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The structural, optoelectronics, and transport properties of TlTaO3 compounds were determined utilizing the full potential augmented plane wave approach using first-principle method. We have considered the generalized gradient approximation for structural optimization and modified Becke-Johnson for electronic properties. The electronic properties reveal that the studied TlTaO3 possesses direct bandgap of magnitude 1.52 eV. Between 0 and 12 eV, optical spectra calculations are made, taking into account the real and imaginary parts of the dielectric function, refractive index, and loss function. The transport properties are estimated considering Boltzmann transport theory. The Seebeck coefficient, electrical conductivity, thermal conductivity, and power factor are all assessed using the Boltzmann transport theory. The optimized thermoelectric response of the examined TlTaO3 is produced by the improved carrier mobility, which also improves the thermoelectric efficiency of the TlTaO3. The obtained results will act as a theoretical road map for upcoming experimental and commercial TlTaO3 applications.
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The structural, magnetic, electronic, elastic, vibrational, optical, thermodynamic as well as thermoelectric properties of newly predicted quaternary LiZrCoX (X = Ge, Sn) Heusler compounds are evaluated intricately with the aid of ab initio techniques developed under the framework of density functional theory. The computed structural properties are found to be in tandem with the existing analogous theoretical and experimental facts. Structural optimization has been carried out in three different structural arrangements, i.e., Type-1, Type-2, and Type-3. Further analysis of the optimization curves reveals that the Type-3 phase, which has the least amount of energy, is the most stable structure for the compounds under consideration. The tabulated cohesive energy and formation energy of these compounds depict their chemical as well as thermodynamic stability. The absence of negative phonon frequencies in the phonon band spectrum of the studied compounds depicts their dynamic stability. Similarly, the tabulated second-order elastic constants (Cij) and the linked elastic moduli show their stability in the cubic phase. The calculated value of Pugh's ratio and Cauchy pressure reveal that LiZrCoGe is brittle whereas LiZrCoSn is ductile. Additionally, the optical characteristics of the compounds are studied in terms of the dielectric function, refractive index, extinction coefficient, absorption coefficient, reflectivity, energy loss function, and optical conductivity. The obtained high value of power factor and figure of merit of the studied lithium-based quaternary compounds predict good thermoelectric behavior in these compounds. Thus, LiZrCoX (X = Ge, Sn) compounds can therefore be used to create innovative and intriguing thermoelectric materials as well as optoelectronic and energy-harvesting equipment.
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OBJECTIVE: Cystic fibrosis associated liver disease (CFLD) is the third largest cause of mortality in CF. Our aim was to define the burden of CFLD in the UK using national registry data and identify risk factors for progressive disease. METHODS: A longitudinal population-based cohort study was conducted. Cases were defined as all patients with CFLD identified from the UK CF Registry, 2008-2013 (n = 3417). Denominator data were derived from the entire UK CF Registry. The burden of CFLD was characterised. Regression analysis was undertaken to identify risk factors for cirrhosis and progression. RESULTS: Prevalence of CFLD increased from 203.4 to 228.3 per 1000 patients during 2008-2013. Mortality in CF patients with CFLD was more than double those without; cirrhotic patients had higher all-cause mortality (HR 1.54, 95% CI 1.09 to 2.18, p = 0.015). Median recorded age of cirrhosis diagnosis was 19 (range 5-53) years. Male sex, Pseudomonas airway infection and CF related diabetes were independent risk factors for cirrhosis. Ursodeoxycholic acid use was associated with prolonged survival in patients without cirrhosis. CONCLUSIONS: This study highlights an important changing disease burden of CFLD. The prevalence is slowly increasing and, importantly, the disease is not just being diagnosed in childhood. Although the role of ursodeoxycholic acid remains controversial, this study identified a positive association with survival.
