Low Frequency In Population Research Articles

Immunohistochemical Investigation of P16 Expression in Curettage Biopsies

Our study aims to investigate the immunohistochemical expression of the P16 molecule, which is involved in the cell cycle and plays a role in developing endometrial cancer in normal epithelium, endometrial polyp, and precursor lesions. A total of 68 patients underwent endometrial sampling for various reasons at the Department of Obstetrics and Gynecology, Faculty of Medicine, Kafkas University, between 2020 and 2021 were included in the study. The selected cases were categorized into four groups: proliferative endometrium, endometrial hyperplasia without atypia, atypical hyperplasia / endometrioid intraepithelial neoplasia (AH / EIN) and endometrial polyp. There were no cases with a diagnosis of endometrial tumors in our study. All patients’ pathology samples were re-evaluated, and P16 immunohistochemistry was applied to tissue samples. Among patients diagnosed with atypical endometrial hyperplasia, 72.7% exhibited moderate P16 protein expression, 18.2% had low expression, and 9.1% had high protein expression. The number of patients diagnosed with AH / EIN had a very low frequency in the study population. Among patients diagnosed with endometrial polyps, 50.0% showed moderate P16 protein expression, 20.0% exhibited low protein expression, and 30.0% had high protein expression. High P16 expression has been reported to be significantly associated with endometrial cancer in the literature. P16 expression is significant in precancerous lesions and stages of cancer development. Larger-scale studies with more cases are needed in this regard.

Pathogenic relationship between phenotypes of ARPKD and novel compound heterozygous mutations of PKHD1.

To investigate whether the novel mutation of PKHD1 could cause polycystic kidney disease by affecting splicing with a recessive inheritance pattern. A nonconsanguineous Chinese couple with two recurrent pregnancies showed fetal enlarged echogenic polycystic kidney and oligoamnios were recruited. Pedigree WES, minigene splicing assay experiment and following bioinformatics analysis were performed to verify the effects, and inheritance pattern of diseasing-causing mutations. WES revealed that both fetuses were identified as carrying the same novel mutation c.3592_3628 + 45del, p.? and c.11207T>C, p.(Ile3736Thr) in the PKHD1 gene (NM_138694.4), which inherited from the father and mother respectively. Both bioinformatic method prediction and minigene splicing assay experience results supported the mutation c.3592_3628 + 45del, p.? affects the splicing of the PKHD1 transcript, resulting in exon 31 skipping. Another missense mutation c.11207T>C, p.(Ile3736Thr) has a low frequency in populations and is predicted to be deleterious by bioinformatic methods. These findings provide a direct clinical and functional evidence that the truncating mutations of the PKHD1 gene could lead to more severe phenotypes, and cause ARPKD as a homozygous or compound heterozygous pattern. Our study broadens the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and diagnosis of ARPKD.

Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI. To understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature. Mutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.

Immunohistochemical Investigation of P16 Expression in Curettage Biopsies

Objective: Our study aims to investigate the immunohistochemical expression of the P16 molecule, which is involved in the cell cycle and plays a role in developing endometrial cancer. Materials and Method: A total of 68 patients who underwent endometrial sampling for various reasons at the Department of Obstetrics and Gynecology, Faculty of Medicine, Kafkas University, between 2020 and 2021 were included in the study. The selected cases were categorized into four groups: proliferative endometrium, simple non-atypical endometrium, atypical endometrial hyperplasia, and endometrial polyp. There were no cases with a diagnosis of endometrial tumors in our study. All patients' pathology samples were re-evaluated, and P16 immunohistochemistry was applied to tissue samples. Results: Among patients diagnosed with atypical endometrial hyperplasia, 72.7% exhibited moderate P16 protein expression, 18.2% had low expression, and 9.1% had high protein expression. The number of patients diagnosed with atypical endometrial hyperplasia had a very low frequency in the study population. Among patients diagnosed with endometrial polyps, 50.0% showed moderate P16 protein expression, 20.0% exhibited low protein expression, and 30.0% had high protein expression. Conclusion: High P16 expression has been reported to be significantly associated with endometrial cancer in the literature. P16 expression is significant in precancerous lesions and stages of cancer development. Larger-scale studies with more cases are needed in this regard.

