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1.
Pak J Med Sci ; 37(3): 651-656, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34104142

RESUMEN

OBJECTIVE: To investigate the role of concomitant Internal Limiting Membrane (ILM) peeling during surgery for macula off Rhegmatogenous Retinal Detachment (RRD) in preventing postoperative Epiretinal Membrane (ERM) formation; and its effect on the visual acuity. METHODS: This was a prospective, quasi-experimental study conducted from August 2018 to July 2019 at LRBT Tertiary Eye Care hospital, Karachi. Fifty-six patients with macula off RRD were divided into groups A (with ILM peeling) and B (without ILM peeling) via non-probability convenience sampling. All patients underwent standard 3 ports pars plana vitrectomy with silicon oil tamponade. In Group-A, ILM was stained using 0.5% ICG. Patients were evaluated clinically and by spectral domain optical coherence tomography (SD-OCT), pre- and post-operatively. Main outcomes recorded were best corrected visual acuity (BCVA) and occurrence of ERM on SD-OCT. RESULTS: There were 26 patients in Group-A and 30 patients in Group-B. At six months' follow-up, ERM had not developed in any case in Group-A compared to five patients (16.7%) in Group-B. There was no statistical difference in mean BCVA change from baseline. CONCLUSION: ILM peeling during vitrectomy for RRD prevents the formation of macular ERM post-operatively. This may reduce the need of a second vitrectomy. However, visual outcomes were comparable to the non-ILM peeling vitrectomy.

2.
Eur Respir J ; 56(5)2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32675200

RESUMEN

BACKGROUND: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter. OBJECTIVES: To prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection. METHODS: Prospective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months. RESULTS: Mortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0-2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3-4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5-7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71-0.83) and 0.77 (95% CI 0.72-0.82), respectively. CONCLUSIONS: The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.


Asunto(s)
Enfermedades Pleurales , Adulto , Humanos , Tiempo de Internación , Proyectos Piloto , Estudios Prospectivos , Factores de Riesgo
3.
J Immunol ; 195(10): 4913-21, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26423149

RESUMEN

Neuronal apoptosis is a key aspect of many different neurologic diseases, but the mechanisms remain unresolved. Recent studies have suggested a mechanism of innate immune-induced neuronal apoptosis through the stimulation of endosomal TLRs in neurons. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including microRNAs released by damaged neurons. In the present study, we identified the mechanism responsible for TLR7/TLR9-mediated neuronal apoptosis. TLR-induced apoptosis required endosomal localization of TLRs but was independent of MyD88 signaling. Instead, apoptosis required the TLR adaptor molecule SARM1, which localized to the mitochondria following TLR activation and was associated with mitochondrial accumulation in neurites. Deficiency in SARM1 inhibited both mitochondrial accumulation in neurites and TLR-induced apoptosis. These studies identify a non-MyD88 pathway of TLR7/ TLR9 signaling in neurons and provide a mechanism for how innate immune responses in the CNS directly induce neuronal damage.


Asunto(s)
Apoptosis/inmunología , Proteínas del Dominio Armadillo/inmunología , Proteínas del Citoesqueleto/inmunología , Glicoproteínas de Membrana/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Neuritas/inmunología , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 9/inmunología , Animales , Apoptosis/genética , Proteínas del Dominio Armadillo/genética , Proteínas del Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Ratones , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/inmunología , Factor 88 de Diferenciación Mieloide/genética , Receptor Toll-Like 7/genética , Receptor Toll-Like 9/genética
4.
Mol Cell ; 32(1): 150-8, 2008 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-18851841

RESUMEN

Cell-density-dependent gene regulation by quorum-sensing systems has a crucial function in bacterial physiology and pathogenesis. We demonstrate here that the Staphylococcus aureus agr quorum-sensing regulon is divided into (1) control of metabolism and PSM cytolysin genes, which occurs independently of the small regulatory RNA RNAIII, and (2) RNAIII-dependent control of additional virulence genes. Remarkably, PSM expression was regulated by direct binding of the AgrA response regulator. Our findings suggest that quorum-sensing regulation of PSMs was established before wide-ranging control of virulence was added to the agr regulon, which likely occurred by development of the RNAIII-encoding region around the gene encoding the PSM delta-toxin. Moreover, the agr regulon in the community-associated methicillin-resistant S. aureus MW2 considerably differed from that previously determined using laboratory strains. By establishing a two-level model of quorum-sensing target gene regulation in S. aureus, our study gives important insight into the evolution of virulence control in this leading human pathogen.


