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Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity. Nanopore sequencing confirmed the lower transcription of the TMEM216 c.-69G>T allele in blood-derived RNA from a heterozygous carrier, and reduced expression was further recapitulated by qPCR, using both leukocytes-derived RNA of c.-69G>T homozygotes and total RNA from genome-edited hTERT-RPE1 cells carrying homozygous TMEM216 c.-69G>A. In conclusion, these variants explain a significant proportion of unsolved cases, specifically in individuals of African ancestry, suggesting that reduced TMEM216 expression might lead to abnormal ciliogenesis and photoreceptor degeneration.
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Linhagem , Polimorfismo de Nucleotídeo Único , Retinose Pigmentar , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Adulto Jovem , Alelos , Haplótipos , Heterozigoto , Homozigoto , Proteínas de Membrana/genética , Fenótipo , Retinose Pigmentar/genética , Retinose Pigmentar/patologiaRESUMO
Tea leaf spot caused by Didymella segeticola is a disease that has recently been discovered in the tea plantations of Southwest China, and which has a significant negative impact on the yield and quality of tea leaves. Wuyiencin is a nucleotide antimicrobial that is effective against a range of fungal diseases. However, its mode of action is still unclear. The current study found that wuyiencin inhibited the mycelial growth of D. segeticola in vitro. Meanwhile, in vivo experiments confirmed that wuyiencin had a significant curative effect on tea leaf spot. Microscopic observation represented it damaged the organelles and nucleus in fungal cells. Reverse transcription quantitative PCR assays revealed that mycelium treated with wuyiencin at the half-maximal effective concentration (EC50) dosage for 1 hour exhibited 3.23 times lower expression of Threonine dehydratase (Td) gene, which is responsible for producing pyruvate. The wild type (WT) strain had a 1.77-fold higher pyruvate concentration than that in the td mutant (P < 0.05). The td mutant was more sensitive than the WT to wuyiencin treatment, with the EC50 value in the td mutant being 30.01 µg/ml, compared with 82.34 µg/ml in the WT. Molecular docking demonstrated that wuyiencin bound to Td, with a binding energy of -10.47 kcal/mol. Compared with the WT strain, wuyiencin significantly reduced ATP concentration of the td mutant strain at dosages of 80.0 and 160.0 µg/ml. In total, wuyiencin reduced Td activity, inhibited pyruvate production, and decreased ATP content in the phytopathogenic fungus, ultimately disturbing the growth of the mycelium.
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BACKGROUND: Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023. METHODS: Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total of 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines. RESULTS: A total of 277 unique sequence variants in 87 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 88.81% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (41.88%), followed by Indels/frameshift (26.35%), nonsense (19.13%), splice site (12.27%) and synonymous change (0.36%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77.32% vs. 22.68%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber's congenital amaurosis (LCA). Altogether, mutations in PDE6A gene was the leading cause of IRDs in Pakistani families followed by mutations in TULP1 gene. CONCLUSION: In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of rare pathogenic variants in homozygous state.
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Distrofias Retinianas , Retinose Pigmentar , Humanos , Paquistão/epidemiologia , Estudos Retrospectivos , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/genética , Retina/patologia , Retinose Pigmentar/genética , Mutação , Linhagem , Proteínas do Olho/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genéticaRESUMO
Pakistan has a high burden of hereditary and congenital anomalies and their incidence rate almost doubles against the background of parental consanguinity. Consanguineous unions (CU) are customary in Pakistan and deeply rooted socio-cultural norms favour CU. This study aimed to elucidate the determinants and temporal change in CU in four northwestern populations of Pakistan. In a cross-sectional study, data on marital union types, bio-demographic factors, and paternal consanguinity were collected from 6,323 ever-married individuals in four districts of northwest Pakistan: Haripur, Muzaffarabad, Mansehra, and Shangla. We used descriptive statistics and multivariable logistic regression analysis. The CU were calculated to be 55%, and inbreeding coefficient F (ICF) was estimated to be 0.029. Eight factors, including district, rural origin, age of husband, occupational group of husband, literacy of husband, parental consanguinity, exchange marriage, and extended family type, were found to be significant predictors of consanguinity in the multivariable logistic regression analysis. The rate of consanguinity decreased significantly in the younger age categories of individuals. The rate of CU was seen to be declining over time and in marriages that started 'before 1980' and 'after 2010', respectively, and there was a decline in ICF from 0.030 to 0.027. These analyses also showed that the literacy rate improved, the average age at marriage increased, and the frequency of exchange marriages decreased over time. This study employs a sizable first-hand dataset to demonstrate a lowering CU rate in northwest Pakistan. It is anticipated that the burden of inherited and congenital anomalies may likely to diminish in the study populations along with the fall in ICF.