Clinical and genetic analysis of a patient with HUPRA syndrome due to missense variants of SARS2 gene and literature review

Objective: To explore the clinical manifestations and genotype of an infant with hyperuricemia, pulmonary hypertension, renal failure in infancy, and alkalosis syndrome (HUPRAS). Methods: Clinical data of the patient were collected. Peripheral blood samples from the patient and his parents were acquainted for whole exome sequencing. The filtrated variants were verified by Sanger sequencing. The pathogenicity of the variants was predicted by bioinformatic tools. Results: The patient is a male infant of 6 months old, carrying two missense variants in the SARS2 allele: a paternal inherited c.1205G>A (p. Arg402His) and a maternal inherited c.680G>A (p. Arg227Gln). The two variants were in extremely low population frequencies. The pathogenetic prediction tools categorized them as deleterious. Arg402 and Arg227 were highly conserved in evolution. The variants led to changes in the hydrogen bonds and hydrophobicity of seryl-tRNA synthetase encoded by SARS2. Conclusions: c.1205G>A (p. Arg402His) and c.680G>A (p. Arg227Gln) are the possible causative variants of the HUPRA syndrome.

Characterization of T-/natural killer cell lymphoproliferative neoplasms associated with systemic, chronic, active Epstein-Barr virus in adults: A report of 5 cases in a Western population.

Because of its low frequency in adult populations and clinical and laboratory overlap with hemophagocytic lymphohistiocytosis and other T-cell lymphomas, T-cell/natural killer (NK) cell systemic, chronic, active Epstein-Barr virus (EBV) (T/NK sCAEBV) infection remains underdiagnosed, preventing critical, prompt therapeutic interventions. We report a 5-case series that included 2 adult patients with T/NK sCAEBV and 3 additional adult patients with T/NK lymphomas with concomitant systemic EBV infection to review these entities' overlapping diagnostic and clinical features. Approximately 95% of the world population has been infected with EBV during their lifetime, and infection is usually asymptomatic, with symptomatic cases eventually resolving spontaneously. A small subset of immunocompetent patients develops CAEBV, a life-threatening complication resulting from EBV-infected T-cell or NK cell neoplastic lymphocytes. The sites of end-organ damage in T/NK sCAEBV demonstrate pathologic findings such as reactive lymphoid proliferations, making the diagnosis difficult to establish, with the only curative option being an allogeneic hematopoietic stem cell transplant. This diagnosis is most prevalent in Asia, with few cases reported in Western countries. Adult age is an independent risk factor for poor outcomes, and most cases are diagnosed in pediatric populations.

Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population.

Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a hematologic cancer, using unbiased recruitment from the full state population. We identified pathogenic/likely pathogenic (P/ LP) variants among 1,172 selected cancer genes that were private or present at low allele frequencies in reference populations. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In 8 of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sibling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lymphoma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demonstrating the value of this discovery process in diverse, population-based registries.

CCDC88C variants are associated with focal epilepsy and genotype-phenotype correlation.

CCDC88C gene, which encodes coiled-coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole-exome sequencing (trio-based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in thegnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult-onset epilepsy, whereas patients with biallelic variants displayed infant-onset epilepsy. They all responded well to anti-seizure medications and were seizure-free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non-classical splicing and a variant located at crucial domain, suggesting a sub-molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy-associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus-associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.

No Association between SARS-CoV-2 Infection and the Polymorphism of the Toll-like Receptor 7 (TLR7) Gene in Female Population

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus. Toll-like receptor 7 (TLR7) recognizes single-stranded RNA viruses. The TLR7 gene plays a critical role in the human innate and adaptive immune response to SARS-CoV-2 infections. Genetic factors probably affect SARS-CoV-2 infection susceptibility. In the current study, our aim was to search for genetic variations associated with COVID-19 patients in the TLR7 gene of a Korean population. We designed five gene-specific primers to cover the coding region of the human TLR7 gene. Using amplicon sequencing, we screened the genetic polymorphisms in the coding region of the TLR7 gene in COVID-19 patients and healthy controls. The genotype frequencies, allele frequencies, and Hardy–Weinberg equilibrium (HWE) were examined. We identified a low-frequency synonymous single nucleotide polymorphism (SNP) (rs864058) in the coding region of the TLR7 gene. There were no significant differences in the genotype or allele frequencies of the TLR7 rs864058 polymorphism between COVID-19 female patients and healthy controls (p = 1.0). In conclusion, TLR7 (rs864058) polymorphism is low frequency in Korean populations and is not associated with SARS-CoV-2 infection.

Novel genetic variant associated with globoid cell leukodystrophy in a family of mixed breed dogs.

