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1.
J Antimicrob Chemother ; 78(6): 1476-1479, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37071590

RESUMEN

BACKGROUND: We conducted a nationwide cross-sectional study to estimate pretreatment drug resistance (PDR) prevalence in adults initiating ART in Sri Lanka following the WHO's recommendations. METHODS: HIV drug resistance was determined on dried blood spots (DBSs) using population-based sequencing of the protease and reverse transcriptase genes and interpretation was based on Stanford HIVdb v9.0. Analyses were weighted to adjust for multistage sampling and genotypic failure rate. We used logistic regression to assess differences between groups. RESULTS: Overall, in 10% (15 of 150) of patients initiating ART, HIV drug resistance mutations were detected. The prevalence of resistance to NNRTI drugs efavirenz/nevirapine was 8.4% (95% CI 4.6-15.0) but differed among those reporting having prior antiretroviral (ARV) exposure (24.4%, 95% CI 13.8-39.5) compared with 4.6% (95% CI 1.6-12.8) for those reporting as being ARV naive (OR 4.6, 95% CI 1.3-16.6, P = 0.021). PDR to efavirenz/nevirapine was also nearly twice as high among women (14.1%, 95% CI 6.1-29.4) compared with men (7.0%, 95% CI 3.1-14.7) (P = 0.340) and three times high among heterosexuals (10.4%, 95% CI 2.4-35.4) compared with MSM (3.8%, 95% CI 1.1-12.7) (P = 0.028). NRTI PDR prevalence was 3.8% (95% CI 1.1-12.1) and no PI PDR was observed in the study. CONCLUSIONS: A high prevalence of efavirenz/nevirapine PDR was reported, especially in patients with prior ARV exposure, in women and those reporting being heterosexual. These findings highlight the need to fast-track the transition to the WHO-recommended dolutegravir-based first-line ART.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Minorías Sexuales y de Género , Adulto , Masculino , Humanos , Femenino , Nevirapina/uso terapéutico , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Homosexualidad Masculina , Prevalencia , Estudios Transversales , Sri Lanka/epidemiología , VIH-1/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Mutación , Farmacorresistencia Viral/genética
2.
Langmuir ; 35(44): 14339-14347, 2019 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-31597425

RESUMEN

Silicone oil has been widely utilized in the pharmaceutical industry especially as a lubricant coating commonly used in syringes for the smooth delivery of drugs. Protein structure perturbation and aggregation have been reported upon protein contacting silicone oil by using indirect methods and ex-situ techniques. The conclusions derived from such indirect and ex-situ methods may not truly reflect the exact nature of the protein-silicone oil interfacial interactions. Recently, we have successfully demonstrated that sum frequency generation (SFG) vibrational spectroscopy can be used as a powerful and direct method of studying the fusion protein-silicone oil interfacial interactions in situ and in real time. In this article, we studied monoclonal and bispecific antibody interactions with the silicone oil surface by using SFG spectroscopy. Being structurally and functionally different in the nature of fusion proteins and antibodies, this study is important in enhancing our current understanding of protein-silicone oil interfacial interactions. Both types of antibodies investigated here readily and strongly adsorb onto the silicone oil surface and remain stable at least for 10 h. SFG spectra in the amide I region for monoclonal and bispecific antibodies centered at 1660 and 1665 cm-1, respectively, suggest the difference in their molecular structures. The absence of the antibody signals in the amide I region of time-dependent and static SFG spectra obtained for preadsorbed antibodies onto silicone oil after contacting polysorbate 80 (PS-80) surfactant suggests that PS-80 can effectively remove both types of antibodies from the silicone oil surface. This study demonstrated the feasibility of using SFG spectroscopy as a powerful tool for probing the antibody-interfacial interactions in situ and in real time.