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Pai , Casamento , Masculino , Humanos , Consanguinidade , Paquistão/epidemiologia , Estudos TransversaisRESUMO
BACKGROUND: Retinitis pigmentosa (RP) is one of the most frequent hereditary retinal diseases that often starts with night blindness and eventually leads to legal blindness. Our study aimed to identify the underlying genetic cause of autosomal recessive retinitis pigmentosa (arRP) in a consanguineous Pakistani family. METHODS: Following a detailed ophthalmological examination of the patients by an ophthalmologist, whole-exome sequencing was performed on the proband's DNA to delineate the genetic cause of RP in the family. In-depth computational methods, in-silico analysis, and familial co-segregation study were performed for variant detection and validation. RESULTS: We studied an inbred Pakistani family with two siblings affected by retinitis pigmentosa. The proband, a 32 years old female, was clinically diagnosed with RP at the age of 6 years. A classical night blindness symptom was reported in the proband since her early childhood. OCT report showed a major reduction in the outer nuclear layer and the ellipsoid zone width, leading to the progression of the disease. Exome sequencing revealed a novel homozygous missense mutation (c.938C > T;p.Thr313Ile) in exon 12 of the PDE6B gene. The mutation p.Thr313Ile co-segregated with RP phenotype in the family. The altered residue (p.Thr313) was super conserved evolutionarily across different vertebrate species, and all available in silico tools classified the mutation as highly pathogenic. CONCLUSION: We present a novel homozygous pathogenic mutation in the PDE6B gene as the underlying cause of arRP in a consanguineous Pakistani family. Our findings highlight the importance of missense mutations in the PDE6B gene and expand the known mutational repertoire of PDE6B-related RP.
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Cegueira Noturna , Retinose Pigmentar , Pré-Escolar , Feminino , Humanos , Consanguinidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Análise Mutacional de DNA , Proteínas do Olho/genética , Mutação , Cegueira Noturna/genética , Paquistão , Linhagem , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , HomozigotoRESUMO
INTRODUCTION: Retinitis pigmentosa (RP) is a rare degenerative retinal disease caused by mutations in approximately seventy genes. Currently, despite the availability of large-scale DNA sequencing technologies, â¼30-40% of patients still cannot be diagnosed at the molecular level. In this study, we investigated a novel intronic deletion of PDE6B, encoding the beta subunit of phosphodiesterase 6 in association with recessive RP. METHODS: Three unrelated consanguineous families were recruited from the northwestern part of Pakistan. Whole exome sequencing was performed for the proband of each family, and the data were analyzed according to an in-house computer pipeline. Relevant DNA variants in all available members of these families were assessed through Sanger sequencing. A minigene-based splicing assay was also performed. RESULTS: The clinical phenotype for all patients was compatible with rod cone degeneration, with the onset during childhood. Whole exome sequencing revealed a homozygous 18 bp intronic deletion (NM_000283.3:c.1921-20_1921-3del) in PDE6B, which co-segregated with disease in 10 affected individuals. In vitro splicing tests showed that this deletion causes aberrant RNA splicing of the gene, leading to the in-frame deletion of 6 codons and, likely, to disease. CONCLUSION: Our findings further expand the mutational spectrum of the PDE6B gene.
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Retinose Pigmentar , Humanos , Análise Mutacional de DNA , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Mutação , Splicing de RNA , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Linhagem , Proteínas do Olho/genéticaRESUMO
Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.