Globoid cell leukodystrophy (GCL) is a fatal autosomal recessive disease caused by variants in the galactosylceramidase (GALC) gene. Two dog breed-specific variants are reported. Characterize the putatively causative GALC variant for GCL in a family of dogs and determine population allele frequency. Four related mixed-breed puppies with signs of neurologic disease were evaluated. Subsequently, 33 related dogs were tested for genetic markers for parentage and the identified GALC variant. Additional GALC genotyping was performed on 278 banked samples from various breeds. The 4 affected puppies had neurological exams and necropsies. DNA was isolated from blood samples. Variants in GALC were identified via Sanger sequencing. Parentage testing was performed using short tandem repeat markers. Prevalence of the GALC variant of interest was investigated in other breeds. GCL was confirmed histopathologically. A novel missense variant in GALC (NC_006590.4:g.58893972G>A) was homozygous in all affected animals (n = 4). A recessive mode of inheritance was confirmed by parentage testing as was variant linkage with the phenotype (LOD = 3.36). Among the related dogs (n = 33), 3 dogs were homozygous and 7 heterozygous. The variant allele was not detected in screening 278 dogs from 5 breeds. The novel variant is either unique to this family or has an extremely low allele frequency in the general population. A novel GALC variant was identified that likely explains GCL in this cohort. The identification of multiple causal variants for GCL in dogs is consistent with findings in humans.

Clinical and genetic analysis of a very early-onset inflammatory bowel disease type 28 child with atypical clinical manifestation

To explore the clinical and genetic characteristics of a very early-onset inflammatory bowel disease (VEO-IBD) type 28 child with atypical clinical manifestations. A VEO-IBD type 28 child with atypical clinical manifestations admitted to the Department of Neonatology, Children's Hospital Affiliated to Shandong University on November 5, 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral venous blood samples of the child and his parents were collected for high-throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. The child, a 50-day-old male, had manifested bronchitis, ulcerative stomatitis, eczema and slightly loose stool. High-throughput sequencing revealed that he has harbored compound heterozygous variants of the IL-10RA gene, namely c.299T>G (p.V100G) and c.301C>T (p.R101W), which were inherited from his father and mother, respectively. Bioinformatic analysis showed that both variants have been recorded in the HGMD database, though the c.299T>G variant has not been included in the gnomAD, 1000 Genomes, ExAC and ESP6500 databases, while the c.301C>T variant has a low population frequency. Both variants were predicted to be deleterious by the online software including SIFT, PolyPhen-2 and Mutation Taster. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PS3+PM2_Supporting+PP3). The c.299T>G and c.301C>T variants of the IL-10RA gene probably underlay the VEO-IBD type 28 in this child. Above finding has expanded the phenotypic spectrum of VEO-IBD type 28 due to variants of the IL-10RA gene and provided a reference for the clinical diagnosis of this disease.

Performance of SNP barcodes to determine genetic diversity and population structure of Plasmodium falciparum in Africa.

Panels of informative biallelic single nucleotide polymorphisms (SNPs) have been proposed to be an economical method to fast-track the population genetic analysis of Plasmodium falciparum in malaria-endemic areas. Whilst used successfully in low-transmission areas where infections are monoclonal and highly related, we present the first study to evaluate the performance of these 24- and 96-SNP molecular barcodes in African countries, characterised by moderate-to-high transmission, where multiclonal infections are prevalent. For SNP barcodes it is generally recommended that the SNPs chosen i) are biallelic, ii) have a minor allele frequency greater than 0.10, and iii) are independently segregating, to minimise bias in the analysis of genetic diversity and population structure. Further, to be standardised and used in many population genetic studies, these barcodes should maintain characteristics i) to iii) across various iv) geographies and v) time points. Using haplotypes generated from the MalariaGEN P. falciparum Community Project version six database, we investigated the ability of these two barcodes to fulfil these criteria in moderate-to-high transmission African populations in 25 sites across 10 countries. Predominantly clinical infections were analysed, with 52.3% found to be multiclonal, generating high proportions of mixed-allele calls (MACs) per isolate thereby impeding haplotype construction. Of the 24- and 96-SNPs, loci were removed if they were not biallelic and had low minor allele frequencies in all study populations, resulting in 20- and 75-SNP barcodes respectively for downstream population genetics analysis. Both SNP barcodes had low expected heterozygosity estimates in these African settings and consequently biased analyses of similarity. Both minor and major allele frequencies were temporally unstable. These SNP barcodes were also shown to identify weak genetic differentiation across large geographic distances based on Mantel Test and DAPC. These results demonstrate that these SNP barcodes are vulnerable to ascertainment bias and as such cannot be used as a standardised approach for malaria surveillance in moderate-to-high transmission areas in Africa, where the greatest genomic diversity of P. falciparum exists at local, regional and country levels.