Asunto(s)
Anticuerpos Biespecíficos/química , Anticuerpos Monoclonales/química , Biopolímeros/química , Siliconas/química , Péptidos/química , Proteínas/química
3.
Int Urogynecol J ; 28(12): 1849-1855, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28299405

RESUMEN

INTRODUCTION: The multifaceted nature of pelvic floor disorders means that a systematic evaluation is required for optimal treatment outcome. It is also generally acknowledged that a valid tool is necessary to objectively assess symptoms reported by affected women. METHODS: The International Consultation on Incontinence Questionnaire-Vaginal Symptoms (ICIQ-VS) questionnaire was translated to Sinhala and Tamil and a validation study carried out among women attending gynecology clinics at North Colombo Teaching Hospital, Ragama, and the district general hospitals Mannar and Vavuniya. RESULTS: Content validity was assessed by the level of missing answers, which was < 4% and 2% for each item in Sinhala and Tamil, respectively. Construct validity was assessed by the ability of the questionnaire to differentiate between patients and controls. Both differentiated patients from controls on vaginal symptoms score (VSS) (p < 0.001), sexual symptoms score (SSS) (p < 0.01), and quality of life (QoL) (p < 0.001). There was a strong positive correlation between Pelvic Organ Prolapse Quantification (POP-Q) scores and VSS (Sinhala r s = 0.64, p < 0.001, Tamil r s = 0.65, p < 0.001), and QoL (Sinhala r s = 0.49, p < 0.001, Tamil r s = 0.60, p < 0.001). Internal consistency as assessed using Cronbach's coefficient alpha: 0.78 (0.76-0.78) and 0.83 (0.80-0.84) in Sinhala and Tamil, respectively. Test-retest reliability was assessed by weighted kappa scores (Sinhala 0.58-0.88 and Tamil 0.76-0.90). Both questionnaires were sensitive to change and showed that VSS and QoL improved following surgery (Wilcoxon matched-pairs signed-rank test p < 0.001). CONCLUSION: The validated Sinhala and Tamil translations of ICIQ-VS will be useful for assessing vaginal and sexual symptoms among women speaking Sinhala and Tamil.


Asunto(s)
Trastornos del Suelo Pélvico/diagnóstico , Encuestas y Cuestionarios/normas , Evaluación de Síntomas/normas , Incontinencia Urinaria/diagnóstico , Enfermedades Vaginales/diagnóstico , Adulto , Femenino , Humanos , India , Lenguaje , Persona de Mediana Edad , Trastornos del Suelo Pélvico/complicaciones , Calidad de Vida , Reproducibilidad de los Resultados , Sri Lanka , Estadísticas no Paramétricas , Evaluación de Síntomas/métodos , Traducciones , Incontinencia Urinaria/etiología , Enfermedades Vaginales/etiología
4.
Ceylon Med J ; 62(2): 92-96, 2017 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-28697590

RESUMEN

Introduction: Fragile X syndrome (FXS) is a genetically determined developmental disorder. Underlying genotype is cytosine-guanine-guanine (CGG) repeat expansions with over 200 repeats in the fragile X mental retardation 1 (FMR1) gene. Children with FXS are most accessible in special education institutions in Sri Lanka, with a total of approximately 6000 registered attendees. Objectives: The aim of the current study was to estimate the prevalence of FXS among special school attendees and to screen first degree relatives of affected children. Methods: A nationally representative sample of 850 children (5-18 years) was selected using multi-level stratified sampling. Screening was performed by 3' direct triplet primed PCR, followed by melting curve analysis. Expanded repeat status of the screened positives were confirmed using capillary electrophoresis, methylation specific PCR and Southern hybridization. Screening of available first degree relatives (n=12) were carried out using the same method of screening and diagnosis. Results: Eleven had FXS. Prevalence of FXS was 1.3% (95% CI 0.9-1.6). Among the 11 with FXS 9 had more than 350 CGG repeats, while the rest had around 300. Twelve first degree relatives consisting of nine mothers, two female siblings and a male sibling were tested. All mothers and female siblings had either full mutation or premutation while the male sibling had CGG repeats in the normal range. Conclusions: Among the special school attendees, prevalence of FXS was 1.3% which has a high risk for autism and attention deficit hyperactivity disorder.

