RESUMEN
Prior studies have reported the prevalence of colorectal cancer (CRC) in average-risk screening population ages 50-75 to be 0.7%-1.0%.1,2 However, no estimates from studies enrolling individuals undergoing screening colonoscopy have been reported. The experience of ongoing studies enrolling average-risk individuals is that the prevalence rates are substantially lower. A 2020 study from a community-based cohort undergoing CRC screening with fecal immunochemical testing followed by diagnostic colonoscopy reported a CRC prevalence rate of 1.46 per 1000, or 0.15%.3 The aim of our study is to report the screen-detected prevalence of CRC and advanced neoplasia in average-risk asymptomatic individuals from selected academic and community medical centers in the United States, Canada, and Germany and describe associated risk factors.
Asunto(s)
Colonoscopía , Neoplasias Colorrectales , Humanos , Estados Unidos , Persona de Mediana Edad , Anciano , Prevalencia , Sangre Oculta , Detección Precoz del Cáncer , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Tamizaje Masivo , Factores de RiesgoRESUMEN
BACKGROUND: Glycosaminoglycans (GAGs) are negatively charged long linear (highly sulfated) polysaccharides consisting of repeating disaccharide units that are expressed on the surfaces of all nucleated cells. The expression of GAGs is required for embryogenesis, regulation of cell growth and proliferation, maintenance of tissue hydration, and interactions of the cells via receptors. Mucopolysaccharidoses (MPS) are caused by deficiency of specific lysosomal enzymes that result in the accumulation of GAGs in multiple tissues leading to organ dysfunction. Therefore, GAGs are important biomarkers for MPS. Without any treatment, patients with severe forms of MPS die within the first two decades of life. SCOPE OF REVIEW: Accurate measurement of GAGs is important to understand the diagnosis and pathogenesis of MPS and to monitor therapeutic efficacy before, during, and after treatment of the disease. This review covers various qualitative and quantitative methods for measurement of GAGs, including dye specific, thin layer chromatography (TLC), capillary electrophoresis, high-performance liquid chromatography (HPLC), liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography, ELISA, and automated high-throughput mass spectrometry. Major conclusion: There are several methods for GAG detection however, specific GAG detection in the various biological systems requires rapid, sensitive, specific, and cost-effective methods such as LC-MS/MS. GENERAL SIGNIFICANCE: This review will describe different methods for GAG detection and analysis, including their advantages and limitation.
Asunto(s)
Biomarcadores/metabolismo , Glicosaminoglicanos/metabolismo , Mucopolisacaridosis/diagnóstico , Humanos , Mucopolisacaridosis/metabolismoRESUMEN
Patients with Barrett's esophagus (BE) and low-grade dysplasia (LGD) are at increased risk of esophageal adenocarcinoma (EAC), although many regress to nondysplastic BE. This has significant clinical importance for patients being considered for endoscopic eradication therapy. Our aim is to determine the risk for progression in patients with confirmed persistent LGD. We performed a single-center retrospective cohort study of patients with BE and confirmed LGD between 2006 and 2016. Confirmed LGD was defined as LGD diagnosed by consensus conference with an expert GI pathologist or review by an expert GI pathologist and persistence as LGD present on subsequent endoscopic biopsy. The primary outcome was the incidence rate of HGD (high-grade dysplasia)/EAC. Secondary outcomes included risk factors for dysplastic progression. Risk factors for progression were assessed using univariate and multivariate analysis with logistic regression. Of 69 patients (mean age 65.2 years) with confirmed LGD were included. In total, 16 of 69 patients (23.2%) with LGD developed HGD/EAC during a median follow-up of 3.74 years (IQR, 1.24-5.45). For persistent confirmed LGD, the rate was 6.44 (95% confidence interval (CI), 2.61-13.40) compared to 2.61 cases per 100 patient-years (95% CI, 0.83-6.30) for nonpersistent LGD. Persistent LGD was found in only 29% of patients. Persistent LGD was an independent risk factor for the development of HGD/EAC (OR 4.18; [95% CI, 1.03-17.1]). Persistent confirmed LGD, present in only 1/3 of patients, was an independent risk factor for the development of HGD/EAC. Persistence LGD may be useful in decision making regarding the management of BE.
