Wide Phenotypic Variability Research Articles

CFTR complex alleles and phenotypic variability in cystic fibrosis disease.

Cystic fibrosis (CF) is inherited by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. A variety of mutations have been identified in the CFTR gene that may be associated with cystic fibrosis, and these mutations demonstrate extensive molecular genetic heterogeneity in this disease. Little is known about the molecular mechanism by which mutations affect CFTR function, and only a minority of mutations have been characterized by functional studies. There has been an increase in the number of complex alleles. This may partly explain the difficulty in establishing genotype-phenotype correlations and complicate genetic counseling and diagnosis in some cases. Therefore, the identification of complex alleles has several important implications for recessive disorders. This will facilitate diagnosis; improve judgements concerning prognosis, and enable appropriate genetic counselling for affected families. This review describes the complex cystic fibrosis allele to better understand the contribution of this allele in the wide phenotypic variability of cystic fibrosis disease. It occurs in the complex allele that the second cis mutation can modulate the effects of the first mutation or vice versa. The phenotypic variability between CF or CFTR-RD (CFTR related disease) patients may be due to several factors, including different genetic and environmental backgrounds. It is important to determine the allele complex so that optimal treatment can be established.

Phenotype and genotype features of isolated cystic kidney diseases with autosomal recessive type of inheritance in children

The relevance of the problem of hereditary cystic kidney diseases (cystosis) is due to the wide variability of the renal phenotype and the genotype that determines the prognosis, the progression to renal failure as early as in childhood. Purpose. To present the results of the analysis of the correlation of genotype and phenotype, renal function in isolated cystic kidney diseases with an autosomal recessive type of inheritance in children. Material and methods. in 14 children (from 13 families) aged 9 months — 17 years, the features of the clinical phenotype of kidney cysts with autosomal recessive type of inheritance and gene mutation were evaluated according to the results of a molecular genetic study. Results. In 3 (23 %) of 13 families, the family history is burdened by kidney cysts. The characteristic of gene mutation in cystic kidney diseases with autosomal recessive type of inheritance in 13 patients is presented (in 2 tables). Of the 21 identified variants in the genes PKHD1, INVS, NPHP1, TMEM67, 15 (71 %) had known pathogenic significance, 6 (29 %) had previously undescribed variants in data-bases. Variants of the PKHD1 gene were identified in 11 children with the phenotype of polycystic kidney disease with autosomal recessive type of inheritance and liver fibrosis. In the study, variant C.107C>T (Thr36Met) is the most common among children with identified variants of the PKHD1 gene in autosomal recessive polycystic kidney disease in 5 out of 21 (23.8 %), c.664A>G (Ile222Val) in 1 (4.8 %), c.6992T>A (Ile2331Lys) in 1 (4.8 %), c.10444C>T (Arg3482Cys) at 1 (4.8 %). Infantile (n=1) and juvenile (n = 2) nephronophthysis were confirmed in 3 children with homozygous and compound heterozygous pathogenic variants in the INVS, NPHP1, TMEM67 genes. Conclusion. The features of the genotype and phenotype are presented in 14 children with autosomal recessive type of inheritance of isolated kidney cysts in autosomal recessive polycystic kidney disease (n = 11) and nephronophthysis (n = 3), of whom chronic kidney disease was established in 13 children aged 2–17 years: in 4 (30.8 %) C1, in 4 (30.8 %) C2, in 3 (23 %) C3, in 1 (7.7 %) C4, in 1 (7.7 %) C5.

Optimisation de la prise en charge par l’activité physique des patients atteints d’un syndrome d’Ehlers-Danlos hypermobile

IntroductionHypermobile Ehlers-Danlos syndrome (hEDS) is a hereditary connective tissue disorder with a wide phenotypic variability. The aim of this thesis was to optimize the management by physical activity of hEDS patients. MethodsTo meet this objective, five studies were conducted. The first study (questionnaire with Delphi method) showed that pain, fatigue and sleep disorders, as well as musculoskeletal disorders, were among the most important symptoms to assess according to patients. ResultsTwo studies (retrospective and prospective) were conducted on the effects of a rehabilitation program, demonstrating the benefits of this form of care in many health areas. Finally, two studies on respiratory physiology showed ventilatory mechanical constraints during exercise and altered perception of lung volume and erratic ventilation when performing a cognitive task.

