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1.
Front Immunol ; 15: 1375486, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39007142

RESUMO

Introduction: It is unknown how intestinal B cell populations and B cell receptor (BCR) repertoires are established and maintained over time in humans. Following intestinal transplantation (ITx), surveillance ileal mucosal biopsies provide a unique opportunity to map the dynamic establishment of recipient gut lymphocyte populations in immunosuppressed conditions. Methods: Using polychromatic flow cytometry that includes HLA allele group-specific antibodies distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establishment of recipient B cell populations and BCR repertoire in the allograft mucosa of ITx recipients. Results: We confirm the early presence of naïve donor B cells in the circulation (donor age range: 1-14 years, median: 3 years) and, for the first time, document the establishment of recipient B cell populations, including B resident memory cells, in the intestinal allograft mucosa (recipient age range at the time of transplant: 1-44 years, median: 3 years). Recipient B cell repopulation of the allograft was most rapid in infant (<1 year old)-derived allografts and, unlike T cell repopulation, did not correlate with rejection rates. While recipient memory B cell populations were increased in graft mucosa compared to circulation, naïve recipient B cells remained detectable in the graft mucosa for years. Comparisons of peripheral and intra-mucosal B cell repertoires in the absence of rejection (recipient age range at the time of transplant: 1-9 years, median: 2 years) revealed increased BCR mutation rates and clonal expansion in graft mucosa compared to circulating B cells, but these parameters did not increase markedly after the first year post-transplant. Furthermore, clonal mixing between the allograft mucosa and the circulation was significantly greater in ITx recipients, even years after transplantation, than in deceased adult donors. In available pan-scope biopsies from pediatric recipients, we observed higher percentages of naïve recipient B cells in colon allograft compared to small bowel allograft and increased BCR overlap between native colon vs colon allograft compared to that between native colon vs ileum allograft in most cases, suggesting differential clonal distribution in large intestine vs small intestine. Discussion: Collectively, our data demonstrate intestinal mucosal B cell repertoire establishment from a circulating pool, a process that continues for years without evidence of stabilization of the mucosal B cell repertoire in pediatric ITx patients.


Assuntos
Mucosa Intestinal , Receptores de Antígenos de Linfócitos B , Humanos , Criança , Pré-Escolar , Adolescente , Lactente , Mucosa Intestinal/imunologia , Masculino , Feminino , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Adulto , Linfócitos B/imunologia , Adulto Jovem , Intestinos/imunologia , Intestinos/transplante , Transplante de Órgãos , Rejeição de Enxerto/imunologia
2.
Nutrients ; 16(13)2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38999749

RESUMO

Undernutrition (UN) increases child vulnerability to illness and mortality. Caused by a low amount and/or poor quality of food intake, it impacts physical, cognitive, and social development. Modern types of food consumption have given highly processed food a higher cultural value compared to minimally processed food. OBJECTIVE: The objective of this study was to evaluate the effect on growth, metabolism, physical activity (PA), memory, inflammation, and toxicity of an enriched black corn chip (BC) made with endemic ingredients on post-weaned UN mice. METHODS: A chip was made with a mixture of black corn, fava beans, amaranth, and nopal cactus. To probe the effects of UN, UN was induced in 3wo post-weaned male C57Bl/6j mice through a low-protein diet (LPD-50% of the regular requirement of protein) for 3w. Then, the BC was introduced to the animals' diet (17%) for 5w; murinometric parameters were measured, as were postprandial glucose response, PA, and short-term memory. Histological analysis was conducted on the liver and kidneys to measure toxicity. Gene expression related to energy balance, thermogenesis, and inflammation was measured in adipose and hypothalamic tissues. RESULTS: Treatment with the BC significantly improved mouse growth, even with a low protein intake, as evidenced by a significant increase in body weight, tail length, cerebral growth, memory improvement, physical activation, normalized energy expenditure (thermogenesis), and orexigenic peptides (AGRP and NPY). It decreased anorexigenic peptides (POMC), and there was no tissue toxicity. CONCLUSIONS: BC treatment, even with persistent low protein intake, is a promising strategy against UN, as it showed efficacy in correcting growth deficiency, cognitive impairment, and metabolic problems linked to treatment by adjusting energy expenditure, which led to the promotion of energy intake and regulation of thermogenesis, all by using low-cost, accessible, and endemic ingredients.