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Oftalmopatias Hereditárias , Receptor Quinase 1 Acoplada a Proteína G , Cegueira Noturna , Oftalmopatias Hereditárias/genética , Receptor Quinase 1 Acoplada a Proteína G/genética , Humanos , Cegueira Noturna/genéticaRESUMO
Pakistan is located at an important cross-road of human history and has been a passageway for many invaders and dynasties in the past. The historic human migrations across this country have resulted in a blend of ancient civilizations, which are still reflected in the current socio-cultural fabrication of this population. This makes Pakistan an ideal country to study the genetic differentiation and various other genomic aspects of a human population.
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Etnicidade/genética , Variação Genética , Genética Populacional/estatística & dados numéricos , Impressões Digitais de DNA/estatística & dados numéricos , Frequência do Gene , Humanos , PaquistãoRESUMO
Spectrophotometric technique is considered to be the simplest and operator friendly among other available analytical methods for pharmaceutical analysis. The objective of the study was to develop a precise, accurate and rapid UV-spectrophotometric method for the estimation of chlorpheniramine maleate (CPM) in pure and solid pharmaceutical formulation. Drug absorption was measured in various solvent systems including 0.1N HCl (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and distil water (pH 7.0). Method validation was performed as per official guidelines of ICH, 2005. High drug absorption was observed in 0.1N HCl medium with λmax of 261nm. The drug showed the good linearity from 20 to 60µg/mL solution concentration with the correlation coefficient linear regression equation Y= 0.1853 X + 0.1098 presenting R2 value of 0.9998. The method accuracy was evaluated by the percent drug recovery, presents more than 99% drug recovery at three different levels assessed. The % RSD value <1 was computed for inter and intraday analysis indicating the high accuracy and precision of the developed technique. The developed method is robust because it shows no any significant variation in with minute changes. The LOD and LOQ values were assessed to be 2.2µg/mL and 6.6µg/mL respectively. The investigated method proved its sensitivity, precision and accuracy hence could be successfully used to estimate the CPM content in bulk and pharmaceutical matrix tablets.
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Clorfeniramina/análise , Preparações de Ação Retardada/análise , Espectrofotometria Ultravioleta/métodos , Comprimidos/análise , Concentração de Íons de Hidrogênio , Limite de Detecção , Sensibilidade e Especificidade , SolventesRESUMO
The north-western populations of Pakistan in the Federally Administered Tribal Areas (FATA) adjoining the Pakistan-Afghanistan border are an amalgamation of native and migrated Pashtun tribes. These tribal populations are in transition due to war conditions and geo-political turmoil on both sides of the border since the Soviet invasion in 1979. Bio-demographic and epidemiological data for these tribes are scarce. A prospective cross-sectional sample of 967 males was selected from a representative Pashtun population of Bajaur Agency, and information obtained on bio-demographic variables and marital union types. Analysis of these data revealed that consanguinity was 22.34% and the inbreeding coefficient F was calculated to be 0.0134. The inbreeding coefficient was observed to be higher in subjects who were illiterate, had unskilled jobs and who belonged to younger age categories, extended families and the Tarkalani tribe. Further analyses with respect to temporal variables like subject's age, year of marriage and age at marriage revealed that after a transition in marital union types in the early 80s, there has been a declining trend in the rate of consanguineous unions. Further, consanguineous unions in the parental generation were only 5%, but parental marriage types were predictors of subjects' marital union types. The data further establish that, contrary to a general notion about a high consanguinity rate in Pakistan, consanguineous unions are not common in Bajaur Agency and first cousin marriage is not the preferred type. Furthermore, this research shows that there is a great regional variation in the pattern of consanguinity in Pakistan that needs to be documented in order to draw a more comprehensive picture of the inbreeding coefficient in the country.