Joint GWAS and WGCNA Identify Genes Regulating the Isoflavone Content in Soybean Seeds.

Isoflavone is a secondary metabolite of the soybean phenylpropyl biosynthesis pathway with physiological activity and is beneficial to human health. In this study, the isoflavone content of 205 soybean germplasm resources from 3 locations in 2020 showed wide phenotypic variation. A joint genome-wide association study (GWAS) and weighted gene coexpression network analysis (WGCNA) identified 33 single-nucleotide polymorphisms and 11 key genes associated with soybean isoflavone content. Gene ontology enrichment analysis, gene coexpression, and haplotype analysis revealed natural variations in the Glyma.12G109800 (GmOMT7) gene and promoter region, with Hap1 being the elite haplotype. Transient overexpression and knockout of GmOMT7 increased and decreased the isoflavone content, respectively, in hairy roots. The combination of GWAS and WGCNA effectively revealed the genetic basis of soybean isoflavone and identified potential genes affecting isoflavone synthesis and accumulation in soybean, providing a valuable basis for the functional study of soybean isoflavone.

"If you cannot measure it, you cannot improve it". Outcome measures in Duchenne Muscular Dystrophy: current and future perspectives.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder primarily affecting males, caused by mutations in the dystrophin gene. The absence of dystrophin protein leads to progressive skeletal muscle degeneration. Recent advances in the therapeutic landscape underscore the need to identify appropriate outcome measures to assess treatment efficacy in ambulant and non-ambulant DMD patients, across clinical and research settings. This is essential for accurately evaluating new treatments and attributing therapeutic benefits.It is crucial to establish a robust correlation between outcome scores and disease progression patterns. This task is challenging since functional test performance may be influenced by different patient's characteristics, including the physiological evolution of the neurodevelopment together with the disease progression. While widely used DMD outcomes such as the North Star Ambulatory Assessment, the 6-Minute Walking Test, the 4 stairs climbed, and the Performance of the Upper Limb exhibit reliability and validity, their clinical significance is influenced by the wide phenotype and progression variability of the disease.We present and discuss the features (relevance, quantifiability, validity, objectivity, reliability, sensitivity, specificity, precision) of available DMD outcome measures, including new potential measures that may be provided by digital tools and artificial intelligence.

The natural history of dihydrolipoamide dehydrogenase deficiency in Israel.

Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in DLD were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six DLD variants were noted, the most common of which was the c.685G>T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A>T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations.

Altered expression of miR-17 and miR-148b in pediatric familial mediterranean fever patients.

Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder with wide phenotypic variation that has been observed among individuals who have the same genotype.Modifying genes, epigenetic factors, or environmental factors might all have an impact on genotype-phenotype correlation in FMF. The current research aims to determine the expression levels of microRNAs (miR-148b and miR-17) in Egyptian FMF participants. We also aimed to investigate Caspase -1 gene expression to make a correlation with disease severity. The study comprised 25 clinically diagnosed FMF cases and 25 healthy subjects matched for age and sex. The molecular diagnosis of FMFcases was assessed using real-time SNP genotyping assay. MiR-148b and miR-17 expression were profiled using TaqMan assay technology. The expression level of Caspase -1 gene was also verified using qRT-PCR. MiR-17 in the studied cases was significantly upregulated compared to healthy individuals (P = 0.006), whereas miR-148b was significantly downregulated in the examined patients (P = 0.030). Moreover, statistically significant upregulation of Caspase-1 expression was also elucidated in relation to normal subjects (P = 0.033). The results obtained indicated that miR-17 and miR-148b might be potential regulatory biomarkers in FMF cases. We further hypothesized that the upregulation of Caspase-1 could hint at its significance as a future therapeutic target to alleviate the inflammatory process in these patients. Key Points • The role of miRNAs in FMF and various mechanisms involved in FMF pathogenesis has received increasing attention. • Studying the expression profiles of miR-17 and miR-148b in FMF patients revealed their potential role as regulatory biomarkers in these patients. • Significant upregulation of Caspase-1 expression in FMF cases could hint at its significance as a future therapeutic target. • Future studies on larger cohorts are warranted to clarify and better understand the role of miRNAs in the pathogenesis and severity of FMF.

