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Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.
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Objective: To identify possible tests along with their accuracies that may be used to diagnose irritable bowel syndrome. METHODS: The systematic review comprised literature search on Cochrane Library, PubMed, Science Direct and Elsevier databases for randomised controlled trials and cohort studies conducted from January 1, 2015, to December 31, 2022, using appropriate key words and Boolean operators. Focus was kept on studies that reported irritable bowel syndrome diagnosis as the primary outcome. The risk of bias was assessed using quality assessment, data abstraction, and synthesis version 2. RESULTS: Of the 2,798 studies initially identified, 10(0.35%) were analysed in detail. Of them, 4(40%) used enzyme-linked immunosorbent assay kits to test for anti-cytolethal distending toxin B and anti-vinculin levels, 2(20%) used the kits for serum cytokine profiling and serum calprotectin levels, and 4(40%) used either magnetic resonance imaging scans, faecal metabolic profiling, intestinal biopsy analysis with immunostaining or polymerase chain reaction for differential transferribonucleic acid-derived small ribonucleic acid. Out of the 4(40%) studies on anti-cytolethal distending toxin B and anti-vinculin levels, optical densities >1.56 and >1.60 recorded 100% specificity for irritable bowel syndrome with diarrhoea, but sensitivity was 22%. In contrast, rectal biopsies for cell densities of somatostatin and peptide YY showed high sensitivity and specificity for irritable bowel syndrome ranging 80-90%. Conclusion: Enzyme-linked immunosorbent assay testing for anti-cytolethal distending toxin B and anti-vinculin as well as rectal biopsies for cell densities could be potential diagnostic tests for irritable bowel syndrome.
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Síndrome do Intestino Irritável , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/sangue , Humanos , Ensaio de Imunoadsorção Enzimática , Complexo Antígeno L1 Leucocitário/análise , Complexo Antígeno L1 Leucocitário/sangue , Biomarcadores/sangue , Biomarcadores/análiseRESUMO
Parkinson's disease (PD) presents as a complex neurodegenerative disorder characterized by motor and non-motor symptoms, resulting from dopaminergic neuron degeneration. Current treatment strategies primarily aim to alleviate symptoms through pharmacotherapy and supportive therapies. However, emerging research explores novel therapeutic avenues, including the repurposing of drugs like lixisenatide, a GLP-1 receptor agonist initially developed for type 2 diabetes. This correspondence summarizes a phase 2 clinical trial investigating lixisenatide's efficacy in early PD, demonstrating a potential for mitigating motor disability progression. Findings reveal a marginal improvement or stabilization in motor function among lixisenatide-treated individuals compared to placebo, emphasizing its therapeutic promise. Nonetheless, the emergence of gastrointestinal adverse events underscores the need for careful monitoring and management. Further extensive trials are warranted to delineate lixisenatide's efficacy and safety profile, fostering collaborative efforts towards precision treatments in PD.
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Doença de Parkinson , Peptídeos , Humanos , Doença de Parkinson/tratamento farmacológico , Peptídeos/uso terapêutico , Resultado do Tratamento , Antiparkinsonianos/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 2RESUMO
Objectives Eating disorders (ED) are an emerging public health issue globally, especially in young adults studying at the undergraduate level. This study aims to assess the frequency of eating disorders, their types, and disordered eating behaviors among such students. Moreover, it aims to identify factors like weight concern, shape concern, eating concern, and restraint, along with assessing the shifting trend of BMI impact on eating disorders using a standardized Eating Disorder Examination Questionnaire (EDE-Q). Methods In this cross-sectional study, 400 undergraduate students (aged 18-25) from four public universities participated from July 2022 to November 2023. Data was collected using the Eating Disorder Examination Questionnaire (EDE-Q). The frequency of eating disorders was computed using SPSS version 27. Results Among the participants, 21.75% (n=84) were identified as having a score surpassing the clinical cut-off. This group comprised 5.5% males (n=22) and 16% females (n=64). The highest prevalence among the four subscales was observed in the Shape Concern subscale (10.5%). Objective binge episodes (19.3%) emerged as the most notable disordered eating attitude. Atypical anorexia nervosa accounted for 13.8% of different eating disorders, while disordered eating was noted in 19.5% (n=78) of individuals. Discussion This study offers critical insights into eating disorders among Pakistan undergraduate students, utilizing the EDE-Q 6.0. Disordered eating behaviors, particularly shape concern and objective binge eating, exhibit significant correlations with these disorders. Weight dissatisfaction emerges as a prominent predictor, suggesting societal influence. The study also reveals a moderate correlation between BMI and eating disorders, challenging conventional assumptions. Furthermore, a changing trend in the prevalence of eating disorders is observed among the male population.
