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1.
Genes (Basel) ; 14(6)2023 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-37372428

RESUMEN

The snATAC + snRNA platform allows epigenomic profiling of open chromatin and gene expression with single-cell resolution. The most critical assay step is to isolate high-quality nuclei to proceed with droplet-base single nuclei isolation and barcoding. With the increasing popularity of multiomic profiling in various fields, there is a need for optimized and reliable nuclei isolation methods, mainly for human tissue samples. Herein we compared different nuclei isolation methods for cell suspensions, such as peripheral blood mononuclear cells (PBMC, n = 18) and a solid tumor type, ovarian cancer (OC, n = 18), derived from debulking surgery. Nuclei morphology and sequencing output parameters were used to evaluate the quality of preparation. Our results show that NP-40 detergent-based nuclei isolation yields better sequencing results than collagenase tissue dissociation for OC, significantly impacting cell type identification and analysis. Given the utility of applying such techniques to frozen samples, we also tested frozen preparation and digestion (n = 6). A paired comparison between frozen and fresh samples validated the quality of both specimens. Finally, we demonstrate the reproducibility of scRNA and snATAC + snRNA platform, by comparing the gene expression profiling of PBMC. Our results highlight how the choice of nuclei isolation methods is critical for obtaining quality data in multiomic assays. It also shows that the measurement of expression between scRNA and snRNA is comparable and effective for cell type identification.


Asunto(s)
Epigenómica , Leucocitos Mononucleares , Humanos , Multiómica , Reproducibilidad de los Resultados , ARN Nuclear Pequeño/genética
2.
Cell Mol Biol (Noisy-le-grand) ; 69(2): 45-51, 2023 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-37224047

RESUMEN

The use of metformin in diabetic patients causes vitamin B12 deficiency, but there is not enough evidence about the existence of a correlation between different doses of metformin and vit B12 deficiency. Therefore, this study was conducted with the aim of investigating the correlation between different doses of metformin and vitamin B12 deficiency. This cross-sectional study was conducted on 200 patients with type 2 diabetes referred to the diabetes clinic of the central hospital of Sulaimani city in 2022. Demographic data were collected by a questionnaire and the serum level of Vit B12 data was by testing the blood samples. Data analysis was done using SPSS ver.23 and descriptive tests, chi-square, Pearson correlation and logistic regression. The results showed that 24% of patients had vitamin B12 deficiency. 45 (93.8%) patients with vitamin B12 deficiency have taken metformin. The mean vitamin B12, mean metformin consumption per year and metformin dose were significantly different between the two groups. Based on the regression model, it was shown that there was no significant relationship between the serum level of vitamin B12 and the duration of metformin medication (P=0.134). And the relationship between gender, occupation, alcohol and metformin dose (mg) was significant, so these factors have the ability to predict the serum level of vitamin B12. The results showed that vitamin B12 deficiency is common in diabetic patients who take metformin, and the vitamin deficiency will increase with the increase in the dosage.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Deficiencia de Vitamina B 12 , Humanos , Metformina/uso terapéutico , Estudios Transversales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Vitamina B 12
3.
Technol Forecast Soc Change ; 190: 122470, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36896408

RESUMEN

The COVID-19 pandemic is a serious global issue destroying financial markets awfully. The proper estimation effect of COVID-19 pandemic on dynamic emerging financial markets is a big challenge due to a complex multidimensional data. However, the present study proposes a Deep Neural Network (DNN)-based multivariate regression approach with backpropagation algorithm and structural learning-based Bayesian network with constraint-based algorithm to investigate the influence of COVID-19 pandemic on the currency and derivatives markets of an emerging economy. The output shows that the COVID-19 pandemic has negatively influenced the financial markets as indicated by sharply depreciating currency value around 10 % to 12 % and reducing short-position of futures derivatives around 3 % to 5 % for currency risk hedging. The robustness estimation shows that there have probabilistic distributed between Traded Futures Derivatives Contracts (TFDC), Currency Exchange Rate (CER), and Daily Covid Cases (DCC) and Daily Covid Deaths (DCD). Moreover, the output represents that the futures derivatives market conditionally depends on the currency market volatility given percentage of COVID-19 pandemic. This study may help to policymakers of financial markets in decision-making to control CER volatility that may promote currency market stability to enhance currency market activities and boost confidence of foreign investors in extreme financial crisis circumstances.