Asunto(s)
Adenocarcinoma/patología , Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Lesiones Precancerosas/patología , Adenocarcinoma/epidemiología , Adulto , Anciano , Progresión de la Enfermedad , Neoplasias Esofágicas/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III.
Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Terapia Genética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Lisosomas/metabolismo , Mucolipidosis/diagnóstico , Animales , Transporte Biológico Activo , Modelos Animales de Enfermedad , Glicosaminoglicanos/metabolismo , Humanos , Manosafosfatos/metabolismo , Mucolipidosis/enzimología , Mucolipidosis/fisiopatología , Mucolipidosis/terapiaRESUMEN
To explore the correlation between glycosaminoglycan (GAG) levels and mucopolysaccharidosis (MPS) type, we have evaluated the GAG levels in blood of MPS II, III, IVA, and IVB and urine of MPS IVA, IVB, and VI by tandem mass spectrometry. Dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS; mono-sulfated KS, di-sulfated KS), and the ratio of di-sulfated KS in total KS were measured. Patients with untreated MPS II had higher levels of DS and HS in blood while untreated MPS III had higher levels of HS in blood than age-matched controls. Untreated MPS IVA had higher levels of KS in blood and urine than age-matched controls. The ratio of blood di-sulfated KS/total KS in untreated MPS IVA was constant and higher than that in controls for children up to 10â¯years of age. The ratio of urine di-sulfated KS/total KS in untreated MPS IVA was also higher than that in age-matched controls, but the ratio in untreated MPS IVB was lower than controls. ERT reduced blood DS and HS in MPS II, and urine KS in MPS IVA patients, although GAGs levels remained higher than the observed in age-matched controls. ERT did not change blood KS levels in MPS IVA. MPS VI under ERT still had an elevation of urine DS level compared to age-matched controls. There was a positive correlation between blood and urine KS in untreated MPS IVA patients but not in MPS IVA patients treated with ERT. Blood and urine KS levels were secondarily elevated in MPS II and VI, respectively. Overall, measurement of GAG levels in blood and urine is useful for diagnosis of MPS, while urine KS is not a useful biomarker for monitoring therapeutic efficacy in MPS IVA.
Asunto(s)
Glicosaminoglicanos/sangre , Glicosaminoglicanos/orina , Mucopolisacaridosis/sangre , Mucopolisacaridosis/orina , Adolescente , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Niño , Preescolar , Dermatán Sulfato/sangre , Dermatán Sulfato/orina , Femenino , Glicosaminoglicanos/aislamiento & purificación , Heparitina Sulfato/sangre , Heparitina Sulfato/orina , Humanos , Sulfato de Queratano/sangre , Sulfato de Queratano/orina , Masculino , Mucopolisacaridosis/clasificación , Mucopolisacaridosis/patología , Mucopolisacaridosis II/sangre , Mucopolisacaridosis II/patología , Mucopolisacaridosis II/orina , Mucopolisacaridosis III/sangre , Mucopolisacaridosis III/patología , Mucopolisacaridosis III/orina , Mucopolisacaridosis IV/sangre , Mucopolisacaridosis IV/patología , Mucopolisacaridosis IV/orina , Mucopolisacaridosis VI/sangre , Mucopolisacaridosis VI/patología , Mucopolisacaridosis VI/orina , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
This study was planned to determine the relationship between semen quality parameters and the levels of biochemical constituents of seminal plasma of Teddy (Capra hircus) buck semen. For this purpose, semen ejaculates were collected from five mature healthy Teddy bucks. All the experimental bucks were kept under natural environmental conditions. Semen was collected twice in a week for the duration of 6 weeks by Artificial Vagina (AV) in the breeding season (February-April). Two successive ejaculates of single buck were pooled at time of collection, and a total of 60 semen samples were processed for semen analysis. Sperm per cent motility, sperm concentration, dead sperm percentage, morphological abnormal spermatozoa, plasma membrane integrity were correlated with biochemical constituents of seminal plasma. The mean per cent motility (89.18% ± 0.37%), sperm