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Fibrosis Quística/epidemiología , Quistes/epidemiología , Enfermedades del Sistema Digestivo/epidemiología , Cirrosis Hepática/epidemiología , Hepatopatías/epidemiología , Adulto , Niño , Preescolar , Estudios de Cohortes , Fibrosis Quística/complicaciones , Fibrosis Quística/patología , Quistes/complicaciones , Quistes/patología , Enfermedades del Sistema Digestivo/complicaciones , Enfermedades del Sistema Digestivo/patología , Femenino , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Hepatopatías/complicaciones , Hepatopatías/patología , Masculino , Factores de Riesgo , Índice de Severidad de la Enfermedad , Reino Unido/epidemiología , Adulto JovenRESUMEN
AIMS: ß-lactamase inhibitor resistance (BLIR) among the uropathogenic Escherichia coli (UPEC) minimizes treatment options. This study aimed to identify inhibitor-resistant TEM (IRT) ß-lactamase that impart BLIR phenotype and explore non-ß-lactams as alternative therapeutics. METHODS AND RESULTS: Thirty BLIR UPEC isolates were detected by Kirby-Bauer disc diffusion technique using ß-lactam-ß-lactamase inhibitor combination. Conjugal transfer of BLIR was successful from 17 isolates. PCR and sequencing of the TEM ß-lactamases from the transconjugants indicated 14 TEM-84 (IRT) and three novel IRT variants (pUE184TEM, pUE203TEM, pUE210TEM). Three-dimensional models of the latter were predicted and validated. Molecular docking of selected non-ß-lactams (morin, catechin, naringenin triacetate) with the variants using AutoDock 4.2 showed comparable docking scores with significant hydrogen bond and hydrophobic interactions. Molecular dynamics simulation study confirmed stability of the non-ß-lactams inside the catalytic pocket of the enzymes. Moreover, all three non-ß-lactams were found to inhibit the purified TEM ß-lactamase variants in vitro. Microbroth dilution method indicated naringenin triacetate 64 µg ml-1 in combination with ceftazidime (CAZ) 30 µg ml-1 to be most effective against the BLIR transconjugants. CONCLUSIONS: BLIR phenotypes were primarily attributed to the production of IRT ß-lactamases. Administration of the non-ß-lactams with CAZ demonstrated an alternative therapeutic strategy against the IRT ß-lactamase producers. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates high risk of transmission of IRT ß-lactamases and suggests ß-lactam-non-ß-lactam combination therapy to combat BLIR.
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Antibacterianos/farmacología , Escherichia coli Uropatógena/efectos de los fármacos , Inhibidores de beta-Lactamasas/farmacología , Ceftazidima/farmacología , Cefalosporinas/farmacología , Análisis por Conglomerados , Flavanonas/farmacología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Fenotipo , Reacción en Cadena de la Polimerasa , Resistencia betalactámica/genética , beta-Lactamasas/genética , beta-Lactamas/químicaRESUMEN
Tyro3, Axl, MERTK (TAM) receptor tyrosine kinases are implicated in the regulation of the innate immune response through clearance of apoptotic cellular debris and control of cytokine signaling cascades. As a result they are pivotal in regulating the inflammatory response to tissue injury. Within the liver, immune regulatory signaling is employed to prevent the overactivation of innate immunity in response to continual antigenic challenge from the gastrointestinal tract. In this review we appraise current understanding of the role of TAM receptor function in the regulation of both innate and adaptive immunity, with a focus on its impact upon hepatic inflammatory pathology.
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Hepatopatías/inmunología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Citocinas/genética , Citocinas/metabolismo , Humanos , Inmunidad Innata , Hepatopatías/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Transducción de Señal , Tirosina Quinasa c-Mer , Tirosina Quinasa del Receptor AxlRESUMEN
A 65-year-old gentleman with a previous history of pulmonary embolus presented with a subacute onset of shortness of breath, haemoptysis and chest pain associated with a swollen left leg. Ultrasound Doppler scanning of the leg revealed no deep-vein thrombosis. Thereafter, a CT scan of the pulmonary vasculature revealed a large right-sided pulmonary embolus. CT scanning of the abdomen and pelvis was performed to look for evidence of an intra-abdominal source of thrombus and revealed evidence of a moderate sized pelvic mass causing obstructive uropathy. Urological review of the patient revealed a hard prostate and raised prostate specific antigen, consistent with a diagnosis of primary prostatic carcinoma, which after investigation with a radioisotope bone scan was found to have metastasised to the bony pelvis.