An ABCC9 Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs.

Sudden cardiac death in the young (SCDY) is a devastating event that often has an underlying genetic basis. Manchester Terrier dogs offer a naturally occurring model of SCDY, with sudden death of puppies as the manifestation of an inherited dilated cardiomyopathy (DCM). We performed a genome-wide association study for SCDY/DCM in Manchester Terrier dogs and identified a susceptibility locus harboring the cardiac ATP-sensitive potassium channel gene ABCC9. Sanger sequencing revealed an ABCC9 p.R1186Q variant present in a homozygous state in all SCDY/DCM-affected dogs (n = 26). None of the controls genotyped (n = 398) were homozygous for the variant, but 69 were heterozygous carriers, consistent with autosomal recessive inheritance with complete penetrance (p = 4 × 10-42 for the association of homozygosity for ABCC9 p.R1186Q with SCDY/DCM). This variant exists at low frequency in human populations (rs776973456) with clinical significance previously deemed uncertain. The results of this study further the evidence that ABCC9 is a susceptibility gene for SCDY/DCM and highlight the potential application of dog models to predict the clinical significance of human variants.

A male-killing Wolbachia endosymbiont is concealed by another endosymbiont and a nuclear suppressor.

Bacteria that live inside the cells of insect hosts (endosymbionts) can alter the reproduction of their hosts, including the killing of male offspring (male killing, MK). MK has only been described in a few insects, but this may reflect challenges in detecting MK rather than its rarity. Here, we identify MK Wolbachia at a low frequency (around 4%) in natural populations of Drosophila pseudotakahashii. MK Wolbachia had a stable density and maternal transmission during laboratory culture, but the MK phenotype which manifested mainly at the larval stage was lost rapidly. MK Wolbachia occurred alongside a second Wolbachia strain expressing a different reproductive manipulation, cytoplasmic incompatibility (CI). A genomic analysis highlighted Wolbachia regions diverged between the 2 strains involving 17 genes, and homologs of the wmk and cif genes implicated in MK and CI were identified in the Wolbachia assembly. Doubly infected males induced CI with uninfected females but not females singly infected with CI-causing Wolbachia. A rapidly spreading dominant nuclear suppressor genetic element affecting MK was identified through backcrossing and subsequent analysis with ddRAD SNPs of the D. pseudotakahashii genome. These findings highlight the complexity of nuclear and microbial components affecting MK endosymbiont detection and dynamics in populations and the challenges of making connections between endosymbionts and the host phenotypes affected by them.

Whole Transcriptome Analysis in Mexican Children with High-Risk Acute Lymphoblastic Leukemia: A Preliminary Report from the Migiccl