concentration (1.86 ± 0.04 × 109 /ml), dead sperm percentage (8.08% ± 0.29%), morphological abnormal spermatozoa (6.05% ± 0.29%) and plasma membrane integrity (88.22% ± 0.34%) were recorded. The seminal plasma contained Na+ (144.12 ± 1.59 mEq/L), K+ (27.38 ± 0.49 mEq/L), Cl- (65.73 ± 0.45 mEq/L), Ca++ (9.34 ± 0.22 mg/dl), P (19.32 ± 0.97 mg/dl), aspartate aminotransferase (AST; 26.48 ± 1.30 IU/L), alanine aminotransferase (ALT; 168.47 ± 5.18 IU/L), lactate dehydrogenase (LDH; 215.98 ± 6.06 IU/L), albumin (1.90 ± 0.10 g/dl), globulins (2.08 ± 0.11 g/dl) and total protein (3.98 ± 0.20 g/dl). The collected data were analysed by applying Pearson's correlation coefficients. Dead sperm percentage had negative correlation with sodium (r = -.278, p < .05), albumin (r = -.294, p < .05), globulin (r = -.266, p < .05) and total protein (r = -.295, p < .05). Phosphorus was negatively associated with sperm concentration (r = -.262, p < .05). AST was negatively correlated with plasma membrane integrity (r = -.292, p < .05). It was concluded that most of the semen quality parameters of Teddy bucks were positively correlated with biochemical constituents, but opposite trends were found in case of dead sperm percentage. The seminal biochemical constituents dynamically interact with each other.
Asunto(s)
Semen/química , Motilidad Espermática/fisiología , Espermatozoides/citología , Animales , Forma de la Célula/fisiología , Cabras , Masculino , Análisis de Semen/veterinariaRESUMEN
The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both, Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low.
Asunto(s)
Mucopolisacaridosis/epidemiología , Recolección de Datos , Europa (Continente)/epidemiología , Alemania/epidemiología , Glicosaminoglicanos/orina , Humanos , Incidencia , Japón/epidemiología , Mucopolisacaridosis/clasificación , Mucopolisacaridosis I/epidemiología , Mucopolisacaridosis II/epidemiología , Mucopolisacaridosis III/epidemiología , Mucopolisacaridosis VI/epidemiología , Países Bajos/epidemiología , Prevalencia , Estudios RetrospectivosRESUMEN
Fibrosis is an ominous pathological process in failing myocardium, but its pathogenesis is poorly understood. We recently reported that loss of an extracellular matrix (ECM) protein, fibulin-2, protected against ventricular dysfunction after myocardial infarction (MI) in association with absence of activation of transforming growth factor (TGF)-ß signaling and suppressed upregulation of ECM protein expression during myocardial remodeling. Here we investigated the role of fibulin-2 in the development of myocardial hypertrophy and fibrosis induced by continuous pressor-dosage of angiotensin II (Ang II) infusion. Both wild type (WT) and fibulin-2 null (Fbln2KO) mice developed comparable hypertension and myocardial hypertrophy by Ang II infusion. However, myocardial fibrosis with significant upregulation of collagen type I and III mRNA was only seen in WT but not in Fbln2KO mice.Transforming growth factor (TGF)-ß1 mRNA and its downstream signal, Smad2, were significantly upregulated in WT by Ang II, whereas there were no Ang II-induced changes in Flbn2KO, suggesting fibulin-2 is necessary for Ang II-induced TGF-ß signaling that induces myocardial fibrosis. To test whether fibulin-2 is sufficient for Ang II-induced TGF-ß upregulation, isolated Flbn2KO cardiac fibroblasts were treated with Ang II after transfecting with fibulin-2 expression vector or pretreating with recombinant fibulin-2 protein. Ang II-induced TGF-ß signaling in Fbln2KO cells was partially rescued by exogenous fibulin-2, suggesting that fibulin-2 is required and probably sufficient for Ang II-induced TGF-ß activation. Smad2 phosphorylation was induced just by adding recombinant fibulin-2 to KO cells, suggesting that extracellular interaction between fibulin-2 and latent TGF-ß triggered initial TGF-ß activation. Our study indicates that Ang II cannot induce TGF-ß activation without fibulin-2 and that fibulin-2 has an essential role in Ang II-induced TGF-ß signaling and subsequent myocardial fibrosis. Fibulin-2 can be considered as a critical regulator of TGF-ß that induces myocardial fibrosis.