Asunto(s)
Proteínas Bacterianas/fisiología , Genes Bacterianos , ARN Bacteriano/genética , Staphylococcus aureus/genética , Staphylococcus aureus/fisiología , Transactivadores/fisiología , Proteínas Bacterianas/genética , Toxinas Bacterianas/genética , Secuencia de Bases , ADN Bacteriano/genética , Evolución Molecular , Regulación Bacteriana de la Expresión Génica , Humanos , Resistencia a la Meticilina/genética , Modelos Biológicos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Percepción de Quorum/genética , Percepción de Quorum/fisiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad , Transactivadores/genética , Virulencia/genética , Virulencia/fisiología
5.
Pharmacogenet Genomics ; 25(7): 343-353, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25946405

RESUMEN

OBJECTIVES: Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. METHODS: We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). RESULTS: We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. CONCLUSION: Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.


Asunto(s)
/genética , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Indígenas Norteamericanos/genética , Warfarina/administración & dosificación , Warfarina/farmacocinética , Alaska , Ligasas de Carbono-Carbono/genética , Citocromo P-450 CYP2C9/genética , Familia 4 del Citocromo P450/genética , Femenino , Frecuencia de los Genes , Variación Genética , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Vitamina K/antagonistas & inhibidores , Vitamina K Epóxido Reductasas/genética
6.
Pak J Med Sci ; 31(5): 1197-200, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26649013

RESUMEN

OBJECTIVE: To assess the visual outcome and complications of 25-gauge micro incision vitrectomy surgery (MIVS) in diabetic vitreous haemorrhage. METHODS: This Quasi Experimental study was conducted at LRBT, Tertiary eye care hospital Karachi, from February 2012 to January 2013. Sixty eyes of sixty patients with uncontrolled type II diabetes mellitus (DM) were included. There were 43 (71.7%) males and 17 (28.3%) females. Age range was 40 - 60 years. All randomly selected patients underwent 25-gauge sutureless micro incision vitrectomy surgery for diabetic vitreous haemorrhage. Main outcomes measured were best corrected visual acuity (BCVA) assessed with logMAR and post-operative complications. Follow ups were at one day, one week, one month, three months and six months post-operatively. RESULT: Best corrected visual acuity (BCVA) gradually improved in majority of subjects in each subsequent follow up visit. Preoperative visual acuity was 1.023 ±0.226 logMAR, which was improved after final follow up to 0.457±0.256 and P-value was < 0.001. Five patients developed recurrent vitreous haemorrhage during study period, one patient developed cataract (1.7%), one (1.7%) had ocular hypotony defined as intraocular pressure < 5 mmHg and one (1.7%) developed endophthalmitis. CONCLUSION: 25-gauge micro incision vitrectomy surgery (MIVS) is an effective sutureless parsplana vitrectomy surgery which has good visual outcome in diabetic vitreous haemorrhage with minimum manageable complications.