Exploring natural genetic diversity in a bread wheat multi-founder population: Dual imaging of photosynthesis and stomatal kinetics.

A better understanding of crop phenotype under dynamic environmental conditions will help inform the development of new cultivars with superior adaptation to constantly changing field conditions. Recent research has shown that optimising photosynthetic and stomatal conductance traits holds promise for improved crop performance. However, standard phenotyping tools such as gas-exchange systems are limited by their throughput. In this work, a novel approach based on a bespoke gas-exchange chamber allowing combined measurement of the quantum yield of photosystem II (PSII) with an estimation of stomatal conductance via thermal imaging, was used to phenotype a range of bread wheat (Triticum aestivum L.) genotypes, that were a sub-set of a multi-founder experimental population. Datasets were further supplemented by measurement of photosynthetic capacity and stomatal density. First, we showed that measurement of stomatal traits using our dual imaging system compared to standard IRGA methods showed good agreement between the two methods (R2=0.86) for the rapidity of stomatal opening (Ki), with the dual-imager method resulting in less intra-genotype variation. Using the dual-imaging methods, and traditional approaches we found broad and significant variation in key traits, including photosynthetic CO2 uptake at saturating light and ambient CO2 concentration (Asat), photosynthetic CO2 uptake at saturating light and elevated CO2 concentration (Amax), the maximum velocity of Rubisco for carboxylation (Vcmax), time for stomatal opening (Ki), and leaf evaporative cooling. Anatomical analysis revealed significant variation in flag leaf adaxial stomatal density. Associations between traits highlighted significant relationships between leaf evaporative cooling, leaf stomatal conductance under low (gsmin) and high (gsmax) light intensity, and the operating efficiency of PSII (Fq'/Fm'), highlighting the importance of stomatal conductance and stomatal rapidity in maintaining optimal leaf temperature for photosynthesis in wheat. Additionally, gsmin and gsmax were positively associated, indicating that potential combination of preferable traits (i.e. inherently high gsmax, low Ki and maintained leaf evaporative cooling) are present in wheat. This work highlights for the first time the effectiveness of thermal imaging in screening dynamic stomatal conductance in a large panel of wheat genotypes. The wide phenotypic variation observed suggested the presence of exploitable genetic variability in bread wheat for dynamic stomatal conductance traits and photosynthetic capacity for targeted optimisation within future breeding programs.

Fruit sugar and organic acid composition and inheritance analysis in an intraspecific cross of Chinese cherry

Chinese cherry is an economically significant fruiting cherry species within Rosaceae family. Soluble sugar and organic acid are crucial factors affecting fruit flavor, while the genetic basis for these traits in Chinese cherry remains largely unknown. In this study, we determined sugar and acid components in 190 and 187 representative hybrids from an intraspecific cross of Chinese cherry over two consecutive years. Fructose and glucose were the major sugars in both progeny and parents, but their contents varied considerably between years. Fructose represented a higher proportion in progeny than in parents. Malic acid was the most predominant component, accounting for a relatively stable proportion (∼70%) for both years. The F1 population exhibited wide phenotypic variations, with coefficient of variation ranging from 6.57% to 108.63%. Regarding inheritance patterns, sugars tended towards smaller values, while malic acid exhibited significant transgressive heterosis. Sugars and acids were primarily governed by 2 MG-AD or 2 MG-EA model. Major gene heritability exceeded 88% for acids but much lower (12%–75%) for sugars. These results suggest that acid contents might be controlled by two major genes, while sugars are mainly governed by polygenes. This study provides a theoretic basis for understanding genetic predisposition underlying sugar-acid fractions in Chinese cherry fruit.