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Consanguinidade , Etnicidade/estatística & dados numéricos , Casamento/etnologia , Casamento/estatística & dados numéricos , Adolescente , Adulto , Afeganistão , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Família/etnologia , Família/psicologia , Características da Família/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Estudos Prospectivos , População Rural/estatística & dados numéricos , Inquéritos e Questionários , População Urbana/estatística & dados numéricos , Guerra , Adulto JovemRESUMO
This study aimed to fabricate and characterize feboxostat (FXT) loaded nanoemulgel (NEG) for transdermal delivery. NEG was prepared by high sheared homogenization technique and characterized for thermodynamic stability, pH analysis, drug content, zeta analysis, viscosity, spreadability, FTIR, in-vitro drug release and ex-vivo permeation. In vivo anti-inflammatory activity was evaluated in albino rats by inducing edema in hind paws using carrageenan. The formulations showed optimum thermodynamic stability, having no phase separation and color change. The pH was in the range of human skin range i.e. 5.5-6.5. The drug content of F3 and F4 formulations were 97.56 ± 3.45 % and 83.88 ± 3.12 % respectively which were in official limit of USP i.e. 90 ± 10 %. No interaction was found between the FXT and various components after FTIR analysis. The viscosity of NEG was 4587 cp at 6 rpm and 2681 cp at 12 rpm. The droplet sizes of F1 (Blank NE), F2 (Blank NEG), F3 (Drug loaded NE) and F4 (Drug loaded NEG) were 148.6 nm, 153.4 nm, 402.1 nm and 498.3 nm respectively. The percent drug release of F3 was 82 ± 0.97 %, while F4 released 78 ± 0.91 % after 24 h. The drug permeation was 77 ± 1.28 % and 74 ± 1.10 % for F3 and F4 respectively. The optimized formulation significantly (p < 0.05; ANOVA) inhibited the paw edema in albino rats as compared to the control and standard group. It has been concluded that FXT loaded NEG can be a safe and effective alternative to the oral therapy of FXT.
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Absorção Cutânea , Pele , Ratos , Animais , Humanos , Administração Cutânea , Pele/metabolismo , Portadores de Fármacos/química , Edema/induzido quimicamente , Edema/tratamento farmacológicoRESUMO
Herein, Ni2+-Cu2+ co-doped barium hexaferrites (BaFe11Cu1-xNixO19, 0.0 ≤ x≤ 1.0 with an interval of 0.25) were successfully synthesized using a co-precipitation method. The formation of a magnetoplumbite structure with the P63/mmc space group was confirmed by Rietveld refinement of the obtained X-ray diffraction patterns. Microstructural investigations revealed grains in the shape of hexagonal plates, while co-doping resulted in a variation in the grain sizes of the prepared samples. X-ray photoelectron spectroscopy was performed to determine the valence state of iron in the prepared hexaferrites. Impedance spectroscopy analysis revealed that dielectric permittivity initially decreased with an increase in the co-dopant content up to x = 0.5 and then increased by two orders of magnitude for x = 1.0. Alternatively, resistive properties showed microstructural resistance values in the range 105-108 Ω, with the highest value obtained for the sample with x = 0.5. Furthermore, magnetic measurements indicated that all the prepared samples exhibited ferrimagnetic behaviour. Saturation magnetization and magnetic anisotropy values were found to be the highest for the sample with x = 1.0, which also had the lowest coercivity among the prepared samples. Herein, the observed variations in the obtained results can be explained by the variations in grain sizes and the Fe2+/Fe3+ ratio associated with the preferential occupation of co-dopants at octahedral sites. Based on our findings, the BaFe11Ni1O19 (x = 1.0) composition appears to be the most promising choice as a microwave absorption material among the prepared samples owing to the coexistence of high dielectric permittivity (>103 at 107 Hz) and saturation magnetization (73 emu g-1).
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[This retracts the article DOI: 10.1021/acsomega.1c00654.].