4.
Commun Biol ; 6(1): 215, 2023 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-36823213

RESUMEN

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.


Asunto(s)
Proteínas Nucleares , Factores de Transcripción , Ratones , Animales , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Reprogramación Celular/genética , Elementos de Facilitación Genéticos , Cromatina/genética
5.
One Health ; 16: 100487, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36683958

RESUMEN

One Health is increasingly recognized as an optimal approach to address the global risk of health threats originating at the human, animal, and ecosystem interface, and their impact. Qatar has successfully practiced One Health approach for investigation and surveillance of zoonotic diseases such as MERS-CoV, and other health threats. However, the current gaps at institution and policy level hinder the sustainment of One Health. In this paper, we have assessed the potential for implementation of One Health Framework to reinforce and sustain One Health capacities in Qatar for 2022-2027. To implement One Health Framework in the country, Qatar Joint External Evaluation (JEE) report, lessons learnt during One Health experiences on zoonotic, vector-borne, and food borne diseases were used to present an outline for multisectoral coordination. In addition, technical capacities of One Health and factors that are required to operationalize it in the country were also assessed in series of meetings and workshops held at Ministry of Public Health on March 2022. Present health care infrastructure and resources were found to be conducive for effective management and response to shared health threats as evident during MERS-CoV, despite being more event based. Regardless, the need for more sustainable capacity development was unanimously emphasized. The consensus between all relevant stakeholders and partners was that there is a need for better communication channels, policies and protocols for data sharing, and the need to invest more resources for better sustainability. The proposed framework is expected to strengthen and facilitate multilateral coordination, enhanced laboratory capacity and network, improve active surveillance and response, risk communication, community engagement, maximize applied research, and build One Health technical work force. This would enable advancement and sustainment of One Health activities to prevent and control health threats shared between humans-animals-ecosystem interface.

6.
Front Immunol ; 13: 1021695, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36341374

RESUMEN

Atractylodes macrocephala Koidz. is one of the most frequently used traditional Chinese medicines for the treatment of ulcerative colitis (UC). The beneficial effect of polysaccharide from Atractylodes macrocephala Koidz. (PAMK) on UC has been reported, while the underlying mechanism and target remain unclear. In this study, we systematically investigated the therapeutic effect and the underlying mechanism of PAMK in UC based on a mouse model of dextran sodium sulfate (DSS)-induced colitis. PAMK treatment (100 mg/kg, 200 mg/kg and 400 mg/kg) significantly ameliorated DSS-induced colitis, manifested as a reduction in weight loss, disease activity index (DAI), colon shortening, spleen index and histological score. Moreover, PAMK treatment inhibited inflammation and improved the integrity of the intestinal barrier in colitis mice. Mechanistically, microarray analysis determined the critical role of the immunoregulatory effect of PAMK in alleviating UC. Flow cytometry analysis further demonstrated that PAMK treatment regulated the balance between T helper (Th) 17 and regulatory T (Treg) cells in the mesenteric lymph nodes (MLN) and spleen in mice with colitis. In addition, PAMK treatment downregulated the expression of IL-6 and suppressed the phosphorylation of STAT3. Together, these data revealed that PAMK treatment alleviated DSS-induced colitis by regulating the Th17/Treg cell balance, which may be dependent on the inhibition of the IL-6/STAT3 signaling pathway. Our study is the first to elucidate that the underlying mechanism by which PAMK treatment alleviates DSS-induced colitis is associated with an improved the Th17/Treg cell balance. Collectively, the study provides evidence for the potential of PAMK to treat UC.