Cystic Fibrosis Lung Disease: A Narrative Literature Review

Cystic fibrosis (CF) is caused by mutations in autosomal recessive genes that code for proteins cystic fibrosis transmembrane conductance regulator (CFTR) which is located on chromosome seven. The CFTR protein under normal conditions acts as a chloride channel and helps the movement of sufficient electrolytes and water across the membrane. Mutations in CFTR cause abnormalities in chloride ion transport through epithelial cells and impaired sodium and water transport resulting in viscous secretions with low water content. This thick and sticky secretion will inhibit the normal function of various organs, although pulmonary complications are the most common cause of death. Cystic fibrosis has wide genotypic and phenotypic variations. There are six categories of mutations based on their effect on the CFTR protein, where these categories are not only used to predict the phenotype but also to determine better therapeutic strategies based on the identified mutations.

Experience with the use of risdiplam in a familial case of spinal muscular atrophy 5q in patients with a homozygous deletion of the SMN1 gene and the same copy number of the SMN2 gene

Advances in the treatment of spinal muscular atrophy (SMA) have revolutionized the field. SMA is a rare autosomal recessive neurodegenerative motor neuron disease in which wide phenotypic variability has been described. The rate of increase in neurological deficit and the severity of the disease is mainly determined by the amount of functional SMN (Survival of Motor Neuron) protein. However, the clinical picture may differ significantly in patients carrying homozygous deletions of the SMN1 gene (Survival of Motor Neuron 1) and an identical number of copies of the SMN2 gene (Survival of Motor Neuron 2). A family clinical case of adult patients with spinal muscular atrophy 5q with a homozygous deletion of the SMN1 gene and the same number of copies of the SMN2 gene, having a different clinical picture of the disease, is presented, and the dynamics of the condition against the background of oral pathogenetic therapy is presented.

Retrospective Analysis of Canadian Adults with Tuberous Sclerosis Complex.

Our study goal was to characterize the relative frequencies of molecular and phenotypic traits of tuberous sclerosis complex (TSC) in a Canadian adult population. Previous studies have sought to identify TSC-related genotypic and phenotypic trends in pediatric cohorts, but little is known about clinical manifestations and severity when it presents in adults. We conducted a retrospective chart review of adult patients seen at the TSC clinic at the University Health Network genetics clinics (Toronto, Ontario) to compare trends in the relative frequency of TSC manifestations with genotype. Fifty-one patients were eligible for this study. Eight patients had a pathogenic/likely pathogenic variant in the tuberous sclerosis complex 1 (TSC1) gene, 18 had a tuberous sclerosis complex 2 (TSC2) pathogenic/likely pathogenic variant, 6 patients had multiple variants identified in TSC1/TSC2 or TSC2/PKD1, 11 had no mutation identified (NMI) and 8 had no genetic testing done. Patients with a pathogenic/likely pathogenic variant in TSC2 presented with an increased involvement of multiple systems and a higher frequency of TSC-related manifestations relative to the other mutation groups. Previous studies comparing the wide phenotypic variability with TSC genotype have mainly comprised pediatric cohorts. With a focus on adults, we found trends to be similar across previous literature. An informed multidisciplinary approach should be taken to ensure proper surveillance and management of adults with TSC until a correlation between genotype and phenotype, especially past infancy, is better understood.

EPRS1-related disorder: A genotype-phenotype correlation study reveals distinct neurological disease types and wide phenotypic variability

EPRS1-related disorder: A genotype-phenotype correlation study reveals distinct neurological disease types and wide phenotypic variability

A Review of Oral Fixed-Dose Sodium Phenylbutyrate and Ursodoxicoltaurine in People with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is estimated to affect approximately 300,000 individuals worldwide. From symptom onset, the disease has rapid progression, and typically leads to death in approximately 3 years, though there is wide phenotypic variability. ALS pathophysiology is probably driven by several cellular and molecular mechanisms, including endoplasmic reticulum (ER) dysfunction, apoptosis, oxidative stress, impaired intracellular transport, neuroinflammation, and defective RNA metabolism and protein homeostasis. Several agents that target these pathways are in development, and a few are approved in certain regions. A fixed-dose combination of sodium phenylbutyrate and ursodoxicoltaurine (PB and TURSO, also known as AMX0035) was developed to target ER stress and mitochondrial dysfunction. This combination was approved for the treatment of ALS in the USA and Canada in 2022, following findings from the CENTAUR trial. CENTAUR was a Phase II trial comprising a 24-week randomised placebo-controlled phase and an open-label extension (OLE) phase. Treatment with PB and TURSO significantly slowed the rate of functional decline over 24 weeks compared with placebo, meeting the primary endpoint of the study. Over long-term follow-up, median survival duration was about 4.8 months longer in the group originally randomised to PB and TURSO, compared with the group originally randomised to placebo. PHOENIX, a Phase III trial of PB and TURSO planned to be completed in 2024, includes a 48-week randomised controlled phase, followed by an OLE. The PHOENIX trial is expected to provide additional insights regarding the effects of PB and TURSO in ALS.