5.
J Biol Chem ; 289(41): 28363-75, 2014 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-25160619

RESUMEN

Integrin-linked kinase (ILK) is a distinct intracellular adaptor essential for integrin-mediated cell-extracellular matrix adhesion, cell spreading, and migration. Acting as a major docking platform in focal adhesions, ILK engages many proteins to dynamically link integrins with the cytoskeleton, but the underlying mechanism remains elusive. Here, we have characterized the interaction of ILK with kindlin-2, a key regulator for integrin bidirectional signaling. We show that human kindlin-2 binds to human ILK with high affinity. Using systematic mapping approaches, we have identified a major ILK binding site involving a 20-residue fragment (residues 339-358) in kindlin-2. NMR-based analysis reveals a helical conformation of this fragment that utilizes its leucine-rich surface to recognize the ILK pseudokinase domain in a mode that is distinct from another ILK pseudokinase domain binding protein, α-parvin. Structure-based mutational experiments further demonstrate that the kindlin-2 binding to ILK is crucial for the kindlin-2 localization to focal adhesions and cell spreading (integrin outside-in signaling) but dispensable for the kindlin-2-mediated integrin activation (integrin inside-out signaling). These data define a specific mode of the kindlin-2/ILK interaction with mechanistic implications as to how it spatiotemporally mediates integrin signaling and cell adhesion.


Asunto(s)
Proteínas de la Membrana/química , Proteínas de Neoplasias/química , Proteínas Serina-Treonina Quinasas/química , Proteínas Recombinantes de Fusión/química , Secuencia de Aminoácidos , Sitios de Unión , Adhesión Celular , Línea Celular Tumoral , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Transducción de Señal
6.
J Pediatr Hematol Oncol ; 36(8): e490-2, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24276030

RESUMEN

The national screening policy for hemoglobinopathies uses the cutoffs for red cell indices mean corpuscular volume >80 and mean corpuscular hemoglobin >27, a strategy known to miss some individuals with Hb E trait (EBT), the most common abnormal hemoglobin in Sri Lanka. We wanted to determine if red cell distribution width (RDW) cutoff values would help in increasing the sensitivity of screening for Hb E trait. High-performance liquid chromatography was carried out as the gold standard to detect hemoglobinopathies and red blood cell parameters with colter counter. Receiver operating characteristic curve was drawn to determine the cutoff value for EBT against ß-trait (BTT) and other anemias. Of the 504 patients, 246 had BTT, 110 had EBT, and 151 had other types of anemias. Mean (SD) RDW among patients with BTT was 16 (2.8), with EBT 14.5 (2.9), and with other anemias 15.8 (4.2) (P>0.001). With 14.45 as the cutoff for RDW and considering accepted values for mean corpuscular volume >80 and mean corpuscular hemoglobin >27, it gave a predictive sensitivity of 98.2% for EBT. By using RDW cutoff at 14.45 in addition to the accepted screening indices, sensitivity of Hb E trait detection went up to 98.2% from 86.6%. This study highlights the importance of taking RDW into consideration for screening.


Asunto(s)
Anemia/diagnóstico , Índices de Eritrocitos , Hemoglobina E/metabolismo , Tamizaje Masivo/métodos , Talasemia/diagnóstico , Anemia/sangre , Diagnóstico Diferencial , Humanos , Curva ROC , Sensibilidad y Especificidad , Sri Lanka , Talasemia/sangre
7.
Methods Appl Fluoresc ; 12(3)2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38670142

RESUMEN

In the past, there were limited efforts to use light-emitting diodes (LEDs) for pumping solid-state lasers. However, these attempts were overshadowed by the introduction of laser diodes, which offered more favourable pumping conditions. Nevertheless, recent advancements in high-power LEDs, coupled with the utilization of luminescent concentrators (LC), have paved the way for a novel approach to pump solid-state lasers. The combination of LEDs and LC in this LED-LC system presents several advantages, including enhanced ruggedness, stability, and cost-effectiveness compared to other laser pumping methods. This review explores the various techniques employed to pump solid-state lasers using LED-LC as a pump source, along with improvements made to enhance the brightness of LEDs in this context.