7.
Pak J Pharm Sci ; 28(1): 23-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25553682

RESUMEN

Plants are one of the precious creatures of Allah, producing a verity of useful bioactive compounds having definite pharmacological actions on human body. Keeping in view this idea, the methanolic extract from the bark of Cornus macrophylla was investigated for phytochemicals, antioxidant, total phenolic conte nts (TPC) and phytotoxic activities. Phytochemical analysis of Cornus macrophylla revealed the presence of tannins, anthraquinones, glycosides, reducing sugar, saponins and flavonoids. The percent free radicals scavenging potential of DPPH at 20, 40, 60, 80 and 100µg/ml was 72.69%, 73.32%, 73.51, 73.83% and 74.33% respectively and were compared to ascorbic acid (84.6%, 92.83%, 95.36%, 96.40% and 98.03%), gallic acid (85.49%, 92.47%, 95.14%, 98.22% and 98.03%) and quercetin (95.35%, 96.30%, 97.16%, 98.02% and 98.28%) as standards. The IC(50) value of Cornus macrophylla was 14.5/µg/ml. The TPC of the methanolic bark extract was 2.916 mg gallic acid equivalents/g of extract. The extract displyed excellent phytotoxic activity against the tested plant Lemna minor and inhibited the growth at 1000 µg/ml. Our findings revealed that the crude methanolic extract of Cornus macrophylla is a potential source of natural antioxidants and herbicidal.


Asunto(s)
Antioxidantes/farmacología , Araceae/efectos de los fármacos , Cornus , Herbicidas/farmacología , Fenoles/farmacología , Extractos Vegetales/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Cornus/química , Herbicidas/química , Herbicidas/aislamiento & purificación , Metanol/química , Pakistán , Fenoles/análisis , Fitoterapia , Corteza de la Planta , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Solventes/química
8.
Matern Child Health J ; 18(1): 120-128, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23423858

RESUMEN

Studies indicate nicotine metabolism varies by race and can change during pregnancy. Given high rates of tobacco use and limited studies among Alaska Native (AN) women, we estimated associations of saliva cotinine levels with cigarette use and second-hand smoke (SHS) exposure and estimated a saliva cotinine cutoff to distinguish smoking from non-smoking pregnant AN women. Using questionnaire data and saliva cotinine, we utilized multi-variable linear regression (n = 370) to estimate cotinine associations with tobacco use, SHS exposure, demographic, and pregnancy-related factors. Additionally, we estimated an optimal saliva cotinine cutoff for indication of active cigarette use in AN pregnant women using receiver operating characteristic (ROC) curve analysis (n = 377). Saliva cotinine significantly decreased with maternal age and significantly increased with cigarettes smoked per day, SHS exposure, and number of previous full term pregnancies. Using self-reported cigarette use in the past 7 days as indication of active smoking, the area under the ROC curve was 0.975 (95 % CI: 0.960-0.990). The point closest to 100 % specificity and sensitivity occurred with a cotinine concentration of 1.07 ng/mL, which corresponded to sensitivity of 94 % and specificity of 94 %. We recommend using a saliva cotinine cutoff of 1 ng/mL to distinguish active smoking in pregnant AN women. This cutoff is lower than used in other studies with pregnant women, most likely due to high prevalence of light or intermittent smoking in the AN population. Continued study of cotinine levels in diverse populations is needed.


Asunto(s)
Cotinina/análisis , Mujeres Embarazadas/etnología , Fumar/etnología , Adulto , Alaska/epidemiología , Femenino , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Inuk/estadística & datos numéricos , Embarazo , Curva ROC , Saliva/química , Sensibilidad y Especificidad , Fumar/metabolismo , Encuestas y Cuestionarios , Contaminación por Humo de Tabaco/análisis , Adulto Joven
9.
J Community Health ; 38(1): 86-94, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22772841