Almost 20% of Mexican children with acute lymphoblastic leukemia (ALL) die within the first 2 years, and relapses are over 4 times more frequent in Mexico than in high-income countries, mainly early relapses (<36 months from diagnosis or at treatment completion)(Núñez-Enríquez et al., BMC Cancer 2019). It has been observed that gene fusions associated with good prognosis are less common in Mexican ALL cases, but biomarkers associated with older age and poor prognostic molecular subtypes are more frequent. These observations have been reported in Hispanics in the US and in other Latin-American populations. For instance, ETV6-RUNX1, a favorable prognosis marker, shows low frequency in Mexican children and other Native American populations (~10%), but Ph-like subtype is more common in Hispanics (11-15%) and has been associated with ancestry (Lee et al., JAMA Oncol, 2022). This project aimed to identify gene fusions by whole transcriptome sequencing (RNA-seq) in a sub-cohort of Mexican children with ALL. We carried out a retrospective multicenter cohort study as part of the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL). From a cohort of 496 children with ALL treated in public hospitals from Mexico City, we selected 49 patients for RNA-seq analysis. All patients were followed-up for at least 36 months. Total RNA was extracted from bone marrow and sequencing was done with Illumina. Fusion detection was performed with FusionCatcher software and differential expression was done with DESeq2. All fusions were manually curated and inspected in IGV software to eliminate false positives. In cases without an identified fusion, raw reads were aligned to GRCh38 genome with STAR software and soft-clipped reads mapping upstream of CRLF2, DUX4, and to IGH locus were searched to identify IGH alterations. Known fusions were validated by RT-PCR and novel ones by RT-PCR and Sanger sequencing. By National Cancer Institute (NCI, USA) risk criteria, thirty-five (71.4%) patients were classified as high-risk, 23 (47%) had early relapse (Table 1). The 4-year overall survival (OS) of the studied population was 50% (95% CI: 37-67). No differences in EFS and OS were observed between patients classified as high- or standard-risk (p=0.87 and p=0.78, respectively). Overall, 65.3% of patients had at least one fusion. Thirty-one different fusions were found and 14 are considered recurrent in B-ALL. Nine fusions (18.4%) were not previously reported or had a novel partner fused to a recurrently mutated gene. By grouping them into well-known B-ALL subtypes, the most common were DUX4 (13%), CRLF2 (10.87%) and BCR-ABL1 (10.87%) (Figure 1). Four DUX4 cases had DUX4-IGH fusion, one case had a novel DUX4-ETV6 fusion and in another one the underlying genetic alteration could not be found but had the highest DUX4 expression. Regarding CRLF2r, P2RY8-CRLF2 was the most common fusion (4/5 cases), and one case had a CRLF2-IGH fusion that was missed by the fusion detection software but identified with targeted search via soft-clipped reads. ETV6-RUNX1 was found in 6.5%, in line with the low frequency reported in Latinos. The frequency of newly discovered subtypes like MEF2D, PAX5 (including a novel 3' partner in PAX5-ST18) and ZNF384 alterations was 6.5%, 4.3% and 2.2%, respectively, similar frequencies to those reported in bigger cohorts. As expected, none of TCF3-PBX1 and ETV6-RUNX1 patients died during follow-up. The remaining genetic subtypes had poor outcome. Four-year OS for kinase-driven subtypes was 50%, P2RY8-CRLF2 having the worst outcome (3/4 died before treatment completion). It was surprising to find the low OS of DUX4, a subtype associated with an excellent prognosis even in adult ALL. The 4-year OS of DUX4 was 33%, and all patients classified as DUX4 who relapsed also died during treatment. The outcome of patients without fusions was also poor, of just 51% after 4 years. We report the first RNA-seq-based analysis in Mexican children with high-risk ALL. We were able to classify around 60% of patients based on transcriptome data alone. Although the implementation of these technologies in a clinical setting is still a challenge, especially for developing countries, some genetic subtypes deserve consideration to explore their prognostic significance in bigger cohorts, perhaps using more feasible techniques to identify them, and to provide a more precise risk stratification. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The prevalence association between the pattern of impacted third molars and their common hard tissues pathologies among the big Tripoli city population: A digital panoramic radiography retrospective study

Background: Third molar impaction is a prevalent condition that affects a substantial percentage of the global population, with a global prevalence ranging from 16.7% to 68.6%. 2. Nearly half of impacted third molars are associated with some form of pathology.Aim: To ascertain the prevalence of third molars that have been impacted in the large Tripoli, Libyan population, in relation to the level of eruption, the angulation of impaction, their accompanying pathologies, and associated demographic data (sex and age of the patients).Material and Methods: The 8860 digital panoramic radiographs (PRs) from the large Tripoli city population were obtained retrospectively for the current investigation. Using Microsoft Excel, the sampled PRs were assessed, and the information gathered was collated and examined (Microsoft Office 2013). The data was examined using the Chi-Square analysis technique.Results: A total sample of 8860 digital panoramic radiograph, 2077 (23.4%) cases of impacted third molars to show at least one impacted third molar. The prevalence of impacted third molars was found significantly higher in the twenties and thirties age groups (35.1%).A total of 2077 digital PRS were diagnosed with impacted third molars out of which 642 (31%) were associated with pathologies.Conclusion: This study's sample of impacted third molars demonstrated a low frequency in the large Tripoli population. Males are more prone than females to have an impaction. The most prevalent impaction patterns were mesioangular angulation, level C impaction, and class II impaction. The enlargement of the periodontal ligament space was one of the most frequent related hard tissue diseases.