Asunto(s)
Angiotensina II/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Miocardio/metabolismo , Miocardio/patología , Factor de Crecimiento Transformador beta1/metabolismo , Angiotensina II/administración & dosificación , Animales , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Cardiomegalia/patología , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/deficiencia , Proteínas de la Matriz Extracelular/genética , Fibrosis , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Cardiovasculares , Transducción de Señal , Remodelación VentricularRESUMEN
Bone morphogenetic proteins (BMPs) support malignant hematopoiesis in CML. Conversely, the multi-functional BMP antagonist Gremlin1 supports self-renewing cancer stem cells of other malignancies. Inhibition of BMP signaling in CML, or of Gremlin1 in solid tumors, may therefore have therapeutic potential. However, since BMPs regulate hematopoietic stem cell (HSC) decisions in the stem cell niche, it is necessary to determine how Gremlin1 influences normal HSC. We examined the effects of Gremlin1 on long-term culture-initiating cells (LTC-IC) and transplantable hematopoietic stem cells (SCID-repopulating cells: SRC) in human umbilical cord blood. Gremlin1 inhibited BMP signaling, downregulated BMP-6 and cyclin E2 expression and upregulated hairy and enhancer of split-1 (HES-1; a Notch transcriptional target) and Hedgehog interacting protein-1 (HHIP-1; an inhibitor of Hedgehog signaling). The functional effects of Gremlin1 on SRC, i.e. skewing of their myelopoietic:lymphopoietic potential towards B lymphopoiesis without affecting long-term engraftment potential, were entirely consistent with changes in gene expression induced by Gremlin1. Since both BMPs and Gremlin1 are secreted by osteoblasts in vivo, our studies provide potential insights into the molecular regulation of hematopoiesis in the stem cell niche. These results also suggest that Gremlin1 (and possibly its mimetics that may be developed for therapeutic use) may not adversely affect normal human hematopoietic stem cell survival, though they may reduce their myelopoietic potential.
Asunto(s)
Sangre Fetal/metabolismo , Células Madre Hematopoyéticas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Linfopoyesis/efectos de los fármacos , Mielopoyesis/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Proteína Morfogenética Ósea 6/biosíntesis , Proteínas Portadoras/biosíntesis , Técnicas de Cultivo de Célula , Células Cultivadas , Ciclinas/biosíntesis , Sangre Fetal/citología , Regulación de la Expresión Génica/efectos de los fármacos , Células Madre Hematopoyéticas/citología , Proteínas de Homeodominio/biosíntesis , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Glicoproteínas de Membrana/biosíntesis , Factor de Transcripción HES-1RESUMEN
AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-ß serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-ß signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-ß signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2-/-), heterozygous (Fbln2+/-) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 µg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2-/- showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-ß1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-ß-downstream signalling markers, Smad2, TAK1 (TGF-ß-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2-/- mice. The Fbln2+/- mice consistently displayed AngII-induced effects intermediate between WT and Fbln2-/-. Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2-/- mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-ß-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2-/- cells, suggesting that fibulin-2 is essential for AngII-induced TGF-ß activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-ß-mediated cardiac hypertrophy via enhanced TGF-ß activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.