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Neoplasias Óseas/diagnóstico por imagen , Carcinoma/secundario , Neoplasias de la Próstata/patología , Embolia Pulmonar/complicaciones , Lesión Renal Aguda/complicaciones , Anciano , Anticoagulantes/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Carcinoma/complicaciones , Carcinoma/tratamiento farmacológico , Humanos , Hidronefrosis/complicaciones , Hidronefrosis/diagnóstico por imagen , Masculino , Huesos Pélvicos/diagnóstico por imagen , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/tratamiento farmacológico , Embolia Pulmonar/diagnóstico por imagen , Embolia Pulmonar/tratamiento farmacológico , Radiografía , CintigrafíaRESUMEN
Old World, monopartite begomoviruses associated with satellite DNA ß were observed in papaya showing symptoms of leaf curl disease sampled randomly over five years from within a radius of 250 km in north-central India. Three groups of DNA A sequences were evident. One group resembled chili leaf curl virus infecting tomatoes (ChiLCuV). Another group resembled tomato leaf curl New Delhi virus (ToLCuNDV). The third group was novel (tentatively named papaya leaf crumple virus, PaLCrV), with less than 89% identity to known begomovirus sequences in the GenBank database. At least seven DNA A sequences were putative recombinants. The AC4-encoding regions exhibited highest numbers of non-synonymous substitutions. Most DNA ß sequences resembled tomato leaf curl virus-associated DNA ßs. A few DNA ß sequences were similar to that of croton yellow vein mosaic virus-associated DNA ß (CroYVMVß). One DNA ß sequence was novel and showed <65% similarity to its counterparts. Mixed infections and sequence diversity among 25 cloned av1 genes indicated that papayas grown in plantations, kitchen gardens and feral patches in the region are vulnerable to disease outbreak. No geographic or temporal patterns were discernable in the distribution of these viruses.
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Begomovirus/clasificación , Begomovirus/genética , Carica/virología , Variación Genética , Enfermedades de las Plantas/virología , Secuencia de Aminoácidos , ADN Viral/genética , Regulación Viral de la Expresión Génica/fisiología , Genoma Viral , Anotación de Secuencia Molecular , Datos de Secuencia Molecular , Filogenia , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
Yellow mosaic disease causes severe yield loss in grain legumes in Indian subcontinent and south east Asia. The disease is caused by two virus species, Mungbean yellow mosaic India virus (MYMIV) and Mungbean yellow mosaic virus (MYMV). They have genome organization typical of Old World begomoviruses, the unique feature being the presence of an open reading frame (ORF) AV2 upstream of coat protein gene. In order to elucidate its function, ORF AV2 of blackgram isolate, Mungbean yellow mosaic India virus-[India:New Delhi:Blackgram 3:1991] MYMIV-[IN:ND:Bg3:91] and cowpea isolate, Mungbean yellow mosaic India virus-[India:New Delhi:Cowpea7:1998] MYMIV-[IN:ND:Cp7:98], respectively, were over expressed in Escherichia coli in fusion with maltose binding protein (MBP). The recombinant protein did not show efficient binding to DNA. However, both MBP-BgAV2 and MBP-CpAV2 proteins modulated nicking and ATPase activity of replication initiation protein (Rep). Even low concentration, 20 ng of MBP-BgAV2 and MBP-CpAV2 could bring 20 folds increase in nicking activity of Rep. Similarly in the presence of AV2 protein, two to three fold increase in ATPase activity was observed. It is hypothesized that AV2 protein may play a role of accessory protein modulating Rep activities.