Novel frameshift mutation in LIS1 gene is a probable cause of lissencephaly: a case report

BackgroundLissencephaly (LIS) is a cortical malformation, characterized by smooth or nearly smooth cerebral surface and a shortage of gyral and sulcal development, which is caused by deficient neuronal migration during embryogenesis. Neuronal migration involves many gene products, among which is the product of the PAFAH1B1 gene, associated with this disease. LIS is a rare disease, characterized by low population frequency, and with non-specific clinical symptoms such as early epilepsy, developmental delay or cerebral palsy-like motor problems. Given that high-throughput sequencing techniques have been improving diagnosis, we have chosen this technique for addressing this patient.Case presentationWe present the case of a seven years old male patient with an undiagnosed rare disease, with non-specific clinical symptoms possibly compatible with lissencephaly.The patient was enrolled in a study that included the sequencing of his whole genome. Sequence data was analyzed following a bioinformatic pipeline. The variants obtained were annotated and then subjected to different filters for prioritization. Also mitochondrial genome was analyzed. A novel candidate frameshift insertion in known PAFAH1B1 gene was found, explaining the index case phenotype. The assessment through in silico tools reported that it causes nonsense mediated mechanisms and that it is damaging with high confidence scores. The insertion causes a change in the reading frame, and produces a premature stop codon, severely affecting the protein function and probably the silencing of one allele. The healthy mother did not carry the mutation, and the unaffected father was not available for analysis.ConclusionsThrough this work we found a novel de novo mutation in LIS1/PAFAH1B1 gene, as a likely cause of a rare disease in a young boy with non-specific clinical symptoms. The mutation found correlates with the phenotype studied since the loss of function in the gene product has already been described in this condition. Since there are no other variants in the PAFAH1B1 gene with low population frequency and due to family history, a de novo disease mechanism is proposed.

The plant host environment influences competitive interactions between bacterial pathogens.

Bacteria compete for resources in diverse environments using an array of antagonistic strategies, including the production of narrow-spectrum protein antibacterials termed bacteriocins. Although significant research has focused on bacteriocin-mediated dynamics in culture environments, little research has explored bacteriocin-mediated dynamics within a host context, particularly in plant environments. Here, we show that a bacterial plant pathogen, Pseudomonas syringae pv. syringae (Psy), expresses a bacteriocin both in culture and in leaf apoplast when co-inoculated with a bacteriocin-sensitive competitor, P. syringae pv. phaseolicola (Pph). Although there is an observable negative effect of the bacteriocin on the Pph population at most time points both in culture and in the leaf apoplast, a bacteriocin-mediated benefit to Psy was only observed when the producing strain was co-infiltrated at a low population frequency (1:9) into the leaf apoplast. At 6 days post-infiltration, Psy achieved an eightfold population increase compared to a bacteriocin-deficient mutant in the apoplast. No bacteriocin-mediated benefit for Psy was observed under the culture conditions tested. Additionally, we found that the bacteriocin-mediated benefit for Psy was dependent on the Type III Secretion System. Taken together, our results demonstrate that the fitness benefit of bacteriocin-mediated antagonism is influenced by interactions within the host plant.

No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab.

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer’s disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p’s>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer’s disease.

Treatment Of Hereditary Retinal Dystrophies. Perspectives And Social Aspects

Introduction: Hereditary retinal dystrophies are a heterogeneous group of diseases with a relatively low frequency in the human population, characterized by involvement of different retinal layers, most often the complex retinal pigment epithelium – photoreceptors and causing severe visual impairment – loss of night vision, visual field, color vision and visual acuity in the initial stages and leading to progressive and severe loss of visual function by altering the retinal anatomy and function. Objective: To present the current therapeutic opportunities in treatment of hereditary retinal dystrophies, to analyze the therapies that are currently being experimented with, as well as the perspectives and social aspects, specific to this type of diseases. Methods and results: The development of science and technologies has led to the introduction of new, increasingly sophisticated methods for early diagnosis of these diseases, which enable a very accurate topographical localization of the defect. And together with the advances in genetics, optogenetics, molecular biology, retinal biochemistry and regenerative medicine, they provide a better understanding of the mechanism of these diseases and increase the therapeutic opportunities. The treatment of many of the hereditary retinal dystrophies is still problematic, but since most of them lead to severe disability of the individual, the scientists’ efforts are focused on finding appropriate therapy. Many of these diseases are undergoing clinical trials worldwide, and the results of some are encouraging. Conclusion: Although the treatment of many of the hereditary retinal dystrophies is still in an experimental phase, many effective therapies for these currently incurable diseases are expected to be introduced in the near future.