8.
J Biol Chem ; 287(29): 24585-94, 2012 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-22648415

RESUMEN

Both talin head domain and kindlin-2 interact with integrin ß cytoplasmic tails, and they function in concert to induce integrin activation. Binding of talin head domain to ß cytoplasmic tails has been characterized extensively, but information on the interaction of kindin-2 with this integrin segment is limited. In this study, we systematically examine the interactions of kindlin-2 with integrin ß tails. Kindlin-2 interacted well with ß(1) and ß(3) tails but poorly with the ß(2) cytoplasmic tail. This binding selectivity was determined by the non-conserved residues, primarily the three amino acids at the extreme C terminus of the ß(3) tail, and the sequence in ß(2) was non-permissive. The region at the C termini of integrin ß(1) and ß(3) tails recognized by kindlin-2 was a binding core of 12 amino acids. Kindlin-2 and talin head do not interact with one another but can bind simultaneously to the integrin ß(3) tail without enhancing or inhibiting the interaction of the other binding partner. Kindlin-2 itself failed to directly unclasp integrin α/ß tail complex, indicating that kindlin-2 must cooperate with talin to support the integrin activation mechanism.


Asunto(s)
Citoplasma/metabolismo , Cadenas beta de Integrinas/química , Cadenas beta de Integrinas/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Talina/química , Talina/metabolismo , Animales , Western Blotting , Células CHO , Calorimetría , Cromatografía Líquida de Alta Presión , Cricetinae , Espectroscopía de Resonancia Magnética , Estructura Terciaria de Proteína , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Resonancia por Plasmón de Superficie
10.
RSC Adv ; 13(41): 28852-28860, 2023 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-37790100

RESUMEN

We synthesised a polyaniline/mica (Mica-PANI) nanocomposite using naturally occurring muscovite mica by a top-down approach. The developed coating materials were characterised using a different technique to investigate their chemical and structural properties using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). Furthermore, the electrochemical properties of the coating materials were investigated by linear sweep voltammetry (LSV). SEM images elucidate the composite's average particle diameter of the prepared nano-mica, approximately 80 nm. The existence of relevant functional groups and bonding in the prepared Mica-PANI composite material was confirmed by means of XPS and FTIR techniques. Moreover, the synthesised composite with 5% w/w shows high anticorrosion protection, i.e. 84 µm per year, compared to competing materials, including commercial paint and individual raw materials (0.35 mm per year). The anti-corrosive effect occurs mainly due to two opposing effects: the formation of an Fe(OH)3 passive layer on the steel surface by oxidation of surface iron atoms by the PANI and the barrier effect of mica NPs through inhibition of corrosive agents. Therefore, the eco-inspired composite could be an ideal cost-effective coating material to prevent the corrosion of mild steel surfaces.

11.
Ceylon Med J ; 56(4): 153-8, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22298208

RESUMEN

INTRODUCTION: Many married Sri Lankan women annually migrate for employment overseas. Despite widely speculated psychological consequences in these children, their mental health status has not been systematically studied using validated instruments. OBJECTIVES: To describe mental health status of children of women overseas workers and compare that with children of locally employed women, and to describe socio-demographic factors and risk factors associated with abnormal mental health in these children. METHODS: A cross sectional comparative survey was conducted among 253 children (aged 5-10 years) of women migrant workers in the Colombo District and age and sex matched controls from same neighbourhood. Tools used were the validated Sinhala translation of Child Behaviour Check List (CBCL-S) and questionnaires on socio-demographic/risk factors and school functioning. RESULTS: Mean CBCL-S scores and proportion of children with mental health problems were significantly higher in the study group. Not having an elder sibling, father not living with child, mother educated up to grade 5 or less, change of principal carer (PC) twice or more, living with a relative (or not living in own home), child not communicating freely with PC, and not being permitted to engage in recreational activities at school were significantly associated with abnormal mental health of children of migrant women. CONCLUSIONS: A high awareness is required among health and social care authorities regarding mental health problems in these children and relevant risk factors in order to take preventive measures.