RESUMEN

Type 2 diabetes is a worldwide health problem that has reached epidemic proportions in some communities. Alaska Native and American Indian (AN/AI) people are disproportionately diagnosed with type 2 diabetes and incidence is increasing in many Alaska communities. Developing effective interventions requires understanding the social and psychological factors that impact effective management of diabetes, yet little is known about these factors in AN/AI communities. The objective of this study was to explore perceived psychosocial needs and barriers to management of diabetes among AN/AI adults with type 2 diabetes receiving care at the Alaska Native Primary Care Center (ANPCC) to inform programmatic efforts and potential future research. We conducted three focus groups and five interviews with 13 AN/AI adults with type 2 diabetes. Interview and focus group questions elicited perceived factors that affect management of diabetes, with a focus on the psychological, social and spiritual impacts of diabetes. Data were transcribed, coded and analyzed using thematic analysis. Key themes that emerged from these data included resources and roadblocks, as well as turning points in the trajectory of diabetes. Resources are factors with a perceived positive impact on management of diabetes, including: (1) knowledge and education about diabetes, (2) social support from other people with diabetes, (3) spirituality, and (4) self-efficacy. Roadblocks are factors with a perceived negative impact on management of diabetes and include: (1) self-reported lack of knowledge about nutrition and diet, (2) social difficulties caused by dietary restrictions, and (3) co-morbid medical conditions. Finally, turning points are experiences described by participants as having transformed roadblocks in resources and thus facilitating improvement in the management of diabetes. Future programmatic interventions to improve management of diabetes with this population should focus on improving dietary education and social support opportunities for newly-diagnosed individuals. Also, educational and support opportunities for family members and friends of individuals with diabetes should also be offered to facilitate understanding and support of their loved ones' management of diabetes, especially with regard to dietary restrictions in social settings. Efforts should also focus on strengthening newly-diagnosed individuals' self-efficacy and providing ongoing support as individuals progressively adjust to the illness over time and make behavioral changes. Future research with this population should explore the effects of family support groups and the possibility of Web-based or other alternative interventions for improving psychosocial health and management of diabetes efforts.


Asunto(s)
Diabetes Mellitus Tipo 2/etnología , Indígenas Norteamericanos/estadística & datos numéricos , Adulto , Alaska , Depresión/etnología , Diabetes Mellitus Tipo 2/psicología , Grupos Focales , Conocimientos, Actitudes y Práctica en Salud/etnología , Accesibilidad a los Servicios de Salud , Humanos , Entrevistas como Asunto , Evaluación de Necesidades , Psicología , Investigación Cualitativa , Autoeficacia , Apoyo Social , Espiritualidad
10.
Ethn Dis ; 23(1): 56-64, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23495623

RESUMEN

OBJECTIVES: To assess whether type 2 diabetes mellitus (DM2) and DM2 complications are associated with presence and severity of depression among Alaska Native and American Indian people (AN/Als). DESIGN: Retrospective, cross-sectional analysis of medical records. SETTING: Southcentral Foundation Primary Care Center (SCF-PCC) in Anchorage, Alaska. PARTICIPANTS: Total of 23,529 AN/AI adults. PRIMARY OUTCOME MEASURES: Patient Health Questionnaire (PHQ) scores (0-9 negative, 10-14 mild, 15-19 moderate, 20+ severe) and DSM-IV depression diagnosis. RESULTS: DM2 prevalence was 6% (n=1,526). Of those with DM2, 19% (n = 292) had one or more DM2 complications and average HbAlc was 7.1%. Prevalence of depression diagnosis was similar between AN/Als with and without DM2 (P = .124). Among those screened for depression (n = 12,280), there were similar rates of PHQ severity between those without and with DM2; respectively 4% (n = 452) vs 4% (n = 42) mild, 4% (n = 404) vs 3% (n = 29) moderate, and 4% (n = 354) vs 4% (n = 38) severe. In multivariable logistic regression, DM2 was not associated with PHQ severity (OR 1.02, 95% CI 0.81-1.27) or depression diagnosis (OR 1.27, 95% CI 1.00-1.62). Increased odds of depression and higher depression severity were associated with female sex, younger age, being unmarried, substance abuse/dependence, and increased ambulatory visits. Depression was associated with number of other chronic conditions among AN/Als with DM2 but not with number of complications. CONCLUSIONS: Presence and severity of depression among AN/Al primary care patients was not significantly associated with DM2 nor DM2 complications, despite a slightly higher rate of depression diagnosis among those with DM2.