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The nanocomposites of Co0.5Ni0.5Gd0.03Fe1.97O4/graphene nanoplatelets (CNGF/GNPs) were synthesized by a cost-effective sol-gel auto combustion (SGAC) route. The X-ray diffraction analysis confirmed the cubic structure of the as-prepared nanocomposites, and a crystallite size of 32.28 nm was observed for the 7.5 wt% GNPs. Irregular and unique nanoparticles consisting of short stacks of graphene sheets having a platelet shape were confirmed by the morphological analysis of the as-prepared nanocomposites. Raman analysis revealed a spinel crystal structure along with a new vibrational mode due to the GNPs. The energy bandgap was 3.98 eV for the composite with 7.5 wt% GNP concentration. It was observed that the percentage temperature coefficient of resistance (TCR%) rapidly decreased with an increase in temperature both in low- and high-temperature ranges. Dielectric studies carried out in the frequency range 104-107 Hz confirmed that the graphene-added composites had high values for both the real and imaginary parts of permittivity at low frequencies. A decrease in saturation magnetization with an increase in GNP concentration was observed compared with the pure CNGF samples. Hence, the as-prepared composites are useful for application in high-frequency devices as well as spintronics.
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We investigated the use of titania coated ZnO tetrapods for photocatalytic degradation of two common types of microplastics, namely polyethylene (PE) microparticles and polyester (PES) microfibers. We found that the plastics morphology affects the rate of degradation, and that the use of electron scavengers is needed to maintain the reactivity of the photocatalysts over a prolonged period of time. Complete mass loss of PE and PES is achieved under UV illumination for 480 h and 624 h, respectively. In addition to pristine microplastics, the degradation of environmental microplastics sample (consisting primarily of polypropylene) was also demonstrated, though in this case longer degradation time (â¼816 h) was needed to achieve complete mass loss of the samples.
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Cerium (Ce3+) substitution in Cu-Cd spinel nanoferrites with the compositional formula Cu0.5Cd0.5Fe2-xCexO4 (x = 0.0, 0.0125, 0.0250, 0.0375, 0.050) was performed by the hydrothermal route. The structural, morphological, optical, electrical, and dielectric properties of Ce-substituted Cu-Cd ferrites were explored. X-ray diffraction revealed the single-phase cubic structure of all nanoferrites. The average crystallite size (72.42-11.61 nm) and lattice constant (8.419-8.449 Å) were observed for the synthesized ferrites. The surface shapes of particles were determined by scanning electron microscopy. The substitution was also verified by Fourier transform infrared spectroscopy and ultraviolet-visible spectrophotometry. The semiconducting behavior of ferrites was determined from their electrical properties, such as direct current (DC) electrical resistivity. The Curie temperature was observed at 523 K temperature for all nanoferrites. The dielectric constant and dielectric loss significantly indicated the reducing behavior with an increase in the cerium concentration. The sample Cu0.5Cd0.5Fe1.975Ce0.025O4 resulted in the lowest optical bandgap energy, DC resistivity, and dielectric losses. The nature of the electrical resistivity and dielectric constants indicate that the designed materials are highly appropriate for the design of microwave gadgets.
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Background: Mycoplasma synoviae (MS) is an important poultry pathogen causing heavy economic losses Worldwide. Subclinical persistence of this pathogen is the major issue to control its prevalence. Aim: This study aimed to determine the molecular and cross-immunogenicity of MS among broilers in five Districts of Khyber Pakhtunkhwa (KP). Methods: This study was conducted by collecting 434 specimen samples from 40 broiler farms and desi poultry in five districts of KP. Specimen samples from the broiler birds (n = 150), broiler farm environment (n = 264), and desi poultry birds (n = 20) were aseptically collected and serially passaged in Modified Frey's broth. The homologous and heterologous antibody reactions were studied in rabbits. Before inoculation into rabbits, the MS isolates were inactivated by formalin and adjuvanted with Montanide. Results: The overall turbidity prevalence in Frey's broth was observed as 109/434 (25.11%) samples, and these turbidity-positive samples were shifted on Frey's agar. After the appearance of classic fried egg colonies, the Biochemical confirmation was supported by the production of catalase and phosphatase, reduction of tetrazolium, film and spot assay, and fermentation of glucose for species differentiation in avian mycoplasma. The MS prevalence percentage was recorded as 2% (9/434) through biochemical tests. The PCR results showed 0.5% MS prevalence with two field isolates (named MS-1 and MS-2). Both MS-1 and MS-2 field isolates showed similar values (42.2) of homologous geometric mean titer (GMT). While the heterologous GMT for MS-1 serum against MS-2 isolate was lower (27.9) as compared to MS-2 serum against MS1 isolate (38.9). No titer was detected in the control group (Group-III). Conclusion: In conclusion, the results indicated the existence of MS in broiler birds and high homologous titers recorded between field isolates, which is a perpetual menace to poultry.