Asunto(s)
Salud de la Familia , Estado de Salud , Trastornos Mentales/epidemiología , Migrantes , Adulto , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Masculino , Sri Lanka/epidemiología , Migrantes/psicología
13.
Allergy ; 64(1): 32-9, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19076933

RESUMEN

BACKGROUND: Mechanical strain and cytokine stimulation are two important mechanisms leading to airway remodeling in asthma. The effect of mechanical strain on cytokine secretion in airway fibroblasts is not known. The aim of this study was to determine whether bronchial and nasal fibroblasts differentially alter cytokine secretion in response to mechanical strain. METHODS: We measured secretion of the pro-fibrotic cytokine, interleukin-6 (IL-6), and the pro-inflammatory cytokines, IL-8 and monocyte chemotactic protein 1, before and after mechanical strain in bronchial fibroblasts obtained from asthmatic patients [asthmatic bronchial fibroblasts (BAF)] and normal volunteers [normal bronchial fibroblasts (BNF)], and in nasal fibroblasts (NF) obtained from nasal polyps. Cells were grown on flexible membranes and a mechanical strain of 30% amplitude, 1 Hz frequency was applied for 3, 6 and 24 h. Control cells were unstrained. IL-6, IL-8 and monocyte chemotactic protein 1 was measured after 24 h strain using enzyme-linked immunoassay; mRNA was measured by real time polymerase chain reaction. We also measured mRNA for versican, a matrix proteoglycan, known to be upregulated in the asthmatic airway wall. RESULTS: In unstrained conditions, no differences in cytokine secretion were observed. After 24 h strain, BAF secreted more IL-6 than BNF. Mechanical strain increased IL-8 mRNA in BAF, BNF and NF; and IL-6 and versican mRNA, in BAF, only. CONCLUSIONS: Cytokine responses to mechanical strain varied in different airway fibroblast populations, and depended on the site of origin, and the underlying inflammatory state. Strain resulted in IL-6 upregulation and increased message for extracellular matrix protein in bronchial fibroblasts from asthmatic patients only, and may reflect these patients' propensity for airway remodeling.


Asunto(s)
Asma/patología , Fenómenos Biomecánicos/genética , Bronquios/patología , Quimiocinas/genética , Citocinas/genética , Fibroblastos/patología , Adolescente , Adulto , Asma/inmunología , Bronquios/inmunología , Estudios de Casos y Controles , Proteínas de la Matriz Extracelular/genética , Femenino , Fibroblastos/inmunología , Humanos , Interleucina-6/genética , Masculino , Regulación hacia Arriba , Adulto Joven
14.
J Trop Pediatr ; 55(6): 402-5, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19401407

RESUMEN

All children aged 18-24 months in a defined geographical area were initially screened for autism, using 'Red Flag' criteria. All the children with one or more positive 'Red Flag' signs were further screened using Modified Checklist for Autism in Toddlers (M-CHAT) translated to Sinhala, followed by a comprehensive clinical assessment. Of a sample of 374 children, 'Red Flag' signs were positive in 28 (7.4%). Four children received a diagnosis of autism on clinical assessment giving a prevalence of 1.07% or 1 per 93 in the 18-24-month age group. Sensitivity of M-CHAT was only 25%, and specificity 70%. The high prevalence detected strongly justifies early community-based screening, but a culturally sensitive screening tool needs to be developed for Sri Lanka.