Asunto(s)
Depresión/etnología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/etnología , Indígenas Norteamericanos , Adolescente , Adulto , Alaska , Depresión/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Atención Primaria de Salud , Adulto Joven
11.
Infect Immun ; 79(5): 1927-35, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21402769

RESUMEN

The molecular basis underlying the pathogenic success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is not completely understood, but differential gene expression has been suggested to account at least in part for the high virulence of CA-MRSA strains. Here, we show that the agr gene regulatory system has a crucial role in the development of skin infections in the most prevalent CA-MRSA strain USA300. Importantly, our data indicate that this is due to discrepancies between the agr regulon of CA-MRSA and those of hospital-associated MRSA and laboratory strains. In particular, agr regulation in strain USA300 led to exceptionally strong expression of toxins and exoenzymes, upregulation of fibrinogen-binding proteins, increased capacity to bind fibrinogen, and increased expression of methicillin resistance genes. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon contributed to the evolution of highly pathogenic CA-MRSA.


Asunto(s)
Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica/genética , Staphylococcus aureus Resistente a Meticilina/genética , Infecciones Cutáneas Estafilocócicas/genética , Transactivadores/genética , Animales , Infecciones Comunitarias Adquiridas/genética , Expresión Génica , Perfilación de la Expresión Génica , Resistencia a la Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Ratones , Ratones Desnudos , Análisis de Secuencia por Matrices de Oligonucleótidos , Regulón/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones Cutáneas Estafilocócicas/inmunología , Virulencia
12.
PLoS Pathog ; 5(7): e1000533, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19649313

RESUMEN

Bacterial virulence and antibiotic resistance have a significant influence on disease severity and treatment options during bacterial infections. Frequently, the underlying genetic determinants are encoded on mobile genetic elements (MGEs). In the leading human pathogen Staphylococcus aureus, MGEs that contain antibiotic resistance genes commonly do not contain genes for virulence determinants. The phenol-soluble modulins (PSMs) are staphylococcal cytolytic toxins with a crucial role in immune evasion. While all known PSMs are core genome-encoded, we here describe a previously unidentified psm gene, psm-mec, within the staphylococcal methicillin resistance-encoding MGE SCCmec. PSM-mec was strongly expressed in many strains and showed the physico-chemical, pro-inflammatory, and cytolytic characteristics typical of PSMs. Notably, in an S. aureus strain with low production of core genome-encoded PSMs, expression of PSM-mec had a significant impact on immune evasion and disease. In addition to providing high-level resistance to methicillin, acquisition of SCCmec elements encoding PSM-mec by horizontal gene transfer may therefore contribute to staphylococcal virulence by substituting for the lack of expression of core genome-encoded PSMs. Thus, our study reveals a previously unknown role of methicillin resistance clusters in staphylococcal pathogenesis and shows that important virulence and antibiotic resistance determinants may be combined in staphylococcal MGEs.


Asunto(s)
Proteínas Bacterianas/genética , Toxinas Bacterianas/genética , Secuencias Repetitivas Esparcidas , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Perforina/genética , Animales , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/inmunología , Toxinas Bacterianas/metabolismo , Secuencia de Bases , Biopelículas/crecimiento & desarrollo , Fenómenos Químicos , Cisteína/metabolismo , Modelos Animales de Enfermedad , Hemólisis , Humanos , Inflamación/inmunología , Inflamación/microbiología , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/metabolismo , Ratones , Datos de Secuencia Molecular , Neutrófilos/citología , Neutrófilos/microbiología , Proteínas de Unión a las Penicilinas , Perforina/metabolismo , Staphylococcus epidermidis/genética , Staphylococcus epidermidis/metabolismo , Staphylococcus epidermidis/patogenicidad
13.
Clin Transl Sci ; 14(4): 1292-1302, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33503331

RESUMEN

The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup'ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4-mediated 4ß-vitamin D hydroxylation activity in Yup'ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele-coupled with low frequency of the functional CYP3A5*1 variant-may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele.