DIVERSIDAD MORFOLÓGICA DE Ardisia compressa Kunth, DEL NORESTE DE CHIAPAS, MÉXICO

<p><strong>Background</strong>. <em>Ardisia compressa </em>Kunth, is a wild species native from tropical evergreen forests of Mexico, it produces fruits with phytochemical, ecological and dietary potencial. Its fruits are appreciated by people from local communities. However, in Mexico there are no studies that allow knowing the state of its phenotypic diversity. <strong>Objective.</strong> Characterize the morphological diversity of <em>A. compressa</em> populations from Chiapas state, Mexico. <strong>Methodology</strong>. Ninety individuals of nine wild populations of <em>A. compressa </em>were evaluated using 45 morphological traits (16 qualitative and 29 quantitative). The qualitative data were subjected to descriptive analysis and quantitative data were used in an analysis of variance (ANOVA) and finally the qualitative and quantitative data were analyzed simultaneously by means of a multivariate analysis with the Ward-MLM Method. <strong>Results. </strong>The qualitative traits showed phenotypic variability in the characteristics of leaf and fruit color. The quantitative data showed significant differences (<em>P</em>≤ 0.05) in all traits evaluated. The results of the principal component analysis (PCA) and cluster analysis (UPGMA) grouped the populations into three morphological groups differentiated by the similarity of the morphological traits of the populations and not by their geographical origin. <strong>Implications.</strong> The results in this study should be considered to implementing strategies of plant production and conservation of <em>A. compressa</em>. <strong>Conclusion. </strong>A wide phenotypic variability was found organized into three morphological groups defined base on characteristics of tree height, number of fruits, number of flowers and ratio of length to thickness leaf. The quantitative traits allowed us to observe the greatest morphological variability in the populations of <em>A. compressa</em>. </p>

SALINITY TOLERANCE OF QUINOA (CHENOPODIUM QUINOA WILLD.) GENOTYPES TO ELEVATED NACL CONCENTRATIONS AT GERMINATION AND SEEDLING STAGES

Evaluating quinoa genotypes for salinity tolerance at germination and seedling stages is a prerequisite for plant breeders. Thus, the scrutiny of 19 quinoa genotypes at different salinity levels under controlled laboratory and greenhouse conditions occurred at the germination and seedling stages. This study aimed to identify the most tolerant genotypes to elevated salinity levels at germination and seedling stages and to determine the traits of a robust association with salinity tolerance using a factorial experiment based on a randomized complete block design in three replications. The four salinity solutions used were zero (control), 3000, 6000, and 9000 ppm NaCl. Increasing concentrations of NaCl caused a gradual and significant decrease for all studied traits except mean germination time, which significantly increased. At all salinity-stress levels (3000, 6000, and 9000 ppm NaCl), the studied 19 genotypes underwent classification based on their salinity tolerance index (STI) into three categories, i.e., tolerant, moderately tolerant, and sensitive. The four most salinitytolerant quinoa genotypes under all studied salinity-stress conditions were Rainbow-2, Ql3, RH, and KvlSRA2. The strongest correlations were between STI and each of seedling length, root length, seedling fresh weight, seedling vigor index I, and seedling vigor index II under 3000 ppm; germination percentage, speed germination index, seedling extent, root length, seedling fresh weight, and seedling vigor index II under 6000 ppm; and shoot length and seedling vigor index I under 9000 ppm salinity concentration level. Traits showing sturdy correlations with STI, high heritability estimates, high expected genetic advance, and wide phenotypic and genotypic variability were seedling dry weight, seedling fresh weight, seedling vigor index II, and speed germination index at all salinity stress concentrations; they are recommendable as selection criteria for salinity tolerance in quinoa at germination and seedling stages.