Asunto(s)
Trastorno Autístico/diagnóstico , Tamizaje Masivo , Atención Primaria de Salud/métodos , Trastorno Autístico/epidemiología , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Tamizaje Masivo/métodos , Valor Predictivo de las Pruebas , Prevalencia , Escalas de Valoración Psiquiátrica , Sistema de Registros , Sensibilidad y Especificidad , Factores Socioeconómicos , Sri Lanka/epidemiología
15.
Case Rep Rheumatol ; 2019: 4364289, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31093408

RESUMEN

BACKGROUND: Polyarteritis nodosa (PAN) is a form of necrotizing vasculitis affecting medium or small blood vessels with multiorgan involvement. Although myalgia is a clinical feature of PAN, severe disabling myalgia as the initial presentation is rarely noted. CASE PRESENTATION: We present a case of 54-year-old male with recently detected chronic kidney disease admitted with progressive severe disabling muscular pains predominantly over calves with constitutional symptoms for seven weeks. He was weak to mobilize out of the bed. Later, he developed a vasculitic rash, unilateral ulnar claw, and bilateral foot drop. His skin and muscle biopsies showed evidence of vasculitis. His renal and mesenteric artery CT angiogram revealed stenosed segment of the celiac artery without evidence of visible aneurysms elsewhere. He completed six cycles of intravenous cyclophosphamide pulse therapy with high-dose oral prednisolone with good response. With continuation of aggressive immunosuppression and rehabilitation for five months, the patient improved and was able to walk without support. CONCLUSION: Musculoskeletal predominant PAN, even though rare, needs to be considered in patients presenting with disabling muscle pain and weakness. These features may herald over days to months along with constitutional symptoms before other systems getting affected. Early recognition of such symptoms and initiating specific treatment would be important for better outcomes.

16.
Ceylon Med J ; 53(2): 40-4, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18678120

RESUMEN

OBJECTIVE: To translate the child behaviour checklist (CBCL) into Sinhala and validate it for assessment of mental health status of children aged 5-10 years. DESIGN AND SETTING: Translation/back-translation method was used to translate the English CBCL into Sinhala. Each item in the Sinhala CBCL (CBCL-S) was rated by mental health professionals to determine semantics, content, and conceptual validity types. To ascertain criterion validity, total scores obtained for CBCL-S by administering it to parents or parent surrogates of 49 girls and 80 boys aged 5-10 years attending the specialist psychiatry clinics and 69 boys and 69 girls in the same age group from the community were compared with clinical diagnoses by a child psychiatrist. Receiver operator characteristic curves were drawn to obtain the cut-off points in CBCL-S for boys and girls separately. RESULTS: Semantics, content, and conceptual and criterion validity of CBCL-S were satisfactory. At the cut-off level of 39, CBCL-S had a sensitivity of 90% and a specificity of 88% for boys and a sensitivity of 89% and a specificity of 92% for girls. Internal consistency, test-retest reliability, and inter-interviewer reliability of CBCL-S were satisfactory. INTERPRETATION: CBCL-S is a valid and reliable instrument to measure mental health status of Sinhalese children aged 5-10 years in Sri Lanka.


Asunto(s)
Conducta Infantil , Indicadores de Salud , Salud Mental , Niño , Humanos , Lenguaje , Sensibilidad y Especificidad
17.
Mol Biol Cell ; 14(7): 2946-58, 2003 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12857877

RESUMEN

Insulin stimulates the movement of glucose transporter-4 (Glut4)-containing vesicles to the plasma membrane of adipose cells. We investigated the role of post-Golgi t-soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in the trafficking of Glut4 in 3T3-L1 adipocytes. Greater than 85% of syntaxin 6 was found in Glut4-containing vesicles, and this t-SNARE exhibited insulin-stimulated movement to the plasma membrane. In contrast, the colocalization of Glut4 with syntaxin 7, 8, or 12/13 was limited and these molecules did not translocate to the plasma membrane. We used adenovirus to overexpress the cytosolic domain of these syntaxin's and studied their effects on Glut4 traffic. Overexpression of the cytosolic domain of syntaxin 6 did not affect insulin-stimulated glucose transport, but increased basal deGlc transport and cell surface Glut4 levels. Moreover, the syntaxin 6 cytosolic domain significantly reduced the rate of Glut4 reinternalization after insulin withdrawal and perturbed subendosomal Glut4 sorting; the corresponding domains of syntaxins 8 and 12 were without effect. Our data suggest that syntaxin 6 is involved in a membrane-trafficking step that sequesters Glut4 away from traffic destined for the plasma membrane. We speculate that this is at the level of traffic of Glut4 into its unique storage compartment and that syntaxin 16 may be involved.