Assuntos
Modelos Animais de Doenças , Desnutrição , Camundongos Endogâmicos C57BL , Zea mays , Animais , Masculino , Camundongos , Metabolismo Energético , Dieta com Restrição de Proteínas , Fígado/metabolismo , Alimentos Fortificados , Termogênese
3.
J Hepatol ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38996924

RESUMO

BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

4.
Front Transplant ; 3: 1367486, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38993771

RESUMO

Introduction: Intestinal transplantation (ITx) is the last remaining therapy for patients with intestinal failure once parenteral nutrition is no longer an option, however its use is limited by immunological complications, including high rates of rejection and morbidity associated with immunosuppression, such as infection and malignancy. We aimed to develop a large animal model of ITx with which to study the immune response to ITx and to design and test tolerance induction regimens. Methods: Learning from prior complications, we developed and progressively improved both surgical methods for the donor and recipient as well as postoperative management strategies. Methods of stoma generation, bowel positioning, vessel preparation, and fluid management were optimized. The immunosuppression strategy mirrored our clinical regimen. Results: As a result of our modifications, results improved from survival less than 1 month to consistent long-term survival with good graft function. We review several techniques that were developed to avoid pitfalls that were encountered, which can be used to optimize outcomes in this model. Discussion: Achieving long-term survival after swine orthotopic ITx permits immunological analysis and pre-clinical trials in a large animal model of ITx.

5.
Sci Data ; 11(1): 650, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906878

RESUMO

Monitoring health is key for identifying priorities in public health planning and improving healthcare services. Life expectancy has conventionally been regarded as a valuable indicator to compare the health status of different populations. However, this measure is simply the mean of the distribution of the length of life and, as such, neglects individual disparities in health outcomes. In this paper, we use life tables from the UN World Population Prospects to develop the most comprehensive dataset of lifespan inequality and polarization for 258 countries and areas for the period 1950-2021. These extensive series on lifespan distributions provide access to crucial information for researchers, practitioners, and the general public, thus contributing to a better understanding of health differences within and between nations.


Assuntos
Expectativa de Vida , Expectativa de Vida/tendências , Humanos , Longevidade , Disparidades nos Níveis de Saúde , Tábuas de Vida
6.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38701882

RESUMO

In Spain, 33% of adults aged 30 to 79 years (10 million) were hypertensive in 2019. Among them, 68% were diagnosed, 57% received drug therapy, and effective therapeutic coverage (control) reached 33%. Both diagnosis and control show geographical and social disparities. Approximately 46 000 cardiovascular deaths per year are attributable to hypertension. In recent decades, the control of hypertension has increased, due to improvements in lifestyle measures and increased use of polytherapy, coinciding with a reduction in stroke mortality. There are several modifiable determinants of the lack of hypertension control: a) white-coat phenomenon affects 22% to 33% of treated individuals, partly due to the limited availability of ambulatory blood pressure monitoring (ABPM) (49%) and self-measured BP (SMBP) (78%); b) inadequate patient adherence to medication and healthy lifestyles (weight loss, the most effective measure, is the least used, ≈40%); and c) insufficient use of polytherapy (≈55%). The remaining challenges include: a) technological aspects, such as measuring BP with more accurate techniques (ABPM, SMBP) and using cardiovascular-risk estimation tools (eg, SCORE); b) clinical challenges, such as reducing therapeutic inertia (≈59%), involving patients in their own management (medication adherence, ≈62%) and effectively implementing clinical guidelines); and c) public health challenges, such as reducing the burden of obesity (≈24%), monitoring progress with updated surveys, and setting national BP control targets.