Asunto(s)
/genética , Citocromo P-450 CYP3A/metabolismo , Indígenas Norteamericanos/genética , Xenobióticos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Línea Celular Tumoral , Niño , Preescolar , Citocromo P-450 CYP3A/genética , Pruebas de Enzimas , Femenino , Humanos , Lactante , Recién Nacido , Desequilibrio de Ligamiento , Masculino , Microsomas Hepáticos , Persona de Mediana Edad , Pruebas de Farmacogenómica , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Adulto Joven
14.
Environ Sci Pollut Res Int ; 28(30): 41000-41015, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33774795

RESUMEN

The pro-poor growth and environmental sustainability are the twin agendas widely discussed in environmental science literature. The technology-embodied growth helps to attain both agendas through knowledge sharing and technology transfer, which trickle down to the poor income group and improve their living standards. Hence, the role of information and communication technologies (ICTs) is deemed crucial in boosting economic growth and is under deep consideration to establish its role in reducing poverty and environmental pollution. The current study examines the long-run relationship between ICTs, poverty reduction, and ecological degradation in Pakistan using time series data from 1975-2018. The short- and long-run parameter estimates were obtained through the Autoregressive Distributed Lag (ARDL) model for robust inferences. The results substantiate the inverted U-shaped Environmental Kuznets Curve relationship between income and emissions with a turning point at US$1000 in the short-run and US$800 in the long-run. The results confirmed the decisive intervention of ICTs factors in the poverty reduction, i.e., computer communications and mobile-telephone-broadband subscriptions support to reduce poverty incidence with the mediation of inbound FDI in a country. As far as income inequality is concerned, it shows that computer services support minimizing income inequality via a channel of high-technology exports in a country. The technology embodied emissions verified in the long-run, where mobile-telephone-broadband subscriptions increase carbon emissions. Finally, mobile-telephone-broadband subscriptions and inbound FDI both are significant contributors to amplify the country's economic growth. The results conclude that poverty reduction and environmental sustainability agenda are achieved by developing green ICT infrastructure in a country.


Asunto(s)
Dióxido de Carbono , Tecnología de la Información , Dióxido de Carbono/análisis , Desarrollo Económico , Contaminación Ambiental/análisis , Lluvia
15.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 2): o397, 2010 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-21579818

RESUMEN

The title compound, C(12)H(14)O(6), features a roughly planar mol-ecule (r.m.s. deviation for all non-H atoms = 0.287 Å). In the crystal, the mol-ecules are held together by C-H⋯O hydrogen bonds.

16.
Environ Sci Pollut Res Int ; 27(9): 10011-10026, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31933090

RESUMEN

The importance of information and communication technologies (ICTs) in environmental resource management opens a new debate for the policy makers in order to promote green technologies to mitigate high mass carbon emissions across the globe. "Digital Pakistan" initiative is taken by the government that aimed to use technology for country's social welfare, which further be enhance for achieving environmental sustainability over a time horizon. This study examined the long-run relationship between ICTs, energy demand, and carbon emissions in a context of Pakistan by using a time series data from 1975 to 2017. The results show that energy demand increases economic growth in the short-run while it decreases economic growth in the long-run. The country's economic growth substantially increases along with an increase in trade openness and mobile-telephone subscription (ICTs) in the short-run; however, the result is changed in the long-run due to increase in carbon emissions in a given time period. The results provoke that continued economic growth and ICT penetration substantially decreases energy demand, whereas urbanization increases energy demand in a country. The results show that variations in emissions associated with proportionate changes in ICTs penetration, economic growth, energy demand, and population growth. Human capital, trade openness, and energy demand are the significant drivers of ICT penetration in a country. The study concludes that the use of green technology is imperative for achieving long-term sustainable growth in a country.


Asunto(s)
Dióxido de Carbono/análisis , Desarrollo Económico , Humanos , Pakistán , Tecnología , Urbanización
17.
J Pak Med Assoc ; 59(10): 719-20, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19813691

RESUMEN

The superior vena caval (SVC) syndrome is a common oncological emergency requiring the quick initiation of appropriate therapy. However, it may also result from a medical procedure e.g. central catheter or temporary pacing wire insertion, with symptoms usually developing acutely and dramatically. If symptoms persist despite removal of the offending device, chemotherapy and radiotherapy are obviously precluded. Alternative treatment modalities include thrombolysis, thrombectomy devices, stents, and surgery. Clinically covert thrombosis is not uncommon, and as interventions and invasive procedures requiring central venous cannulations become commonplace, this iatrogenic complications will inevitably occur more often. Even the use of ultrasound guided insertion does not avoid catheter related obstruction. A case of an iatrogenc haemodialysis catheter related SVCS is presented and the aetiopathogensis, signs and symptoms, diagnosis, and management are discussed.