Asunto(s)
Adipocitos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares , Células 3T3-L1 , Adipocitos/fisiología , Animales , Compartimento Celular/fisiología , Membrana Celular/fisiología , Vesículas Citoplasmáticas/fisiología , Transportador de Glucosa de Tipo 4 , Insulina/metabolismo , Ratones , Proteínas de Transporte de Monosacáridos/fisiología , Estructura Terciaria de Proteína , Transporte de Proteínas/fisiología , Proteínas Qa-SNARE , Proteínas Recombinantes/metabolismo , Fracciones Subcelulares
18.
Stem Cell Investig ; 4: 21, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28447036

RESUMEN

Liposarcomas (LPS) are among the most common soft tissue sarcomas, originating from adipocytes. Treatment for LPS typically involves surgical resection and radiation therapy, while the use of conventional cytotoxic chemotherapy for unresectable or metastatic LPS remains controversial. This review summarizes the results of recent translational research and trials of novel therapies targeting various genetic and molecular aberrations in different subtypes of LPS. Genetic aberrations such as the 12q13-15 amplicon, genetic amplification of MDM2, CDK4, TOP2A, PTK7, and CHEK1, point mutations in CTNNB1, CDH1, FBXW7, and EPHA1, as the fusion of FUS-DDIT3/EWSR1-DDIT3 are involved in the pathogenesis LPS and represent potential therapeutic candidates. Tyrosine kinase inhibitors targeting MET, AXL, IGF1R, EGFR, VEGFR2, PDGFR-ß and Aurora kinase are effective in certain types of LPS. Abnormalities in the PI3K/Akt signaling pathway deregulation of C/EBP-α and its partner PPAR-γ, and the interaction between calreticulin (CRT) and CD47 are also promising therapeutic targets. These promising new approaches may help to supplement existing treatments for LPS.

19.
Forensic Sci Int ; 270: 278.e1-278.e7, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27908672

RESUMEN

Forensic age estimation (FAE) was conducted using a multifactorial method on thirteen Somali detainees claiming juvenile status during the anti-piracy trials of the Seychelles Supreme Court in 2014/2015. A multidisciplinary team, comprising of four of the authors covering specialties in forensic medicine, forensic odontology and radiology, conducted the FAE using a five-stage protocol. Each detainee was interviewed with an interpreter and examined for disorders affecting dental/skeletal development and for assessment of genital development through Tanner staging. Dental maturity was assessed clinically and radiologically. Eruption stage was assessed using Olze et al. and mandibular third-molar maturity was assessed using Demirjian's classification. Skeletal maturity was assessed from hand-wrist X-rays according to Greulich & Pyle and from CT-clavicle according to Kellinghaus et al. and Schultz et al. Interpretation of findings was done using reference population data from similar ethnic and social backgrounds wherever possible. Final age-ranges were calculated by combining dental and clavicle maturity stages using the regression formula developed by Bassed et al. followed by a 10% correction factor. The team later testified on their findings under cross-examination. The protocol adopted by the authors increased the scientific validity of the findings and was useful in addressing cross-examination queries on exclusion of developmental disorders, ethnic/socioeconomic variability and maintaining chain of custody. Unforeseen jurisdictional and practical limitations were experienced but did not affect the outcome. Combining dental and clavicle developmental data provided the court with a much clearer picture on the likelihood of the detainees' juvenile status which emphasizes the importance of conducting more population studies using combinations of different developmental sites. The authors note that available reference data is mostly from affluent populations whereas FAE is mostly required in individuals from less-developed regions. Regional networks that collate and share population-specific data need to be established to overcome these limitations.