Asunto(s)
Atractylodes , Colitis Ulcerosa , Colitis , Ratones , Animales , Linfocitos T Reguladores/patología , Interleucina-6/farmacología , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis Ulcerosa/patología
7.
Preprint en Inglés | bioRxiv | ID: ppbiorxiv-505316

RESUMEN

Coronavirus disease 2019 (COVID-19) is associated with significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. It remains unclear which factors determine severity of illness and long-term outcomes. Emerging evidence points towards an important role of preexisting host factors, such as a deregulated inflammatory response at the time of infection. Here, we demonstrate the negative impact of clonal hematopoiesis, a prevalent clonal disorder of ageing individuals, on COVID-19-related cytokine release severity and mortality. We show that mutations in the gene coding for the methylcytosine dioxygenase TET2 promotes amplification of classical and intermediate monocyte subsets. Using single cell multiomic sequencing approaches, we identify cell-specific gene expression changes associated with the loss of TET2 and significant epigenomic deregulation affecting enhancer accessibility of a subset of transcription factors involved in monocyte differentiation. We further identify EGR1 down-regulation secondary to TET2-mediated hypermethylation, resulting in overexpression of MALAT1, a lncRNA that plays a role in hematopoietic stem cell differentiation and monocyte lineage commitment. Together, these data provide a mechanistic insight to the poor prognostic value of clonal hematopoiesis in patients infected with Sars-COV2.

9.
Oxid Med Cell Longev ; 2022: 1492239, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35770044

RESUMEN

Triptolide (TP) has limited usage in clinical practice due to its side effects and toxicity, especially liver injury. Hepatic macrophages, key player of liver innate immunity, were found to be recruited and activated by TP in our previous study. The nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway exerts a protective role in TP-induced liver damage, but its effect on the functions of hepatic macrophage has not been elucidated. Here, we determined whether TP can regulate the recruitment and polarization of hepatic macrophages by inhibiting Nrf2 signaling cascade. Our results demonstrated that TP inhibited the Nrf2 signaling pathway in hepatic macrophages. The changes in hepatic macrophages were responsible for the increased susceptibility toward inflammatory stimuli, and hence, TP pretreatment could induce severe liver damage upon the stimulation of a nontoxic dose of lipopolysaccharides. In addition, the Nrf2 agonist protected macrophages from TP-induced toxicity and Nrf2 deficiency significantly aggravated liver injury by enhancing the recruitment and M1 polarization of hepatic macrophages. This study suggests that Nrf2 pathway-mediated hepatic macrophage polarization plays an essential role in TP-induced liver damage, which can serve as a potential therapeutic target for preventing hepatotoxicity induced by TP.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Factor 2 Relacionado con NF-E2 , Humanos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Diterpenos/efectos adversos , Compuestos Epoxi/efectos adversos , Hígado/metabolismo , Macrófagos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fenantrenos/efectos adversos , Transducción de Señal
10.
Seizure ; 91: 503-506, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34371246

RESUMEN

Vigabatrin (VGB) is approved as monotherapy for pediatric patients with Infantile Spasms (IS). Duration of VGB use should be limited because of the risk of retinal and neurotoxicity, but the optimal length of treatment is unknown. Our study aimed to determine the risk of spasms relapse after 6 months of VGB as first-line therapy in IS patients deemed VGB good responders. The participants were 44 infants with IS who demonstrated both absence of clinical spasms and hypsarrhythmia four weeks after starting VGB, obtained from two cohorts: 29 patients from a multicenter prospective cohort and 15 patients from a retrospective single-center cohort. We divided them post hoc into two groups according to the duration of VGB treatment: 6-month group (n=34) and >6-month group (n=10) and compared outcome between the two groups. No patient in either group had a relapse of spasms. For patients with non-identified etiology (NIE) in the 6 months treatment group, no other seizure types were observed. Late epilepsy, in the form of focal seizures, emerged in only 5/37 patients (3/30 in the 6-month treatment group; 2/7 in the extended treatment group); all within the first 6-9 months after VGB initiation. Our study provides substantial evidence that a shortened VGB course of 6 months could be sufficient to treat and prevent relapse of spasms in children with IS, particularly those with NIE.