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OBJECTIVE: To assess the knowledge and attitude of female healthcare providers about human papilloma virus and its vaccination, to determine the frequency of respondents vaccinated against the virus, and to evaluate the reasons for non-immunisation. METHODS: The cross-sectional study was conducted at the Jinnah Hospital, Lahore, Pakistan, from January 7 to February 20, 2022, and comprised female health care providers aged 20-60 years. Data was collected using a self-assessing questionnaire. Data was analysed using SPSS 22. RESULTS: Of the 250 individuals approached, 210(84%) took part in the study. The mean age was 28.9+/-7.99 years. Most of the subjects were house officers, medical officers or senior registrars 138(65.7%), and 126(60%) were unmarried. Overall, 170(81%) respondents knew about human papilloma virus and 174(82.9%) were aware of its link with cervical cancer. Even though 128(61%) respondents knew that the virus can be prevented by vaccine, 14(6.7%) were actually vaccinated. The vaccinated individuals had better knowledge about HPV, its spread, complications, its association with cervical cancer, prevention by vaccination and availability of vaccine compared to the non-vaccinated (p =0.05). CONCLUSIONS: The trend of human papilloma virus vaccination among female health professionals was found to be low, and lack of awareness and counselling was the leading cause.
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Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Adulto Jovem , Adulto , Papillomavirus Humano , Neoplasias do Colo do Útero/prevenção & controle , Infecções por Papillomavirus/prevenção & controle , Estudos Transversais , Setor Público , Conhecimentos, Atitudes e Prática em Saúde , Vacinação , Pessoal de Saúde , Hospitais Públicos , Inquéritos e Questionários , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.
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Variações do Número de Cópias de DNA , Doenças Metabólicas , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Paquistão , Sequenciamento do ExomaRESUMO
BACKGROUND AND OBJECTIVE: Initiation of Insulin therapy during earlier stages has proved to significantly improve health outcomes among diabetics in comparison to oral medications. Not only patients but physicians are also often resistant to early initiation of insulin therapy. The objective was to assess misconceptions and barriers to early initiation of insulin therapy among diabetic patients coming to a diabetic clinic. METHODS: This cross sectional study was conducted on 300 patients selected by convenience sampling arriving in Diabetes Outdoor Clinics of Mayo and Services Hospitals, Lahore during August 2017 to May 2018. The data was entered and analyzed by using SPSS version 17. RESULTS: Out of 300 patients included in study, 39% (n= 117) were males and 61% (n=183) were females. The mean age of the participants at presentation was 48.46±13.15 years with a range of 13 to 80 years. Study participants considered it embarrassing to inject insulin in public place (p-value 0.01). The fear associated with lifelong commitment to insulin therapy once it is started, was also found statistically significant (p-value 0.001)particularly in subjects who have long duration of DM (>5 years). CONCLUSION: Perceptions of diabetic patients about insulin therapy are still barriers to early initiation of therapy and tend to prevail in Pakistan and around the globe.
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The title compound, [Ag2(C8H6NO4)2] n , is a silver complex of 2-(2-nitro-phen-yl)acetic acid. The mol-ecules are not conventional crystallographic inversion dimers but consist of two independent ligands and two Ag(I) ions, each with a distorted T-shaped coordination environment. The dihedral angles between acetate groups and the benzene rings are 51.1â (2) and 57.9â (2)°. The nitro groups are oriented at dihedral angles of 23.6â (5) and 32.3â (3)° with respect to the parent benzene rings. The dimers form polymeric chains along the a-axis direction. The Agâ¯Ag separation within a dimer is 2.8200â (5) and between symmetry-related dimers is 3.6182â (5)â Å. The polymeric chains are inter-linked by C-Hâ¯O hydrogen-bond inter-actions.
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In the title one-dimensional coordination polymer, [Sn(CH3)3(C8H6NO4)] n , the Sn(IV) atom is coordinated by three methyl C atoms and two carboxyl-ate O atoms (one symmetry generated), resulting in an almost regular SnC3O2 trigonal pyramid. The C atoms occupy the equatorial sites and the O atoms occupy the axial sites. In the ligand, the dihedral angles between the benzene ring and the pendant acetate and nitro groups are 57.7â (1) and 36.9â (3)°, respectively. The bridging ligand leads to [010] chains in the crystal, with adjacent metal atoms related by a 21 screw axis. A weak π-π inter-action exists between the centroids of symmetry-related benzene rings at a distance of 3.9131â (19)â Å.
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The mol-ecule of the title compound, [Co(C8H6NO4)2(H2O)4], is centrosymmetric. It is a cobalt(II) complex, bearing two (2-nitro-phen-yl)acetate and four aqua ligands. The coordination around the Co(II) atom is distorted octa-hedral, defined by four O atoms of water mol-ecules in the equatorial plane and by two carboxyl-ate O atoms at axial positions. The dihedral angles between the benzene ring and the acetate and nitro groups are 61.90â (10) and 19.21â (11)°, respectively. The water mol-ecules form O-Hâ¯O hydrogen bonds with the nitro and carboxyl-ate groups, leading to a layered structural arrangement parallel to (001).