Asunto(s)
Cateterismo Venoso Central/efectos adversos , Diálisis Renal/efectos adversos , Síndrome de la Vena Cava Superior/etiología , Adulto , Diagnóstico Diferencial , Humanos , Enfermedad Iatrogénica , Masculino
18.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 4): o931, 2009 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-21582631

RESUMEN

The three independent mol-ecules of the title compound, C(15)H(14)O(4), have similar orientations of their aromatic rings, the dihedral angles between the rings being 57.0 (1), 58.1 (1) and 58.2 (1)°. In each mol-ecule, the hydr-oxy group forms an intra-molecular hydrogen bond to the carbonyl O atom, forming an S(10) ring motif.

19.
ACS Omega ; 4(16): 16860-16866, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31646232

RESUMEN

The glassy carbon electrode was fabricated with multifunctional bis-triazole-appended calix[4]arene and then used for the simultaneous detection of Zn(II), Pb(II), As(III), and Hg(II). Before applying the square-wave anodic stripping voltammetry, the sensitivity and precision of the modified electrode was assured by optimizing various conditions such as the modifier concentration, pH of the solution, deposition potential, accumulation time, and supporting electrolytes. The modified glassy carbon electrode was found to be responsive up to picomolar limits for the aforementioned heavy metal ions, which is a concentration limit much lower than the threshold level permitted by the World Health Organization. Importantly, the designed sensing platform showed anti-interference ability, good stability, repeatability, reproducibility, and applicability for the detection of multiple metal ions. The detection limits obtained for Zn(II), Pb(II), As(III), and Hg(II) are 66.3, 14.6, 71.9, and 28.9 pM, respectively.

20.
Nat Microbiol ; 4(7): 1114-1119, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30936487

RESUMEN

Social interactions play an increasingly recognized key role in bacterial physiology1. One of the best studied is quorum sensing (QS), a mechanism by which bacteria sense and respond to the status of cell density2. While QS is generally deemed crucial for bacterial survival, QS-dysfunctional mutants frequently arise in in vitro culture. This has been explained by the fitness cost an individual mutant, a 'quorum cheater', saves at the expense of the community3. QS mutants are also often isolated from biofilm-associated infections, including cystic fibrosis lung infection4, as well as medical device infection and associated bacteraemia5-7. However, despite the frequently proposed use of QS blockers to control virulence8, the mechanisms underlying QS dysfunctionality during infection have remained poorly understood. Here, we show that in the major human pathogen Staphylococcus aureus, quorum cheaters arise exclusively in biofilm infection, while in non-biofilm-associated infection there is a high selective pressure to maintain QS control. We demonstrate that this infection-type dependence is due to QS-dysfunctional bacteria having a significant survival advantage in biofilm infection because they form dense and enlarged biofilms that provide resistance to phagocyte attacks. Our results link the benefit of QS-dysfunctional mutants in vivo to biofilm-mediated immune evasion, thus to mechanisms that are specific to the in vivo setting. Our findings explain why QS mutants are frequently isolated from biofilm-associated infections and provide guidance for the therapeutic application of QS blockers.


Asunto(s)
Biopelículas/crecimiento & desarrollo , Infecciones Relacionadas con Catéteres/microbiología , Evasión Inmune , Leucocitos/inmunología , Percepción de Quorum/fisiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/inmunología , Animales , Proteínas Bacterianas/genética , Infecciones Relacionadas con Catéteres/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones Endogámicos C57BL , Viabilidad Microbiana , Mutación , Percepción de Quorum/genética , Infecciones Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/fisiología , Transactivadores/genética
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