THU184 Varying Presentations Of 46XX OTD

Abstract Disclosure: I. Mishra: None. S.K. Sahoo: None. A.K. Baliarsinha: None. Ovotesticular disorder of sex development (OT-DSD) is a condition associated with presence of both testicular and ovarian tissue in same individual, in which these tissues may co-exist either in the same gonad or independently. 46 XXOTD are most common. We describe 3 cases of 46 XXOTD presenting in their post pubertal years with varied presentation. Case 1: 19 year old reared as male presented with peripubertal gynaecomastia and cyclical pain abdomen. On examination there was symmetrical genitalia, non palpable gonads, microphallus, single genital opening below phallus (Prader 3), pubic hair stage 4, axillary hair stage 3 and breast stage 5. Biochemical evaluation revealed serum testosterone (19 ng/dl), 17-hydroxy progesterone (1.7ng/ml), LH (2.6IU/L), FSH (8.6IU/L) and E2(112pg/ml). Karyotype 46XX, FISH SRY negative. USG abdomen s/o uterus like structure with absent wollfian remnants. Post laproscopy histopathology s/o bilateral ovotestis, normal ovarian stroma with hyalinized seminiferous tubule, sertoli cells and leydig cells. Case 2: 18 year old reared as male presented with peripubertal gynaecomastia and genital ambiguity. On examination there was asymmetrical genitalia, palpable right scrotal gonads, phallus, single genital opening at base of phallus, pubic hair stage 4, axillary hair stage 3 and breast stage 5. Biochemical evaluation revealed serum testosterone (110ng/dl), LH (4.6IU/L), FSH (11.2IU/L) and E2(46pg/ml). Karyotype 46XX.USG abdomen s/o hypoplastic uterus like structure with possible ovary in left side of pelvis, hypoplastic testis in right scrotal sac. Post laproscopy histopathology was s/o left dysgenetic ovary, and hypoplastic uterus. Case 3: 17 year old reared as male presented with peripubertal gynaecomastia. On examination there was symmetrical genitalia, non palpable gonads, microphallus, single genital opening at the base of phallus (Prader 4), pubic hair stage 4, axillary hair stage 2 and breast stage 4. Biochemical evaluation revealed serum testosterone (98ng/dl), 17-hydroxyprogesterone (0.58ng/ml), LH (4.05IU/L), FSH (7.12IU/L) and E2 (96 pg/ml). Karyotype 46XX, FISH SRY positive. USG abdomen s/o uterus like structure with apparent left ovary and non visualization of right gonads. Post laproscopy histopathology s/o rudimentary uterus, left ovary with follicles and right gonads showing semineferous tubules with sertoli cells and few hyperplastic leydig cells. 46 XX OTDSD presents with wide phenotypic variability, which influences decisions about gender assignment and need of surgery. Conservative therapy, whenever feasible, is desirable to achieve fertility. Multidisciplinary team approach is required for healthy physical and psychological well-beings of these individuals. Presentation: Thursday, June 15, 2023

Low prepulse inhibition predicts lower social interaction, impaired spatial working memory, reference memory and cognitive flexibility in genetically heterogeneous rats

The “Genetically Heterogeneous National Institutes of Health (NIHHS)” stock rat (hereafter HS) shows a wide phenotypic variation, as a result of having been derived from eight inbred rat strains. Thus, these rats may be a conceivable parallel model of a healthy human sample. In order to evaluate whether HS rats have face validity as an animal model of schizophrenia-relevant features, it should be demonstrated that they present behavioural traits that may model negative and cognitive symptoms of the disorder. Previous studies on HS rats have shown that prepulse inhibition (PPI, a measure of sensorimotor gating processes), which is impaired in schizophrenic patients, is correlated with their working memory performance. In this study, we evaluated whether low PPI in the HS stock rat predicts impairments of spatial working memory (SWM), spatial reference memory and cognitive flexibility in the Morris water maze (MWM) test, and we evaluated HS rats for social interaction (SI) in a social investigation task. HS rats were stratified into 2 different groups according to their PPI scores, i.e. low- and high-PPI. In the SI task, low-PPI rats showed decreased social behaviour compared to high-PPI rats. In addition, relative to high-PPI HS rats, the low-PPI group displayed poorer SWM performance, impaired cognitive flexibility (in a reversal task) and worsened long-term spatial memory. Such differential behaviours in social and cognitive paradigms provide evidence on the face validity of low-PPI HS rats as a model of negative-like and cognitive schizophrenia-relevant traits.