7.
Front Cell Infect Microbiol ; 14: 1370859, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38572317

RESUMO

Background: The aim of the study was to evaluate the humoral and cellular immunity after SARS-CoV-2 infection and/or vaccination according to the type of vaccine, number of doses and combination of vaccines. Methods: Volunteer subjects were sampled between September 2021 and July 2022 in Hospital Clínico San Carlos, Madrid (Spain). Participants had different immunological status against SARS-CoV-2: vaccinated and unvaccinated, with or without previous COVID-19 infection, including healthy and immunocompromised individuals. Determination of IgG against the spike protein S1 subunit receptor-binding domain (RBD) was performed by chemiluminescence microparticle immunoassay (CMIA) using the Architect i10000sr platform (Abbott). The SARS-CoV-2-specific T-cell responses were assessed by quantification of interferon gamma release using QuantiFERON SARS-CoV-2 assay (Qiagen). Results: A total of 181 samples were collected, 170 were from vaccinated individuals and 11 from unvaccinated. Among the participants, 41 were aware of having previously been infected by SARS-CoV-2. Vaccinated people received one or two doses of the following vaccines against SARS-CoV-2: ChAdOx1-S (University of Oxford-AstraZeneca) (AZ) and/orBNT162b2 (Pfizer-BioNTech)(PZ). Subjects immunized with a third-booster dose received PZ or mRNA-1273 (Moderna-NIAID)(MD) vaccines. All vaccinees developed a positive humoral response (>7.1 BAU/ml), but the cellular response varied depending on the vaccination regimen. Only AZ/PZ combination and 3 doses of vaccination elicited a positive cellular response (median concentration of IFN- γ > 0.3 IU/ml). Regarding a two-dose vaccination regimen, AZ/PZ combination induced the highest humoral and cellular immunity. A booster with mRNA vaccine resulted in increases in median levels of IgG-Spike antibodies and IFN-γ as compared to those of two-dose of any vaccine. Humoral and cellular immunity levels were significantly higher in participants with previous infection compared to those without infection. Conclusion: Heterologous vaccination (AZ/PZ) elicited the strongest immunity among the two-dose vaccination regimens. The immunity offered by the third-booster dose of SARS-CoV-2 vaccine depends not only on the type of vaccine administered but also on previous doses and prior infection. Previous exposure to SARS-CoV-2 antigens by infection strongly affect immunity of vaccinated individuals.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Vacinação , Imunidade Celular , Imunoglobulina G , Anticorpos Antivirais , Imunidade Humoral
8.
Hum Mol Genet ; 33(9): 818-834, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38641551

RESUMO

Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants.


Assuntos
Disceratose Congênita , Telomerase , Humanos , Apoptose/genética , DNA/metabolismo , Dano ao DNA/genética , Disceratose Congênita/genética , Disceratose Congênita/metabolismo , Disceratose Congênita/patologia , Mutação , Estresse Oxidativo/genética , RNA/genética , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo
9.
Hypertens Res ; 47(5): 1235-1245, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38485774

RESUMO

The impact of ambulatory resistant hypertension (ARH) on the occurrence of heart failure (HF) is not yet completely known. We performed for the first time a meta-analysis, by using published data or available data from published databases, on the risk of HF in ARH. Patients with ARH (24-h BP ≥ 130/80 mmHg during treatment with ≥3 drugs) were compared with those with controlled hypertension (CH, clinic BP < 140/90 mmHg and 24-h BP < 130/80 mmHg regardless of the number of drugs used), white coat uncontrolled resistant hypertension (WCURH, clinic BP ≥ 140/90 mmHg and 24-h BP < 130/80 mmHg in treated patients) and ambulatory nonresistant hypertension (ANRH, 24-h BP ≥ 130/80 mmHg during therapy with ≤2 drugs). We identified six studies/databases including 21,365 patients who experienced 692 HF events. When ARH was compared with CH, WCURH, or ANRH, the overall adjusted hazard ratio for HF was 2.32 (95% confidence interval (CI) 1.45-3.72), 1.72 (95% CI 1.36-2.17), and 2.11 (95% CI 1.40-3.17), respectively, (all P < 0.001). For some comparisons a moderate heterogeneity was found. Though we did not find variables that could explain the heterogeneity, sensitivity analyses demonstrated that none of the studies had a significant influential effect on the overall estimate. When we evaluated the potential presence of publication bias and small-study effect and adjusted for missing studies identified by Duval and Tweedie's method the estimates were slightly lower but remained significant. This meta-analysis shows that treated hypertensive patients with ARH are at approximately twice the risk of developing HF than other ambulatory BP phenotypes.


Assuntos
Insuficiência Cardíaca , Hipertensão , Humanos , Anti-Hipertensivos/uso terapêutico , Monitorização Ambulatorial da Pressão Arterial , Hipertensão/tratamento farmacológico , Hipertensão/complicações , Estudos Observacionais como Assunto , Fatores de Risco
10.
Aliment Pharmacol Ther ; 59(10): 1236-1247, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38462727

RESUMO

BACKGROUND: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.