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Adenosina Trifosfatasas/metabolismo , Begomovirus/enzimología , ADN Helicasas/metabolismo , ADN Viral/metabolismo , Desoxirribonucleasa I/metabolismo , Transactivadores/metabolismo , Proteínas Virales/metabolismo , Clonación Molecular , Desoxirribonucleasa I/genética , Escherichia coli/genética , Proteínas Virales/genéticaRESUMEN
Although most lumbar lesions associated with spinal tuberculosis can be satisfactorily resolved with nonoperative treatment, there are cases in which surgery is indicated. Between July 1982 and December 2003 we retrospectively reviewed 51 patients who were operated by anterior débridement and fusion. Twelve patients were lost to followup and one died due to inferior vena cava tear. Followup of 38 patients ranged from 2 to 10 years (average 4 years). There were 22 male and 16 female patients, average age 35 years (range, 8-65 years); upper lumbar area (L1-L3) was involved in 17 cases, lower lumbar (L3-L5) in 19 and lumbosacral area in two patients; 28 patients had two-body and 10 had three-body involvement. In 35 patients we performed single stage débridement and fusion. More recently three patients had two stage (instrumentation plus débridement and fusion) procedure. Followup was based on subjective relief, recovery of neural deficit and consolidation at fusion site. Thirty-six out of 38 patients had complete relief from pain and discomfort along with radiographic fusion. Five patients who had neural deficit recovered completely. Surgical treatment of lumbar spinal tuberculosis in selected cases gives satisfactory results.
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Vértebras Lumbares , Fusión Vertebral/métodos , Tuberculosis de la Columna Vertebral/cirugía , Adolescente , Adulto , Anciano , Niño , Desbridamiento , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Radiografía , Resultado del Tratamiento , Tuberculosis de la Columna Vertebral/diagnóstico por imagenRESUMEN
Femoral diaphyseal fractures usually result after trauma of high magnitude and because of this, can be life-threatening injuries or may result in considerable physical disability if not treated with care and caution. Nonoperative treatment of these fractures continues to be popular among the patient population in the Indian subcontinent, which in majority of cases, leads to healing in malalignment, shortening of the limb, chondromalacia patellae, and loss of knee motion. Although the majority of these fractures are being treated by operative methods today, success of the treatment depends largely on the surgeon's familiarity with the procedure or the type of fracture pattern (comminuted or segmental) particularly in a polytraumatized patient. Delayed union and nonunion of femoral-diaphyseal fractures and implant failures usually result after these procedures or the type of injury. The purpose of this study is to discuss various types of neglected femoral diaphyseal fractures and to review the literature on their treatment.
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Fracturas del Fémur/complicaciones , Fracturas del Fémur/cirugía , Fracturas Mal Unidas/cirugía , Fracturas no Consolidadas/cirugía , Adolescente , Clavos Ortopédicos , Fracturas del Fémur/diagnóstico por imagen , Fracturas Mal Unidas/etiología , Fracturas no Consolidadas/diagnóstico por imagen , Fracturas no Consolidadas/etiología , Fracturas no Consolidadas/microbiología , Humanos , Masculino , RadiografíaRESUMEN
The complete nucleotide sequence of the blackgram isolate of mungbean yellow mosaic virus, IMYMV-Bg, which infects legumes in India, was determined and compared at the amino acid level with those of other whitefly-transmitted geminiviruses. The genome organization of IMYMV-Bg was similar to that of the begomoviruses. A unique feature of the genome organization was the sequence divergence of the common region (CR) between DNA-A and DNA-B. In order to understand the mechanism of viral DNA replication, the replication initiator protein, Rep, of IMYMV-Bg was overexpressed in E. coli. The recombinant and refolded Rep bound to CR-sequences of IMYMV-Bg in a specific manner. In this study, evidence is presented for ATP-upregulated cleavage function and ATP-mediated conformational change of Rep. It is hypothesized that, although ATP is not required for cleavage, ATP-mediated conformational changes may result in better access of Rep to the DNA-cleavage site. Evidence is also presented for a site-specific topoisomerase function of Rep, which has not been demonstrated before. The Rep protein can be classified as a type-I topoisomerase because of its nicking activity and sensitivity towards camptothecin, a topoisomerase type-I inhibitor.