Asunto(s)
Espasmos Infantiles , Vigabatrin , Anticonvulsivantes/efectos adversos , Niño , Humanos , Lactante , Estudios Prospectivos , Estudios Retrospectivos , Espasmo/tratamiento farmacológico , Espasmos Infantiles/tratamiento farmacológico , Resultado del Tratamiento , Vigabatrin/efectos adversos
11.
Craniomaxillofac Trauma Reconstr ; 14(2): 126-134, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33995833

RESUMEN

STUDY DESIGN: A retrospective study investigating maxillofacial bone fractures in the pediatric and adolescent population. OBJECTIVE: The aim of this study was to present our experience in the management of pediatric facial bone fractures. METHODS: This was a retrospective study of maxillofacial bone fractures in children and adolescents between the ages <1 year and 19 years in a Saudi Arabian subpopulation. Data collected include demographics, etiology, pattern, and treatment of maxillofacial bone fractures. Data were analyzed using IBM SPSS Statistics for Windows Version 25 (IBM Corp.). Results were presented as simple frequencies and descriptive statistics. RESULTS: Of the 1297 patients with maxillofacial bone fractures, 247 were cases involving children and adolescents giving a prevalence of 19.0% (247 patients, N = 1297). There were 233 males and 14 females with an M:F ratio of 16.6:1. The ages ranged from 9 months to 19 years with a mean ± SD of 14.4 ± 4.6. The age-group between 16 and 20 years had the highest frequency of patients (144 (58.4%)). In the 1- to 5-year group, falls accounted for most of the etiology (15 (6.1%)), while in the 16- to 20-year group, motor vehicular accident (MVA) was the main reason (120 (48.6%)). The majority of the fractures occurred in the mandible with 151(61.1%) cases. Open reduction and internal fixation (ORIF) were the main treatment modality in 171 (69.2%) patients. CONCLUSIONS: MVA was the main etiology of maxillofacial fractures in children and adolescents with male predominance, while the mandible had been the most frequently fractured bone. ORIF was the main treatment modality.

12.
PLoS One ; 16(2): e0245371, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33539410

RESUMEN

BACKGROUND: While women in low- and middle-income countries face a range of barriers to accessing care for hypertensive disorders of pregnancy, there is little understanding of the pathways taken to overcome these constraints and reach the services they need. This study explores the perspectives of women and communities on the influences that impact care-seeking decisions and pathways to health services. METHODS: To understand individual perspectives, we conducted 22 in-depth interviews (IDIs) with pre-eclampsia and eclampsia survivors (PE/E) in a tertiary hospital, where they received care after initiating PE/E services in different parts of the country. In four districts, we conducted one male and one female focus group discussion (FGD) to unearth care-seeking pathways and explore normative perspectives and the range of internal and external influences. Careful thematic analysis using Atlas-ti was applied. RESULTS: Prevailing views of women and communities across settings in Bangladesh indicate varied pathways to care throughout their pregnancy, during childbirth, and in the postnatal period influenced by internal and external factors at the individual, familial, social, and health systems levels. Internal influences draw on women's own awareness of hypertension complications and options, and their ability to decide to seek care. External factors include social influences like family and community norms, culturally-accepted alternatives, and community perceptions of the health system's capacity to provide quality care. The interaction of these factors often delay care seeking and can lead to complex pathways to care. CONCLUSION: Women's individual pathways to care were diverse, despite the homogenous community perceptions of the influences on women's care-seeking behaviors. This finding supports the need for improving quality of care in primary healthcare facilities and strengthening gender equity and community-based promotion activities through targeted policy and programming.