Asunto(s)
Angiotensina II/farmacología , Proteínas de Unión al Calcio/metabolismo , Cardiomegalia/genética , Proteínas de la Matriz Extracelular/metabolismo , Hipertensión/genética , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Vasoconstrictores/farmacología , Animales , Proteínas de Unión al Calcio/deficiencia , Cardiomegalia/metabolismo , Cardiomegalia/patología , Proteínas de la Matriz Extracelular/deficiencia , Fibrosis/metabolismo , Hipertensión/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/etiología , Infarto del Miocardio/genética , Miocardio/patología , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Glycosaminoglycans (GAGs) are sulfated polysaccharides comprising repeating disaccharides, uronic acid (or galactose) and hexosamines, including chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate. Hyaluronan is an exception in the GAG family because it is a non-sulfated polysaccharide. Lysosomal enzymes are crucial for the stepwise degradation of GAGs to provide a normal function of tissues and extracellular matrix (ECM). The deficiency of one or more lysosomal enzyme(s) results in the accumulation of undegraded GAGs, causing cell, tissue, and organ dysfunction. Accumulation of GAGs in various tissues and ECM results in secretion into the circulation and then excretion in urine. GAGs are biomarkers of certain metabolic disorders, such as mucopolysaccharidoses (MPS) and mucolipidoses. GAGs are also elevated in patients with various conditions such as respiratory and renal disorders, fatty acid metabolism disorders, viral infections, vomiting disorders, liver disorders, epilepsy, hypoglycemia, myopathy, developmental disorders, hyperCKemia, heart disease, acidosis, and encephalopathy. MPS are a group of inherited metabolic diseases caused by the deficiency of enzymes required to degrade GAGs in the lysosome. Eight types of MPS are categorized based on lack or defect in one of twelve specific lysosomal enzymes and are described as MPS I through MPS X (excluding MPS V and VIII). Clinical features vary with the type of MPS and clinical severity of the disease. This chapter addresses the historical overview, synthesis, degradation, distribution, biological role, and method for measurement of GAGs.
Asunto(s)
Glicosaminoglicanos , Mucopolisacaridosis , Humanos , Mucopolisacaridosis/metabolismo , Glicosaminoglicanos/metabolismo , AnimalesRESUMEN
BACKGROUND: Tuberculosis continues to be a leading cause of infectious disease mortality, and effective screening and diagnosis remains crucial. Despite progress made, diagnostic gaps remain due to poor access to diagnostic tools and testing, particularly in rural and remote areas. As such, the development of target product profiles is essential in guiding the development of new diagnostic tools, however target product profiles often lack evidence-based information and do not consider trade-offs between test accuracy and accessibility. METHODS: A simulation-based model, in the form of a decision tree, was used to map out the baseline patient tuberculosis diagnostic pathway for individuals in Kenya, South Africa, and India. The model was then used to adapt this pathway to evaluate the trade-offs between increased access to testing and varying accuracy of new tuberculosis diagnostic tools within the health-care contexts of Kenya, South Africa, and India. The model aims to support target product profile development by quantifying the impact of new diagnostics on the standard of care. The model considered three diagnostic attributes, namely sample type (sputum vs non-sputum), site of testing (point of care, near point of care, and health setting) and turnaround time. FINDINGS: Our results indicate that per sample type, novel point-of-care tests would be the most accessible and even with lower sensitivities can achieve comparable or better case detection than the current standard of care in each country. Non-sputum diagnostics also have lower sensitivity requirements. Overall, target product profile parameters with reduced sensitivities from 70% for non-sputum and 78% for sputum tests could be accepted. INTERPRETATION: Diagnostics which bring tuberculosis tests and test results closer to the patient could reduce overall diagnostic loss despite potential reductions in sensitivity. This work provides a novel framework for guiding the future development of diagnostics, with an approach towards balancing accessibility and test performance. FUNDING: The Bill and Melinda Gates Foundation (INV-045721).