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ADN Helicasas/química , Proteínas de Unión al ADN , Fabaceae/virología , Geminiviridae/genética , Plantas Medicinales , Transactivadores/química , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Secuencia de Bases , Clonación Molecular , ADN Helicasas/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , Genoma Viral , Datos de Secuencia Molecular , Conformación Proteica , Pliegue de Proteína , Proteínas Recombinantes/metabolismo , Transactivadores/metabolismoRESUMEN
Trypsin enhances rotavirus infectivity by an unknown mechanism. To examine the structural basis of trypsin-enhanced infectivity in rotaviruses, SA11 4F triple-layered particles (TLPs) grown in the absence (nontrypsinized rotavirus [NTR]) or presence (trypsinized rotavirus [TR]) of trypsin were characterized to determine the structure, the protein composition, and the infectivity of the particles before and after trypsin treatment. As expected, VP4 was not cleaved in NTR particles and was cleaved into VP5(*) and VP8(*) in TR particles. However, surprisingly, while the VP4 spikes were clearly visible and well ordered in the electron cryomicroscopy reconstructions of TR TLPs, they were totally absent in the reconstructions of NTR TLPs. Biochemical analysis with radiolabeled particles indicated that the stoichiometry of the VP4 in NTR particles was the same as that in TR particles and that the VP8(*) portion of NTR, but not TR, particles is susceptible to further proteolysis by trypsin. Taken together, these structural and biochemical data show that the VP4 spikes in the NTR TLPs are icosahedrally disordered and that they are conformationally different. Structural studies on the NTR TLPs after trypsin treatment showed that spike structure could be partially recovered. Following additional trypsin treatment, infectivity was enhanced for both NTR and TR particles, but the infectivity of NTR remained 2 logs lower than that of TR particles. Increased infectivity in these particles corresponded to additional cleavages in VP5(*), at amino acids 259, 583, and putatively 467, which are conserved in all P serotypes of human and animal group A rotaviruses and also corresponded with a structural change in VP7. These biochemical and structural results show that trypsin cleavage imparts order to VP4 spikes on de novo synthesized virus particles, and these ordered spikes make virus entry into cells more efficient.
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Proteínas de la Cápside , Cápside/química , Rotavirus/química , Tripsina/farmacología , Secuencia de Aminoácidos , Animales , Cápside/metabolismo , Chlorocebus aethiops , Microscopía ElectrónicaRESUMEN
Reovirus virions are nonenveloped icosahedral particles consisting of two concentric protein shells, termed outer capsid and core. Outer-capsid protein sigma1 is the viral attachment protein and binds carbohydrate molecules on the surface of host cells. Monoclonal antibody (MAb) 4F2, which is specific for outer-capsid protein sigma3, blocks the binding of sigma1 protein to sialic acid and inhibits reovirus-induced hemagglutination (HA). To determine whether MAb 4F2 inhibits HA by altering sigma1-sigma3 interactions or by steric hindrance, we analyzed the effect of 4F2 immunoglobulin G (IgG) and Fab fragments (Fabs) on HA induced by reovirus strain type 3 Dearing (T3D). The concentration of 4F2 IgG sufficient to inhibit T3D-induced HA was 12.5 microg per ml, whereas that of Fabs was >200 microg per ml. Dynamic light scattering analysis showed that at the concentration of IgG sufficient to inhibit HA, virion-antibody complexes were monodispersed and not aggregated. The affinity of 4F2 Fabs for T3D virions was only threefold less than that of intact IgG, which suggests that differences in HA inhibition titer exhibited by 4F2 IgG and Fabs are not attributable to differences in the affinity of these molecules for T3D virions. We used cryoelectron microscopy and three-dimensional image analysis to visualize T3D virions alone and in complex with either IgG or Fabs of MAb 4F2. IgG and Fabs bind the same site at the distal portion of sigma3, and binding of IgG and Fabs induces identical conformational changes in outer-capsid proteins sigma3 and mu1. These results suggest that MAb 4F2 inhibits reovirus binding to sialic acid by steric hindrance and provide insight into the conformational flexibility of reovirus outer-capsid proteins.