Asunto(s)
Eclampsia/epidemiología , Aceptación de la Atención de Salud , Atención Perinatal , Preeclampsia/epidemiología , Atención Prenatal , Calidad de la Atención de Salud , Población Rural , Adolescente , Adulto , Bangladesh/epidemiología , Estudios Transversales , Femenino , Grupos Focales , Accesibilidad a los Servicios de Salud , Humanos , Masculino , Servicios de Salud Materna , Embarazo , Investigación Cualitativa , Adulto Joven
13.
BMC Health Serv Res ; 20(1): 838, 2020 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-32894121

RESUMEN

BACKGROUND: Pharmacy workers in Bangladesh play an important role in managing pregnancy complications by dispensing, counselling and selling drugs to pregnant women and their families. This study examined pharmacy workers' drug knowledge and practice for pre-eclampsia and eclampsia (PE/E) management, including antihypertensives and anticonvulsants, and determine factors associated with their knowledge. METHODS: A cross-sectional survey with 382 pharmacy workers in public facilities (government) and private pharmacies and drug stores assessed their knowledge of antihypertensive and anticonvulsant drugs. 'Pharmacy workers' include personnel who work at pharmacies, pharmacists, family welfare visitors (FWVs), sub-assistant community medical officers (SACMOs), drug storekeepers. Exploratory and multivariate logistic models were used to describe association between knowledge of medicines used in pregnancy and demographic characteristics of pharmacy workers. RESULTS: Overall, 53% pharmacy workers interviewed were drug store owners in private pharmacies while 27% FWVs/SACMOs, who are government service providers also work as drug prescribers and/or dispensers in public facility pharmacies. Majority of pharmacy workers had poor knowledge compared to correct knowledge on both antihypertensive (77.8% vs 22.3%; p < 0.001) and anticonvulsant drugs (MgSO4) (82.2% vs 17.8%; p < 0.001). Multivariate analysis showed SACMOs and FWVs were greater than 4 times more likely to have correct knowledge on anti-hypertensives (AOR = 4.2, 95% CI:1.3-12.3, P < 0.01) and anticonvulsant drugs (AOR = 4.9, 95% CI:1.3-18.1, P < 0.01) compared to pharmacists. Pharmacy workers who had received training were more likely to have correct knowledge on antihypertensive and anticonvulsant drugs than those who had no training. CONCLUSIONS: Pharmacy workers' knowledge and understanding of antihypertensive and anticonvulsant drugs, particularly for prevention and management of PE/E is limited in Bangladesh. Most pharmacies surveyed are private and staffed with unskilled workers with no formal training on drugs. Expansion of maternal and newborn health programs should consider providing additional skills training to pharmacy workers, as well as regulating these medicines at informal pharmacies to mitigate any harmful practices or adverse outcomes of unauthorized and incorrectly prescribed and used drugs. It is important that correct messaging and medicines are available as drug stores are often the first point of contact for most of the women and their families.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Antihipertensivos/uso terapéutico , Eclampsia/tratamiento farmacológico , Conocimientos, Actitudes y Práctica en Salud , Farmacéuticos/estadística & datos numéricos , Preeclampsia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bangladesh , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Servicios Farmacéuticos , Farmacias/estadística & datos numéricos , Embarazo , Encuestas y Cuestionarios , Adulto Joven
14.
Br J Anaesth ; 125(3): 282-290, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32536445