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Infecções por Mycoplasma , Mycoplasma synoviae , Doenças das Aves Domésticas , Animais , Coelhos , Galinhas , Infecções por Mycoplasma/epidemiologia , Infecções por Mycoplasma/veterinária , Doenças das Aves Domésticas/epidemiologia , Aves DomésticasRESUMO
BACKGROUND: Pyruvate kinase deficiency is an exceptionally rare autosomal recessive Mendelian disorder caused by bi-allelic pathogenic variants in the PKLR gene. It is mainly characterized by chronic nonspherocytic hemolytic anemia though other symptoms such as splenomegaly, hepatomegaly, pallor, fatigue, iron overload, shortness of breath, hyperbilirubinemia, and gallstones might also prevail. CASE PRESENTATION: We present here a novel genetic defect in the PKLR gene that correlates with pyruvate kinase deficiency phenotype in a consanguineous family from North-Western Pakistan. The family included three affected individuals who were all born to consanguineous parents. The proband, a 13-year-old female of Pashtun ethnicity, showed chronic nonautoimmune hemolytic anemia since birth, extremely low hemoglobin (7.6 g/dL) and pyruvate kinase (12.4 U/g Hb) levels, splenomegaly, and hepatomegaly. Bone marrow aspirate showed a markedly decreased myeloid to erythroid ratio and hypercellular marrow particles due to hyperplasia of the erythroid elements. Molecular characterization of the proband's genomic DNA uncovered a likely pathogenic homozygous missense variant p.[D339N] in exon 7 of the PKLR gene. In-depth in silico analysis and familial cosegregation implies p.[D339N] as the likely cause of pyruvate kinase deficiency in this family. Further in vitro or in vivo studies are required to validate the impact of p.[D339N] on protein structure and/or stability, and to determine its role in the disease pathophysiology. CONCLUSIONS: In summary, these findings suggest a novel genetic defect in the PKLR gene as a likely cause of pyruvate kinase deficiency, thus further expanding the mutational landscape of this rare Mendelian disorder.
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Anemia Hemolítica Congênita não Esferocítica , Erros Inatos do Metabolismo dos Piruvatos , Adolescente , Anemia Hemolítica Congênita não Esferocítica/genética , Feminino , Humanos , Mutação , Paquistão , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/genéticaRESUMO
Background and objective: The risk of adverse reactions necessitated the pharmacovigilance system for patient safety. A literature search documented better health literacy of patients through intervention. This investigation aims to assess the perception and the effect of an intervention on patients regarding adverse reactions caused by drugs. Methods: A pre-diagnostic and post-interventional cross-sectional investigation was designed with a sample size of 423 patients in hospitals of Islamabad. The proportion of patients was selected based on a stratified probability technique. A prevalidated tool was used to collect the response twice through a health promotion brochure with counseling, which was applied as an intervention. Results: The outcome of the investigation revealed that the prerequisite of the pharmacovigilance center in the hospital among respondents was improved significantly by 41.2% after intervention. Knowledge, communication, and practice were significantly different with respect to gender. There was a moderate Pearson correlation between diagnostic and interventional responses of patient's knowledge of adverse reactions by drugs (r = 0.66, p < 0.01) and patient's communication in pharmacovigilance (r = 0.62, p < 0.01) and a strong correlation between diagnostic and interventional responses of patient's practice in the pharmacovigilance system (r = 0.72, p < 0.01). Conclusion: The finding of the investigation provided evidence that patient awareness was significantly improved by the health promotion model. Patient participation in the reporting of adverse reactions of drugs will complement the hospital staff reporting. These reports will construct an authentic, cross-checked database for rational drug safety practices in Pakistan.