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Anticuerpos Monoclonales/inmunología , Cápside/inmunología , Hemaglutininas Virales/inmunología , Reoviridae/inmunología , Animales , Anticuerpos Antivirales/inmunología , Cápside/ultraestructura , Línea Celular , Membrana Celular/química , Membrana Celular/virología , Pruebas de Hemaglutinación , Hemaglutininas Virales/ultraestructura , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Inmunoglobulina G/inmunología , Conformación Molecular , Pruebas de Neutralización , Relación Estructura-ActividadRESUMEN
Pyridine nucleotides are critical during oxidative stress due to their roles in reductive reactions and energetics. The aim of the present study was to examine pyridine nucleotide changes in six brain regions of mice after an intracerebroventricular injection of the oxidative stress inducing agent, t-butyl hydroperoxide (t-BuOOH). A secondary aim was to investigate the correlation between NAD+ levels and DNA fragmentation. Here, we demonstrate that t-BuOOH induced a rapid oxidation of NADPH and a slow depletion of NAD+ in most brain regions. A slight increase in NADH also occurred in five brain regions. NAD+ depletion was associated with increased DNA fragmentation. This suggests the initiation of a death cascade involving poly(ADP-ribose) polymerase (PARP), NAD+, ATP depletion and consequent cell death in brain tissue. PARP activity was accelerated in some brain regions after 20 min of oxidative stress. To counteract oxidative stress induced toxicity, NAD+ levels were increased in the brain using an intraperitoneal injection of nicotinamide. A surplus of brain NAD+ prevented DNA fragmentation in some brain regions. Nicotinamide administration also resulted in higher brain NADH, NADP+ and NADPH levels in some regions. Their synthesis was further upregulated during oxidative stress. Nicotinamide as a precursor for NAD+ may provide a useful therapeutic strategy in the treatment of neurodegeneration.
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Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fármacos Neuroprotectores/farmacología , Niacinamida/farmacología , Nucleótidos de Purina/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Fragmentación del ADN , Masculino , Ratones , Ratones Endogámicos C57BL , NAD/metabolismo , NADP/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Poli(ADP-Ribosa) Polimerasas/metabolismo , terc-Butilhidroperóxido/toxicidadRESUMEN
A novel phosphorous-containing antifungal antibiotic JU-2 was isolated from Streptomyces kanamyceticus M8. Quantitative chemical analysis shows the presence of two phenylalanines, two glucose, one linoleic acid, one crucic acid and one phosphonamide moiety per molcule of the antibiotic. JU-2 shows strong inhibitory activity against various pathogenic and non-pathogenic fungi but no activity against bacteria and yeast.
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Aminoglicósidos , Antibacterianos/farmacología , Antifúngicos/farmacología , Streptomyces/química , Antibacterianos/química , Antifúngicos/química , Espectroscopía de Resonancia MagnéticaRESUMEN
Nine districts in West Bengal, India, and 42 districts in Bangladesh have arsenic levels in groundwater above the World Health Organization maximum permissible limit of 50 microg/L. The area and population of the 42 districts in Bangladesh and the 9 districts in West Bengal are 92,106 km(2) and 79.9 million and 38,865 km(2) and 42.7 million, respectively. In our preliminary study, we have identified 985 arsenic-affected villages in 69 police stations/blocks of nine arsenic-affected districts in West Bengal. In Bangladesh, we have identified 492 affected villages in 141 police stations/blocks of 42 affected districts. To date, we have collected 10,991 water samples from 42 arsenic-affected districts in Bangladesh for analysis, 58,166 water samples from nine arsenic-affected districts in West Bengal. Of the water samples that we analyzed, 59 and 34%, respectively, contained arsenic levels above 50 microg/L. Thousands of hair, nail, and urine samples from people living in arsenic-affected villages have been analyzed to date; Bangladesh and West Bengal, 93 and 77% samples, on an average, contained arsenic above the normal/toxic level. We surveyed 27 of 42 districts in Bangladesh for arsenic patients; we identified patients with arsenical skin lesions in 25 districts. In West Bengal, we identified patients with lesions in seven of nine districts. We examined people from the affected villages at random for arsenical dermatologic features (11,180 and 29,035 from Bangladesh and West Bengal, respectively); 24.47 and 15.02% of those examined, respectively, had skin lesions. After 10 years of study in West Bengal and 5 in Bangladesh, we feel that we have seen only the tip of iceberg.