RESUMEN

BACKGROUND: Postoperative neurocognitive disorders may arise in part from adverse effects of general anaesthetics on the CNS, especially in older patients or individuals otherwise vulnerable to neurotoxicity because of systemic disease or the presence of pre-existing neuropathology. Previous studies have documented cytokine and injury biomarker responses to surgical procedures that included general anaesthesia, but it is not clear to what degree anaesthetics contribute to these responses. METHODS: We performed a prospective cohort study of 59 healthy volunteers aged 40-80 yr who did not undergo surgery. Plasma markers of neurological injury and inflammation were measured immediately before and 5 h after induction of general anaesthesia with 1 minimum alveolar concentration of sevoflurane. Biomarkers included interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), C-reactive protein (CRP), and neural injury (tau, neurofilament light [NF-L], and glial fibrillary acidic protein [GFAP]). RESULTS: Baseline biomarkers were in the normal range, although NF-L and GFAP were elevated as a function of age. At 5 h after induction of anaesthesia, plasma tau, NF-L, and GFAP were significantly decreased relative to baseline. Plasma IL-6 was significantly increased after anaesthesia, but by a biologically insignificant degree (<1 pg ml-1); plasma TNF-α and CRP were unchanged. CONCLUSIONS: Sevoflurane general anaesthesia without surgery, even in older adults, did not provoke an inflammatory state or neuronal injury at a concentration that is detectable by an acute elevation of measured plasma biomarkers in the early hours after exposure. CLINICAL TRIAL REGISTRATION: NCT02275026.


Asunto(s)
Anestesia General/métodos , Anestésicos por Inhalación/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Proteína C-Reactiva/efectos de los fármacos , Estudios de Cohortes , Femenino , Proteína Ácida Fibrilar de la Glía/sangre , Proteína Ácida Fibrilar de la Glía/efectos de los fármacos , Voluntarios Sanos , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Proteínas de Neurofilamentos/efectos de los fármacos , Estudios Prospectivos , Valores de Referencia , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/efectos de los fármacos
15.
Rambam Maimonides Med J ; 11(4)2020 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-32441649

RESUMEN

OBJECTIVE: Inhalational drugs used in treating asthma have several side effects including those on oral tissues. We therefore designed a study to analyze the effects of inhalational drugs on the buccal mucosal cells of the oral cavity. METHODS: Smears were obtained from clinically normal buccal mucosa of 20 randomly selected asthmatic patients who had been under inhalational therapy for at least 6 months. The Papanicolaou-stained smears were then analyzed for average nuclear area, average cytoplasmic area, and average nuclear area:cytoplasmic area ratio for each patient, and the values were compared with those of 10 healthy controls. RESULTS: A statistically significant decrease in cytoplasmic area (P<0.001) was found in asthmatic patients compared to controls. A significant increase in mean nuclear area:cytoplasmic area ratio (P<0.001) was noted in asthmatic patients when compared to controls. CONCLUSION: Prolonged use of inhalational drugs in patients diagnosed with asthma is associated with changes in oral epithelial cells. There is a need to assess whether these are the direct adverse effects of such drugs and whether they have any long-term impact on oral tissues.

16.
DNA Repair (Amst) ; 90: 102852, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32388005

RESUMEN

When its DNA is damaged, Escherichia coli induces the SOS response, which consists of about 40 genes that encode activities to repair or tolerate the damage. Certain alleles of the major SOS-control genes, recA and lexA, cause constitutive expression of the response, resulting in an increase in spontaneous mutations. These mutations, historically called "untargeted", have been the subject of many previous studies. Here we re-examine SOS-induced mutagenesis using mutation accumulation followed by whole-genome sequencing (MA/WGS), which allows a detailed picture of the types of mutations induced as well as their sequence-specificity. Our results confirm previous findings that SOS expression specifically induces transversion base-pair substitutions, with rates averaging about 60-fold above wild-type levels. Surprisingly, the rates of G:C to C:G transversions, normally an extremely rare mutation, were induced an average of 160-fold above wild-type levels. The SOS-induced transversion showed strong sequence specificity, the most extreme of which was the G:C to C:G transversions, 60% of which occurred at the middle base of 5'GGC3'+5'GCC3' sites, although these sites represent only 8% of the G:C base pairs in the genome. SOS-induced transversions were also DNA strand-biased, occurring, on average, 2- to 4- times more often when the purine was on the leading-strand template and the pyrimidine on the lagging-strand template than in the opposite orientation. However, the strand bias was also sequence specific, and even of reverse orientation at some sites. By eliminating constraints on the mutations that can be recovered, the MA/WGS protocol revealed new complexities of SOS "untargeted" mutations.


