined latent classes based on their posterior probabilities. Finally, a logistic regression is fitted to identify predictors associated with latent classes' membership. The final obtained model showed acceptable calibration and discrimination. Its interpretation revealed that the increase of the frequency of amalgam use was associated with significant higher odds of belonging to the high risk latent class. The present study represents an initial step towards the development of diagnosis model that predict clinical profiles according to occupational mercury exposure.

Nutrimetric Validation of Solanidine as Dietary-Derived CYP2D6 Activity Marker InVivo.

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4-OH-solanidine and 3,4-secosolanidine-3,4-dioic acid (SSDA) were determined using a sensitive liquid chromatography-mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra-individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α-OH-metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day.

Phenotypic polymorphism in MAPT associated frontotemporal dementia

Phenotypic polymorphism in MAPT associated frontotemporal dementia