Asunto(s)
Accesibilidad a los Servicios de Salud , Tuberculosis , Humanos , Kenia , India/epidemiología , Sudáfrica , Tuberculosis/diagnóstico , Sensibilidad y Especificidad , Árboles de DecisiónRESUMEN
It is believed that wildlife and livestock can coexist in semiarid savanna rangelands. However, this coexistence is threatened by intense competition for scarce, but nutritionally vital, forage resources. Specifically, there is evidence that grazing livestock seasonally compete for protein-rich forbs (non-grasses) with browsing and mixed-feeding wildlife. While this has been attributed to protein needs, there are no experimental tests of whether grazers in such a context alter their diet selection when supplemented with protein. We compared forage selection between cattle supplemented with protein (cotton seedcake) and those not supplemented during dry and wet periods, in a semiarid African savanna rangeland where they have been demonstrated to compete with wildlife for forage. We further evaluated whether such dietary alteration affected the overall biting and movement behavior, nutrition, and performance of cattle, by comparing bite and step rates, diet quality (crude protein and digestible organic matter), forage intake, and live mass change between these treatment groups. During the dry period, relative consumption of forbs was 76% lower in supplemented cattle than in non-supplemented cattle. Notably, supplemented cattle significantly avoided forbs relative to their abundance in the environment, while non-supplemented cattle over-sampled this herbage type. Conversely, selection and relative use of Brachiaria lachnantha, the most abundant grass species, and Bothriochloa insculpta, a grass species otherwise avoided, increased following protein supplementation. These patterns were similar but nonsignificant during the wet period. Bite and step rates, diet quality, forage intake, and performance were not significantly affected by protein supplementation in either period. Our study shows that foraging cattle partially trade off protein-rich forbs for protein-poor grasses when supplemented with protein, without suffering detrimental behavioral, nutritional, or performance consequences. These results broaden our understanding of the role of non-grasses in the diets of "grazers" and suggest protein supplementation as a potential tool in managing coexistence between grazing livestock and browsing (forb-consuming) wildlife.
Asunto(s)
Bovinos/fisiología , Proteínas en la Dieta/farmacología , Conducta Alimentaria/efectos de los fármacos , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Animales Salvajes , Conservación de los Recursos Naturales , Preferencias Alimentarias , Kenia , Estaciones del Año , Aumento de PesoRESUMEN
Proteoglycans (PGs) are macromolecules formed by a protein backbone to which one or more glycosaminoglycan (GAG) side chains are covalently attached. Most PGs are present in connective tissues, cell surfaces, and intracellular compartments. The major biological function of PGs derives from the GAG component of the molecule, which is involved in cell growth and proliferation, embryogenesis, maintenance of tissue hydration, and interactions of the cells via receptors. PGs are categorized into four groups based on their cellular and subcellular localization, including cell surfaces and extracellular, intracellular, and pericellular locations. GAGs are a crucial component of PGs involved in various physiological and pathological processes. GAGs also serve as biomarkers of metabolic diseases such as mucopolysaccharidoses and mucolipidoses. Detection of specific GAGs in various biological fluids helps manage various genetic metabolic disorders before it causes irreversible damage to the patient (Amendum et al., Diagnostics (Basel) 11(9):1563, 2021). There are several methods for detecting GAGs; this chapter focuses on measuring GAGs using enzyme-linked immunosorbent assay, liquid chromatographic tandem mass spectrometry, and automated high-throughput mass spectrometry.