Asunto(s)
Escherichia coli/genética , Mutagénesis , Mutación , Respuesta SOS en Genética , ADN Bacteriano/metabolismo , ADN Polimerasa Dirigida por ADN/metabolismo , Tasa de Mutación , Secuenciación Completa del Genoma
17.
Reprod Health ; 17(1): 46, 2020 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-32252775

RESUMEN

BACKGROUND: Hypertensive disorders in pregnancy, specifically pre-eclampsia and eclampsia (PE/E), are the second biggest killer of pregnant women globally and remains the least understood and most challenging maternal morbidity to manage. Although great strides were made in reducing maternal and newborn mortality between 1990 and 2015, this was clearly not enough to achieve the global health goals. To reduce maternal deaths: 1) early detection of PE needs to be improved; 2) effective management of PE/E needs to occur at lower health system levels and should encourage timely care-seeking; and 3) prioritizing the scale up of a comprehensive package of services near to where women live. FINDINGS: This commentary describes a pragmatic approach to test scalable and sustainable strategies for expanding access to quality under-utilized maternal health commodities, interventions and services. We present a primary health care (PHC) PE/E Model based on implementation research on identified gaps in care in several countries, accepted global best practice and built on the basic premise that PHC providers can take on additional skills with adequate capacity building, coaching and supervision, and community members desire control over their own health. The PHC PE/E model displays the linkages and opportunities to prevent and treat PE/E in a simplified way; however, there are numerous interlinking factors, angles, and critical points to consider including leadership, policies and protocols; relevant medicines and commodities, ongoing capacity building strategies at lower levels and understanding what women and their communities want for safe pregnancies. CONCLUSION: The PHC model described here uses PE/E as an entry to improve the quality of ANC and by extension the pregnancy continuum. Bringing preventive and treatment services nearer to where pregnant women live makes sense.


Asunto(s)
Eclampsia/tratamiento farmacológico , Sulfato de Magnesio/uso terapéutico , Preeclampsia/tratamiento farmacológico , Atención Primaria de Salud , Competencia Clínica , Eclampsia/diagnóstico , Femenino , Humanos , Modelos Teóricos , Preeclampsia/diagnóstico , Embarazo , Mujeres Embarazadas
18.
Acta Pharm ; 70(2): 145-159, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-31955138

RESUMEN

Middle East respiratory syndrome coronavirus (MERS-CoV) had emerged and spread because of the worldwide travel and inefficient healthcare provided for the infected patients in several countries. Herein we investigated the anti-MERS-CoV activity of newly synthesized sixteen halogenated triazole compounds through the inhibition of helicase activity using the FRET assay. All new compounds underwent justification for their target structures via microanalytical and spectral data. SAR studies were performed. Biological results revealed that the most potent compounds were 4-(cyclopent-1-en-3-ylamino)-5-(2-(4-iodophenyl)hydrazinyl)-4H-1,2,4-triazole-3-thiol (16) and 4-(cyclopent-1-en-3-ylamino)-5-[2-(4-chlorophenyl)hydrazinyl]-4H-1,2,4-triazole-3-thiol (12). In silico molecular docking of the most potent compounds was performed to the active binding site of MERS-CoV helicase nsp13. Molecular docking results are in agreement with experimental findings.


Asunto(s)
Antivirales/farmacología , Diseño Asistido por Computadora , Infecciones por Coronavirus/tratamiento farmacológico , ADN Helicasas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Simulación del Acoplamiento Molecular , Triazoles/farmacología , Proteínas Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Infecciones por Coronavirus/virología , ADN Helicasas/química , ADN Helicasas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/enzimología , Coronavirus del Síndrome Respiratorio de Oriente Medio/crecimiento & desarrollo , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/metabolismo , Proteínas Virales/química , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacos
19.
Ann Maxillofac Surg ; 10(2): 402-408, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33708586