Asunto(s)
Determinación de la Edad por el Esqueleto/métodos , Determinación de la Edad por los Dientes/métodos , Adolescente , Clavícula/diagnóstico por imagen , Clavícula/crecimiento & desarrollo , Huesos de la Mano/diagnóstico por imagen , Huesos de la Mano/crecimiento & desarrollo , Humanos , Tercer Molar/diagnóstico por imagen , Tercer Molar/crecimiento & desarrollo , Prisioneros/legislación & jurisprudencia , Radiografía Dental , Análisis de Regresión , Seychelles , Tomografía Computarizada por Rayos X , Erupción Dental , Adulto Joven
20.
Int J Radiat Oncol Biol Phys ; 28(4): 953-70, 1994 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-8138449

RESUMEN

PURPOSE: Ytterbium-169 (169Yb) is a promising new isotope for brachytherapy with a half life of 32 days and an average photon energy of 93 KeV. It has an Ir-192-equivalent dose distribution in water but a much smaller half-value layer in lead (0.2 mm), affording improved radiation protection and customized shielding of dose-limiting anatomic structures. The goals of this study are to: (a) experimentally validate Monte Carlo photon transport dose-rate calculations for this energy range, (b) to develop a secondary air-kerma strength standard for 169Yb, and (c) to present essential treatment planning data including the transverse-axis dose-rate distribution and dose correction factors for a number of local shielding materials. METHODS AND MATERIALS: Several interstitial 169Yb sources (type 6) and an experimental high dose-rate source were made available for this study. Monte-Carlo photon-transport (MCPT) simulations, based upon validated geometric models of source structure, were used to calculate dose rates in water. To verify MCPT predictions, the transverse-axis dose distribution in homogeneous water medium was measured using a silicon-diode detector. For use in designing shielded applicators, heterogeneity correction factors (HCF) arising from small cylindrical heterogeneities of lead, aluminum, titanium, steel and air were measured in a water medium. Finally, to provide a sound experimental basis for comparing experimental and theoretical dose-rate distributions, the air-kerma strength of the sources was measured using a calibrated ion chamber. To eliminate the influence of measurement artifacts on the comparison of theory and measurement, simulated detector readings were compared directly to measured diode readings. The final data are presented in the format endorsed by the Interstitial Collaborative Working Group. RESULTS: The in-air calibration revealed that the air-kerma strength per unit activity (mCi), as quoted by the vendor, varied from 1.30 to 1.57 cGy.cm2/mCi.h depending on seed design. The maximum difference between measured and MCPT-simulated absolute diode readings on the transverse axis was less than 2%, indicating that MCPT accurately predicts dose rate in medium for brachytherapy sources in this energy range. Comparison of measured and simulated HCFs for each of the 16 different cylindrical heterogeneities demonstrated 1-3% agreement. The HCFs vary by as much as 200% with respect to distance and by as much as 48% as a function of disk diameter, showing that HCF is strongly dependent on heterogeneity location and lateral dimensions as well as thickness. The dose-rate constant for water medium was found to be 1.225 cGy/h per kerma unit air-strength and 1.962 cGy/h per unit mCi as measured by the vendor. CONCLUSION: Monte Carlo simulation is an accurate and powerful tool for dosimetric characterization of brachytherapy sources in this energy range. Thin lead foils produce shielding factors comparable to standard shielded applicators for 137Cs. Meaningful theoretical absolute dose calculations in brachytherapy require accurately implemented air-kerma strength standards.


Asunto(s)
Braquiterapia/métodos , Radioisótopos/uso terapéutico , Iterbio/uso terapéutico , Calibración , Humanos , Método de Montecarlo , Dosificación Radioterapéutica
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