Structured Framework for Multidisciplinary Parent Counseling and Medical Interventions for Fetuses and Infants with Trisomy 13 or Trisomy 18.

Trisomy 13 (T13) and 18 (T18) are aneuploidies associated with multiple structural congenital anomalies and high rates of fetal demise and neonatal mortality. Historically, patients with either one of these diagnoses have been treated similarly with exclusive comfort care rather than invasive interventions or intensive care, despite a wide phenotypic variation and substantial variations in survival length. However, surgical interventions have been on the rise in this population in recent years without clearly elucidated selection criterion. Our objective was to create a standardized approach to counseling expectant persons and parents of newborns with T13/T18 in order to provide collaborative and consistent counseling and thoughtful approach to interventions such as surgery. This article describes our process and presents our resulting clinical care guideline. We formed a multi- and interdisciplinary committee. We used published literature when available and otherwise expert opinion to develop an approach to care featuring individualized assessment of the patient to estimate qualitative mortality risk and potential to benefit from intensive care and/or surgeries centered within an ethical framework. Through multidisciplinary collaboration, we successfully created a patient-centered approach for counseling families facing a diagnosis of T13/T18. Other institutions may use our approach as a model for developing their own standardized approach. · Trisomy 13 and trisomy 18 are associated with high but variable morbidity and mortality.. · Research on which patients are most likely to benefit from surgery is lacking.. · We present our institution's framework to counsel families with fetal/neonatal T13/T18..

Plasma Metabolites Associated with OCT Features of Age-Related Macular Degeneration

The most widely used classifications of age-related macular degeneration (AMD) and its severity stages still rely on color fundus photographs (CFPs). However, AMD has a wide phenotypic variability that remains poorly understood and is better characterized by OCT. We and others have shown that patients with AMD have a distinct plasma metabolomic profile compared with controls. However, all studies to date have been performed solely based on CFP classifications. This study aimed to assess if plasma metabolomic profiles are associated with OCT features commonly seen in AMD. Prospectively designed, cross-sectional study. Subjects with a diagnosis of AMD and a control group (> 50 years old) from Boston, United States, and Coimbra, Portugal. All participants were imaged with CFP, used for AMD staging (Age-Related Eye Disease Study 2 classification scheme), and with spectral domain OCT (Spectralis, Heidelberg). OCT images were graded by 2 independent graders for the presence of characteristic AMD features, according to a predefined protocol. Fasting blood samples were collected for metabolomic profiling (using nontargeted high-resolution mass spectrometry by Metabolon Inc). Analyses were conducted using logistic regression models including the worst eye of each patient (AREDS2 classification) and adjusting for confounding factors. Each cohort (United States and Portugal) was analyzed separately and then results were combined by meta-analyses. False discovery rate (FDR) was used to account for multiple comparisons. Plasma metabolite levels associated with OCT features. We included data on 468 patients, 374 with AMD and 94 controls, and on 725 named endogenous metabolites. Meta-analysis identified significant associations (FDR < 0.05) between plasma metabolites and 3 OCT features: hyperreflective foci (6), atrophy (6), and ellipsoid zone disruption (3). Most associations were seen with amino acids, and all but 1 metabolite presented specific associations with the OCT features assessed. To our knowledge, we show for the first time that plasma metabolites have associations with specific OCT features seen in AMD. Our results support that the wide spectrum of presentations of AMD likely include different pathophysiologic mechanisms by identifying specific pathways associated with each OCT feature. Proprietary or commercial disclosure may be found after the references.