Assuntos
Antibacterianos , Colangite Esclerosante , Doenças Inflamatórias Intestinais , Vancomicina , Humanos , Vancomicina/administração & dosagem , Vancomicina/efeitos adversos , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/complicações , Feminino , Masculino , Estudos Retrospectivos , Criança , Adolescente , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/complicações , Administração Oral , Resultado do Tratamento , Índice de Gravidade de Doença , Indução de Remissão , Estudos de Coortes
11.
Circ Res ; 134(8): e52-e71, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38497220

RESUMO

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.


Assuntos
Síndrome de Andersen , Humanos , Camundongos , Animais , Síndrome de Andersen/genética , Síndrome de Andersen/metabolismo , Mutação , Miócitos Cardíacos/metabolismo , Doença do Sistema de Condução Cardíaco , Dissulfetos , Fosfatidilinositóis/metabolismo
12.
EBioMedicine ; 101: 105028, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38422982

RESUMO

BACKGROUND: Understanding formation of the human tissue resident memory T cell (TRM) repertoire requires longitudinal access to human non-lymphoid tissues. METHODS: By applying flow cytometry and next generation sequencing to serial blood, lymphoid tissue, and gut samples from 16 intestinal transplantation (ITx) patients, we assessed the origin, distribution, and specificity of human TRMs at phenotypic and clonal levels. FINDINGS: Donor age ≥1 year and blood T cell macrochimerism (peak level ≥4%) were associated with delayed establishment of stable recipient TRM repertoires in the transplanted ileum. T cell receptor (TCR) overlap between paired gut and blood repertoires from ITx patients was significantly greater than that in healthy controls, demonstrating increased gut-blood crosstalk after ITx. Crosstalk with the circulating pool remained high for years of follow-up. TCR sequences identifiable in pre-Tx recipient gut but not those in lymphoid tissues alone were more likely to populate post-Tx ileal allografts. Clones detected in both pre-Tx gut and lymphoid tissue had distinct transcriptional profiles from those identifiable in only one tissue. Recipient T cells were distributed widely throughout the gut, including allograft and native colon, which had substantial repertoire overlap. Both alloreactive and microbe-reactive recipient T cells persisted in transplanted ileum, contributing to the TRM repertoire. INTERPRETATION: Our studies reveal human intestinal TRM repertoire establishment from the circulation, preferentially involving lymphoid tissue counterparts of recipient intestinal T cell clones, including TRMs. We have described the temporal and spatial dynamics of this active crosstalk between the circulating pool and the intestinal TRM pool. FUNDING: This study was funded by the National Institute of Allergy and Infectious Diseases (NIAID) P01 grant AI106697.


Assuntos
Células T de Memória , Receptores de Antígenos de Linfócitos T , Humanos , Íleo , Aloenxertos , Memória Imunológica , Linfócitos T CD8-Positivos
15.
Am J Ophthalmol ; 260: 122-131, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38056608

RESUMO

PURPOSE: To evaluate the progression of myopia as assessed by change in axial length (AL) and spherical equivalent (SE) from baseline in Caucasian children wearing extended depth of focus soft contact lenses (CLs) compared to distance single-vision spectacles. DESIGN: Prospective non-randomized comparative clinical trial. METHODS: A total of 90 children (6-13 years of age) with SE ranging from -0.75 to -10.00 diopters (D) were recruited. Of these children, 45 were fitted with CLs (MYLO, mark´ennovy), whereas 45 children wore spectacles. Cycloplegic refraction was measured with an auto-refractometer (Topcon-TRK-2P) and AL with an IOLMaster-700 (Zeiss) at 6-month intervals. Subjective responses after 1 month of CL wear related to vision and comfort were determined using a questionnaire with a scale from 1 (very poor) to 10 (excellent). High-contrast visual acuity (HCVA) and contrast sensitivity (CS) were evaluated at baseline, 12, and 24 months. RESULTS: After 2 years, mean change in SE/AL in the CL group was -0.62 ± 0.30 D/0.37 ± 0.04 mm and -1.13 ± 0.20 D/0.66 ± 0.03 mm in the spectacles group (P < .001). Cumulative absolute reduction in axial elongation (CARE) was 0.29 ± 0.06 mm. Difference in SE change was -0.50 ± 0.34 D. Although 100% of CL group had an AL increase ≤0.50 mm, all participants increased ≥0.50 mm in the spectacles group. In all, 53% of the CL group and 1% in the spectacles group showed a progression in SE ≤ -0.50D. All questionnaire items showed a mean value ≥9. There was a reduction logMAR HCVA in the CL compared to the spectacles group but it was less than 1 line (P < .001). CONCLUSIONS: Use of MYLO CLs reduced axial elongation and myopia progression compared to use of distance single-vision spectacles.