Asunto(s)
Glicosaminoglicanos , Proteoglicanos , Humanos , Glicosaminoglicanos/química , Proteoglicanos/metabolismo , Cromatografía Liquida , Membrana Celular/metabolismo , Espectrometría de Masas en TándemRESUMEN
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a lysosomal enzyme deficiency or malfunction, which leads to the accumulation of glycosaminoglycans in tissues and organs. If not treated at an early stage, patients have various health problems, affecting their quality of life and life-span. Two therapeutic options for MPS are widely used in practice: enzyme replacement therapy and hematopoietic stem cell transplantation. However, early diagnosis of MPS is crucial, as treatment may be too late to reverse or ameliorate the disease progress. It has been noted that the prevalence of MPS and each subtype varies based on geographic regions and/or ethnic background. Each type of MPS is caused by a wide range of the mutational spectrum, mainly missense mutations. Some mutations were derived from the common founder effect. In the previous study, Khan et al. 2018 have reported the epidemiology of MPS from 22 countries and 16 regions. In this study, we aimed to update the prevalence of MPS across the world. We have collected and investigated 189 publications related to the prevalence of MPS via PubMed as of December 2020. In total, data from 33 countries and 23 regions were compiled and analyzed. Saudi Arabia provided the highest frequency of overall MPS because of regional or consanguineous marriages (or founder effect), followed by Portugal, Brazil, the Netherlands, and Australia. The newborn screening is an efficient and early diagnosis for MPS. MPS I has been approved for newborn screening in the United States. After the newborn screening of MPS I, the frequency of MPS I increased, compared with the past incidence rates. Overall, we conclude that the current identification methods are not enough to recognize all MPS patients, leading to an inaccurate incidence and status. Differences in ethnic background and/or founder effects impact on the frequency of MPS, which affects the prevalence of MPS. Two-tier newborn screening has accelerated early recognition of MPS I, providing an accurate incidence of patients.
RESUMEN
AIM: Coronary angiography is indicated in many patients with known or suspected angina for the investigation of coronary artery disease (CAD). However, up to half of patients with symptoms of ischaemia have no obstructive coronary arteries (INOCA). This large subgroup includes patients with suspected microvascular angina (MVA) and/or vasospastic angina (VSA). Clinical guidelines relating to the management of patients with INOCA are limited. Uncertainty regarding the diagnosis of patients with INOCA presents a health economic challenge, both in terms of healthcare resource utilisation and of quality-of-life impact on patients. METHODS: A cost-effectiveness analysis of the introduction of stratified medicine into the invasive management of INOCA, based on clinical and resource-use data obtained in the CorMicA trial, from a UK NHS perspective. The intervention included an invasive diagnostic procedure (IDP) of coronary vascular function during coronary angiography to define clinical endotypes to target with linked medical therapy. Outcomes of interest were mean total cost and QALY gain between treatment groups, and the incremental cost-effectiveness ratio. We undertook probabilistic sensitivity and scenario analyses. RESULTS: The incremental cost per QALY gained at 12 months was £4500 (£2937, £33264). Compared with a willingness-to-pay (WTP) threshold of £20,000 per QALY, the use of the IDP test is cost-effective. At this WTP threshold there is a 96% probability of the IDP being cost-effective, based on the uncertainty described by bootstrap analysis. CONCLUSIONS: The burden of INOCA, particularly in women, is known to be significant. These findings provided new evidence to inform this unmet clinical need.