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Arsénico/análisis , Contaminantes Químicos del Agua/análisis , Arsénico/toxicidad , Arsénico/orina , Bangladesh , Salud Ambiental , Cabello/química , Humanos , India , Concentración Máxima Admisible , Uñas/química , Seguridad , Piel/química , Enfermedades de la Piel/inducido químicamente , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/orinaRESUMEN
AIMS AND OBJECTIVES: To ascertain whether therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for benign biliary disease in frail elderly patients with comorbid conditions can be safely undertaken in a district general hospital, and whether the procedure is facilitated by the use of short-acting general anaesthesia. SETTING: District general hospital in South East England. DESIGN OF STUDY: Clinical study of 25 consecutive patients with benign biliary disease. METHODS: Describes the process of bile duct clearance by therapeutic ERCP under short-acting general anaesthesia in 25 patients with co-morbidity aged > or = 80 years and gives details of the general anaesthesia and monitoring. RESULTS: Twenty-two patients had their bile ducts successfully cleared locally and one patient was stented for a benign biliary stricture. The ampullae of two other patients were lying within diverticula, which hindered cannulation and only pancreatograms were obtained; one of the patients had a successful bile duct clearance at a tertiary centre, the other refused further intervention. Complications (melaena, bronchopneumonia and a Clostridium difficile infection) occurred in two patients (8%). There was no morbidity associated with the anaesthesia, and no mortality occurred within 30 days of the procedure. CONCLUSIONS: Bile duct clearance by therapeutic ERCP can be safely carried out in frail elderly patients in a district general hospital and the process is facilitated by the use of short-acting general anaesthesia. The importance of optimizing the patient's condition before ERCP, and not overfilling the pancreatic duct, is highlighted.
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Anestesia General , Enfermedades de los Conductos Biliares/terapia , Conductos Biliares Extrahepáticos , Colangiopancreatografia Retrógrada Endoscópica , Anciano Frágil , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Stents , Factores de TiempoRESUMEN
This paper reports the isolation and characterization of a cDNA encoding the FtsZ protein of pea. The protein is synthesised as a precursor molecule of 423 amino acids with a molecular mass of 44 kDa. When translated in vitro, the protein is translocated efficiently into isolated, intact pea chloroplasts, demonstrating that the protein is localised in the chloroplast. Pea FtsZ synthesised in vitro formed multimers in a calcium-dependent manner. The pea cDNA complemented the thermosensitive defect of an E. coli ftsZ mutant in vivo and converted the filamentous phenotype of the E. coli mutant into the normal wild-type morphology at 42 degrees C. However, pea FtsZ mutants that were defective in multimerisation in vitro failed to correct the phenotype of the E. coli ftsZ mutant in vivo. The pea ftsZ transcripts were abundantly present in the young leaves, but barely detectable in roots and stems and undetectable in older leaves. Light stimulated transcription of the gene significantly in young and dark-grown leaves. This study strongly suggests that the division mechanisms used by chloroplasts and bacteria show considerable similarity.
Asunto(s)
Proteínas Bacterianas/metabolismo , Cloroplastos/genética , Proteínas del Citoesqueleto , Escherichia coli/genética , Mutación , Pisum sativum/genética , Proteínas Bacterianas/genética , Calcio/fisiología , Clonación Molecular , Reactivos de Enlaces Cruzados , ADN Complementario/metabolismo , Regulación de la Expresión Génica de las Plantas , Prueba de Complementación Genética , Guanosina Trifosfato/fisiología , Luz , Luciferasas/metabolismo , Mutagénesis Sitio-Dirigida , Regiones Promotoras Genéticas , Biosíntesis de Proteínas , Temperatura , Transcripción GenéticaRESUMEN