Assuntos
Lentes de Contato Hidrofílicas , Miopia , Criança , Humanos , Progressão da Doença , Miopia/terapia , Estudos Prospectivos , Refração Ocular , Acuidade Visual , Adolescente
16.
Transplantation ; 108(4): 827-835, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37723639

RESUMO

Intestinal transplant (ITx) rejection lacks a reliable noninvasive biomarker and rejection surveillance relies on serial endoscopies and mucosal biopsies followed by histologic assessment. Endoscopic biopsies are also essential for identifying other ITx-related complications such as infectious, allergic, and inflammatory graft enteritis as well as post-transplant lymphoproliferative disease or graft versus host disease. In spite of its central role in ITx, published guidelines on endoscopy and biopsy are lacking and significant variability between centers in terms of timing and technical performance exists. Therefore, an international expert group convened and discussed several aspects related to the surveillance endoscopy after ITx with the aim to summarize and standardize its practice. This article summarizes these considerations on endoscopic ITx monitoring and highlights practices of surveillance and for-cause endoscopy, biopsy techniques, pathologic evaluation, potential risks and complications, outsourcing, and less-invasive monitoring techniques.


Assuntos
Rejeição de Enxerto , Enteropatias , Humanos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/patologia , Intestinos/transplante , Transplante Homólogo , Endoscopia Gastrointestinal/efeitos adversos , Endoscopia Gastrointestinal/métodos , Aloenxertos , Enteropatias/patologia
18.
J Exp Med ; 221(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38091025

RESUMO

The site of transition between tissue-resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity, and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single-cell level after human intestinal transplantation. Host-versus-graft (HvG)-reactive T cells were mainly distributed to TRM, effector T (Teff)/TRM, and T follicular helper compartments. RNA velocity analysis demonstrated a trajectory from TRM to Teff/TRM clusters in association with rejection. By integrating pre- and post-transplantation (Tx) mixed lymphocyte reaction-determined alloreactive repertoires, we observed that pre-existing HvG-reactive T cells that demonstrated tolerance in the circulation were dominated by TRM profiles in quiescent allografts. Putative de novo HvG-reactive clones showed a transcriptional profile skewed to cytotoxic effectors in rejecting grafts. Inferred protein regulon network analysis revealed upstream regulators that accounted for the effector and tolerant T cell states. We demonstrate Teff/TRM interchangeability for individual T cell clones with known (allo)recognition in the human gut, providing novel insight into TRM biology.


Assuntos
Tolerância Imunológica , Linfócitos T , Humanos , Transplante Homólogo , Células Clonais , Memória Imunológica
19.
Sci Rep ; 13(1): 21540, 2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-38057357

RESUMO

Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10-4 for dominant disorders and MAF ≤ 10-3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06-8.18, p value = 4.5e-12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.


Assuntos
Nefropatias , Hepatopatias , Humanos , Sequenciamento do Exoma , Frequência do Gene , Fenótipo , Hepatopatias/diagnóstico , Hepatopatias/genética
20.
J Liver Transpl ; 122023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38037556

RESUMO

Background: Vascular thromboses (VT) are life-threatening events after pediatric liver transplantation (LT). Single-center studies have identified risk factors for intra-abdominal VT, but large-scale pediatric studies are lacking. Methods: This multicenter retrospective cohort study of isolated pediatric LT recipients assessed pre- and perioperative variables to determine VT risk factors and anticoagulation-associated bleeding complications. Results: Within seven postoperative days, 31/331 (9.37%) patients developed intra-abdominal VT. Open fascia occurred more commonly in patients with VT (51.61 vs 23.33%) and remained the only independent risk factor in multivariable analysis (OR = 2.84, p = 0.012). Patients with VT received more blood products (83.87 vs 50.00%), had significantly higher rates of graft loss (22.58 vs 1.33%), infection (50.00 vs 20.60%), and unplanned return to the operating room (70.97 vs 16.44%) compared to those without VT. The risk of bleeding was similar (p = 0.2) between patients on and off anticoagulation. Conclusions: Prophylactic anticoagulation did not increase bleeding complications in this cohort. The only independent factor associated with VT was open fascia, likely a graft/recipient size mismatch surrogate, supporting the need to improve surgical techniques to prevent VT that may not be modifiable with anticoagulation.

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