Asunto(s)
Enfermedad de la Arteria Coronaria , Angina Microvascular , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Análisis Costo-Beneficio , Femenino , Humanos , Años de Vida Ajustados por Calidad de VidaRESUMEN
INTRODUCTION: In many low- and middle-income countries, HIV viral load (VL) testing occurs at centralized laboratories and time-to-result-delivery is lengthy, preventing timely monitoring of HIV treatment adherence. Near point-of-care (POC) devices, which are placed within health facility laboratories rather than clinics themselves (i.e. "true" POC), can offer VL in conjunction with centralized laboratories to expedite clinical decision making and improve outcomes, especially for patients at high risk of treatment failure. We assessed impacts of near-POC VL testing on result receipt and clinical action in public sector programmes in Cameroon, Democratic Republic of Congo, Kenya, Malawi, Senegal, Tanzania and Zimbabwe. METHODS: Routine health data were collected retrospectively after introducing near-POC VL testing at 57 public sector health facilities (2017 to 2019, country-dependent). Where possible, key indicators were compared to data from patients receiving centralized laboratory testing using hazard ratios and the Somers' D test. RESULTS: Data were collected from 6795 tests conducted on near-POC and 17614 tests on centralized laboratory-based platforms. Thirty-one percent (2062/6694) of near-POC tests were conducted for high-risk populations: pregnant and breastfeeding women, children and those with suspected failure. Compared to conventional testing, near-POC improved the median time from sample collection to return of results to patient [six vs. sixty-eight days, effect size: -32.2%; 95% CI: -41.0% to -23.4%] and to clinical action for individuals with an elevated HIV VL [three vs. fourty-nine days, effect size: -35.4%; 95% CI: -46.0% to -24.8%]. Near-POC VL results were two times more likely to be returned to the patient within 90 days compared to centralized tests [50% (1781/3594) vs. 27% (4172/15271); aHR: 2.22, 95% CI: 2.05 to 2.39]. Thirty-seven percent (340/925) of patients with an elevated near-POC HIV VL result had documented clinical follow-up actions within 30 days compared to 7% (167/2276) for centralized testing. CONCLUSIONS: Near-POC VL testing enabled rapid test result delivery for high-risk populations and led to significant improvements in the timeliness of patient result receipt compared to centralized testing. While there was some improvement in time-to-clinical action with near-POC VL testing, major gaps remained. Strengthening of systems supporting the utilization of results for patient management are needed to truly capitalize on the benefits of decentralized testing.
Asunto(s)
Infecciones por VIH/virología , Sistemas de Atención de Punto , Carga Viral , Adolescente , Adulto , África del Sur del Sahara , Anciano , Niño , Preescolar , Femenino , Infecciones por VIH/tratamiento farmacológico , Instituciones de Salud , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Embarazo , Práctica de Salud Pública , Estudios Retrospectivos , Carga Viral/métodos , Adulto JovenRESUMEN
The Sleeping Beauty (SB) transposon system is a nonviral vector that directs transgene integration into vertebrate genomes. We hydrodynamically delivered SB transposon plasmids encoding human alpha-L-iduronidase (hIDUA) at two DNA doses, with and without an SB transposase gene, to NOD.129(B6)-Prkdc(scid) IDUA(tm1Clk)/J mice. In transposon-treated, nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with mucopolysaccharidosis type I (MPS I), plasma IDUA persisted for 18 weeks at levels up to several hundred-fold wild-type (WT) activity, depending on DNA dose and gender. IDUA activity was present in all examined somatic organs, as well as in the brain, and correlated with both glycosaminoglycan (GAG) reduction in these organs and level of expression in the liver, the target of transposon delivery. IDUA activity was higher in the treated males than in females. In females, omission of transposase source resulted in significantly lower IDUA levels and incomplete GAG reduction in some organs, confirming the positive effect of transposition on long-term IDUA expression and correction of the disease. The SB transposon system proved efficacious in correcting several clinical manifestations of MPS I in mice, including thickening of the zygomatic arch, hepatomegaly, and accumulation of foamy macrophages in bone marrow and synovium, implying potential effectiveness of this approach in treatment of human MPS I.
Asunto(s)
Elementos Transponibles de ADN/genética , Terapia Genética/métodos , Mucopolisacaridosis I/terapia , Animales , Encéfalo/metabolismo , Femenino , Glicosaminoglicanos/metabolismo , Iduronidasa/sangre , Iduronidasa/genética , Iduronidasa/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Reacción en Cadena de la PolimerasaRESUMEN
Thyroid dysfunction in patients with Down's syndrome is well known. Although the majority of children with Down's syndrome appear to have normal thyroid function, however, hypothyroidism is commonly seen. The presence of hyperthyroidism is rare. The etiology is believed to be autoimmune. We report a patient with Down syndrome and Graves' disease who responded well to antithyroid drugs. The rarity of this association, especially in a child younger than eight years of age, has prompted us to report this case.