The major limitation of treatment with antimetabolite drugs is that they produce resistant clones both in vitro and in patients who either do not respond to treatment or relapse soon after response has been documented. To better understand the phenomenon of cross-resistance, we developed seven CEM/ara-C-resistant leukemic clones from the CEM/0 (wt) cell line. These clones ranged from 4- to 3.5 x 10(8)-fold more resistant to ara-C than the wt CEM/0 cell line. Using this model, we determined IC50 concentrations to several chemotherapeutic agents and gamma radiation, and we also studied pro- (p53) and anti-apoptotic (bcl-2) proteins, as well as P-glycoprotein (P-gp) and multidrug resistance related protein (MRP). The cell viability assays showed that these clones were cross-resistant to 6-thioguanine (6-TG) or 6-mercaptoguanosine (6-TGuo) from 1.1- to 8.8-fold with ara-C; cross-resistance to vincristine (VCR) was from 200- to 1 x 10(4)-fold with ara-C. Taxotere (TXR) showed cross-resistance with ara-C from 1.39- to 3.03 x 10(3)-fold; dexamethasone (DEX) also showed a significant degree of cross-resistance from 27.4- to 3.87 x 10(7)-fold. Gamma radiation treatments from 0.77 Gy to 12.3 Gy showed a radiation dose-dependent cross-resistance with ara-C from 1.43- to 2.93-fold. Idarubicin was collaterally sensitive with ara-C from 4.6- to 1 x 10(9)-fold in these cell lines. The CEM/ara-C/G resistant cell line was 3-fold more sensitive to 6-TG or VCR than CEM/0 (wt), and 5-fold more sensitive to 6-TGuo. This cell clone expressed p53 and did not overexpress bcl-2 protein. All of the cell lines studied, CEM/0 (wt) and the ara-C resistant clones, showed functional p53 protein. The cell treatment with 0.1, 1 and 10 microM ara-C for 48 hours showed increased p53 protein expression in most of these lines. No increase in bcl-2 protein expression was seen in the wt cell line after ara-C treatment for 48 hours. Three cell lines resistant to ara-C (CEM/ara-C/B, CEM/ara-C/D and CEM/ara-C/I) showed an important increased expression of bcl-2 protein after treatment with 1 microM ara-C, but not after 10 microM. This alteration may lead to resistance to apoptosis and enhanced cell survival. The ratio of bcl-2 to p53 was increased significantly in these three clones, thus favoring an anti-apoptotic drive. All of the cell lines examined were negative for MRP expression and only two, CEM/ara-C/B and CEM/ara-C/J, were positive for MRP functional activity. However, three ara-C resistant cell clones, CEM/ara-C/7A, CEM/ara-C/B and CEM/ara-C/G, were positive for P-gp expression and functional activity. It is apparent that selection for ara-C resistance confers cross-resistance to many other classes of drugs and gamma radiation, probably due to bcl-2 protein overexpression or P-gp and MRP expression, as independent mechanisms.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Citarabina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Guanosina/análogos & derivados , Leucemia/patología , Células Madre Neoplásicas/efectos de los fármacos , Taxoides , Tioguanina/farmacología , Tionucleósidos/farmacología , Vincristina/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/análisis , Transportadoras de Casetes de Unión a ATP/análisis , Dexametasona/farmacología , Docetaxel , Rayos gamma , Guanosina/farmacología , Humanos , Leucemia/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Proteínas de Neoplasias/análisis , Células Madre Neoplásicas/química , Células Madre Neoplásicas/efectos de la radiación , Paclitaxel/análogos & derivados , Paclitaxel/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Células Tumorales Cultivadas/química , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/efectos de la radiación , Proteína p53 Supresora de Tumor/análisisRESUMEN
p43, a glycoprotein of pea chloroplast (ct), acts as an accessory protein of pea chloroplast DNA polymerase. p43 binds to DNA, binds to ct-DNA polymerase and stimulates the ct-DNA polymerase activity. In the work presented here, the C-terminal domain of p43 (p22) has been overexpressed in E. coli. South Western analysis reveals that the recombinant p22 lacks in DNA binding activity. However, the recombinant p22 can form complex with the pea ct-DNA polymerase quite efficiently and stimulates the DNA polymerase activity to a greater extent than the native p43. Thus the DNA binding domain of p43 appears to be spatially separate from the domain responsible for the DNA polymerase accessory activity. The DNA binding domain is also highly O-glycosylated and loss of glycosylation of p43 leads to enhanced DNA binding as well as repression of ct-DNA polymerase activity. These findings allow us to propose a model to explain how glycosylation of p43 helps ct-DNA polymerase latch onto the DNA template for enhanced processivity. The predictive components of the model have been discussed.