RESUMEN

INTRODUCTION: Special cooperation is required among surgeons and anesthetists in airway management during repair of panfacial fractures, due to problems of shared airway and occlusion. Several methods have been proposed for airway management and sequencing of repair of panfacial fractures. The main objective of the current study was to share our experience in the airway management and sequencing of repair of panfacial fractures. METHODS: This was a retrospective study of panfacial fractures in the Kingdom of Saudi Arabia from January 2008 to December 2018. Data collected included demographics, type of airway management, sequence of repair (as primary variables), and outcome of surgery (secondary variable), while surgeon and anesthetic expertise are confounders. Data were analyzed using IBM SPSS Statistics for Windows Version 25 (Armonk, NY, USA: IBM Corp). Results were presented as simple frequencies and descriptive statistics. Pearson Chi-square was used to compare categorical variables such as airway management and sequencing of repair with the panfacial fractures. Statistical significance was set at P ≤ 0.05. RESULTS: Overall, 1057 patients sustained different categories of maxillofacial bone fractures with 23 females and 1034 males (M:F of 46:1). A total of 43 male patients out of 1057 patients had panfacial fractures during the study period, giving a prevalence rate of 4.1%. Only the 43 male patients with panfacial fractures were analyzed. All cases were as a result of motor vehicular accident. Six (13.9%) patients had tracheostomy while 37 (86.1%) patients had submental intubation. "Bottom-up" and "outside-in" approach was used in 33 (76.7%) patients, while "top-bottom" and "inside-out" approach was used in 10 (23.3%) patients. DISCUSSION: Submental intubation was the major airway management of panfacial fracture, and "bottom-up" and "outside-in" approach was the main sequence of repair in our series. These approaches have been mentioned in the literature. CONCLUSION: From our study, victims of pan-facial fractures were found to be exclusively male with MVA as the sole etiological factor. Barring severe head injuries, which may necessitate the use of tracheostomy to sustain breathing over a longer period, submental intubation is extremely reliable as a mode of airway management during surgical treatment of panfacial fractures. The sequencing of repair of panfacial fractures can only be determined according to the case presentation rather than a predetermined one.

20.
Asian J Surg ; 43(1): 13-19, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30910377

RESUMEN

Etiology of ascites of unknown origin varies with geographic area and ethnic origin. Tuberculous peritonitis and peritoneal carcinomatosis constitute a considerable proportion of patients. Differentiation between both is a major challenge. The role of omental thickness (OT) by ultrasonography to predict risk of malignancy in unexplained ascites. This prospective study was done at Kasr Alainy School of Medicine, Cairo University and included 100 adults with unexplained ascites and thickened omentum (>15 mm) on ultrasonography. An expert performed ultrasonography to assess peritoneum and peritoneal cavity and measure OT. Ascites was assessed regarding volume, echogenicity, and loculation. The ascitic fluid was analyzed to measure lactate dehydrogenase, adenosine deaminase, and total leukocytic count. Laparoscopic exploration with biopsy was done for final diagnosis that divided the patients into; TB Group (n = 44) and peritoneal carcinomatosis group (n = 56). Main Outcome Measures were to determine degree of omental thickness as a predictor of malignancy risk in unexplained ascites and other ultrasonographic features to predict malignancy risk including omental echogenicity and results of diagnostic ascitic tapping. We found that OT was greater in the PC group compared to the TB group (24.6 ± 4.6 mm vs. 17.9 ± 3.0 mm, respectively, p < 0.001). Higher frequency of hypoechogenicity, irregular peritoneal surface, omental cakes, and lymph nodes was seen in PC Group. ADA, TLC, and relative lymphocyte count were higher in TB group. Omental thickness ≥19.5 mm has a sensitivity of 89.3%, specificity of 84.1% to diagnose PC. We can conclude that omental thickness >19 mm is a sensitive and specific predictor of malignancy in patients with unexplained ascites.


Asunto(s)
Ascitis/diagnóstico por imagen , Epiplón/diagnóstico por imagen , Epiplón/patología , Valor Predictivo de las Pruebas , Ultrasonografía , Anciano , Egipto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Riesgo
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