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1.
Nature ; 608(7922): 287-292, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35948709

RESUMO

Particle accelerators and storage rings have been transformative instruments of discovery, and, for many applications, innovations in particle-beam cooling have been a principal driver of that success1. Stochastic cooling (SC), one of the most important conceptual and technological advances in this area2-6, cools a beam through granular sampling and correction of its phase-space structure, thus bearing resemblance to a 'Maxwell's demon'. The extension of SC from the microwave regime up to optical frequencies and bandwidths has long been pursued, as it could increase the achievable cooling rates by three to four orders of magnitude and provide a powerful tool for future accelerators. First proposed nearly 30 years ago, optical stochastic cooling (OSC) replaces the conventional microwave elements of SC with optical-frequency analogues and is, in principle, compatible with any species of charged-particle beam7,8. Here we describe a demonstration of OSC in a proof-of-principle experiment at the Fermi National Accelerator Laboratory's Integrable Optics Test Accelerator9,10. The experiment used 100-MeV electrons and a non-amplified configuration of OSC with a radiation wavelength of 950 nm, and achieved strong, simultaneous cooling of the beam in all degrees of freedom. This realization of SC at optical frequencies serves as a foundation for more advanced experiments with high-gain optical amplification, and advances opportunities for future operational OSC systems with potential benefit to a broad user community in the accelerator-based sciences.

2.
Curr Opin Urol ; 34(2): 44-51, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37962190

RESUMO

PURPOSE OF REVIEW: This study aims to further understand the physiological mechanism of chondroitin sulfate treatment on the urinary bladder in cases of inflammation, by investigating the effect of chondroitin sulfate therapy on recovery of urothelial barrier in an in-vitro chronic injury model. RECENT FINDINGS: With inflammatory bladder conditions, the urothelial barrier seems decreased. Glycosaminoglycan (GAG) replacement therapy is supposed to help restore this barrier. Clinical studies on inflammatory bladder conditions are complicated because of the heterogeneous patient population, hence the need for preclinical models. SUMMARY: In a model using porcine urothelial cells, functional barrier (TEER) and barrier markers were assessed. Chronic urothelial damage was simulated through protamine sulfate instillations with and without subsequent chondroitin sulfate instillations during 3 days. Chondroitin sulfate instillations significantly improved TEER compared to protamine sulfate treatment only (TEER difference 310 Ω.cm 2 , P  < 0.001). This consistent effect over 3 days resulted in a significant higher mean TEER value in the chondroitin sulfate treated group (difference 1855 Ω.cm 2 , P  < 0.001). Enhanced recovery of chondroitin sulfate and other barrier markers was observed.Chondroitin sulfate therapy shows promise in facilitating the recovery of the urothelial barrier in cases of chronic damage. This preclinical study lends support to the use of clinical GAG replenishment therapy for patients with a chronically impaired urothelium.


Assuntos
Sulfatos de Condroitina , Doenças da Bexiga Urinária , Animais , Sulfatos de Condroitina/farmacologia , Protaminas/toxicidade , Suínos , Urotélio
3.
Int J Mol Sci ; 23(6)2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35328824

RESUMO

Stress urinary incontinence (SUI) is a common and burdensome condition. Because of the large knowledge gap around the molecular processes involved in its pathophysiology, the aim of this review was to provide a systematic overview of genetic variants, gene and protein expression changes related to SUI in human and animal studies. On 5 January 2021, a systematic search was performed in Pubmed, Embase, Web of Science, and the Cochrane library. The screening process and quality assessment were performed in duplicate, using predefined inclusion criteria and different quality assessment tools for human and animal studies respectively. The extracted data were grouped in themes per outcome measure, according to their functions in cellular processes, and synthesized in a narrative review. Finally, 107 studies were included, of which 35 used animal models (rats and mice). Resulting from the most examined processes, the evidence suggests that SUI is associated with altered extracellular matrix metabolism, estrogen receptors, oxidative stress, apoptosis, inflammation, neurodegenerative processes, and muscle cell differentiation and contractility. Due to heterogeneity in the studies (e.g., in examined tissues), the precise contribution of the associated genes and proteins in relation to SUI pathophysiology remained unclear. Future research should focus on possible contributors to these alterations.


Assuntos
Incontinência Urinária por Estresse , Animais , Humanos , Camundongos , Ratos , Incontinência Urinária por Estresse/genética
4.
Respir Res ; 21(1): 209, 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32771010

RESUMO

BACKGROUND: Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes. METHODS: We performed a prospective, randomized study in 27 ventilated ewes inducing ARDS using three different techniques to mimic the pulmonary causes of ARDS (ARDSp): warm saline lavage (n = 6), intratracheal hydrochloric acid (HCl; n = 6), intratracheal albumin (n = 10), and one technique to mimic an extrapulmonary cause of ARDS (ARDSexp): intravenous lipopolysaccharide (LPS iv; n = 5). ARDS was defined when PaO2 was < 15 kPa (112 mmHg) when ventilated with PEEP 10 cm H2O and FiO2 = 1.0. The effects on gas exchange were investigated by calculating the oxygenation index (OI) and the ventilation efficacy index (VEI) every 30 min for a period of 4 h. Post mortem lung lavage was performed to obtain broncho-alveolar lavage fluid (BALF) to assess lung injury and inflammation. Lung injury and inflammation were assessed by measuring the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, and interleukine-6 and -8 in the BALF. Histology of the lung was evaluated by measuring the mean alveolar size, alveolar wall thickness and the lung injury score system by Matute-Bello et al., as markers of lung injury. The concentration of interleukin-6 was determined in plasma, as a marker of systematic inflammation. RESULTS: The OI and VEI were most affected in the LPS iv group and thereafter the HCl group, after meeting the ARDS criteria. Diastolic blood pressure was lowest in the LPS iv group. There were no significant differences found in the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, or interleukin-8 in the BALF, histology of the lung and the lung injury score. IL-6 in BALF and plasma was highest in the LPS iv group, but no significant differences were found between the other groups. It took a significantly longer period of time to meet the ARDS criteria in the LPS iv group. CONCLUSIONS: The LPS model caused the most severe pulmonary and cardiovascular insufficiency. Surprisingly, there were limited significant differences in lung injury and inflammatory markers, despite the different pathophysiological models, when the clinical definition of ARDS was applied.


Assuntos
Albuminas , Lavagem Broncoalveolar , Modelos Animais de Doenças , Ácido Clorídrico , Lipopolissacarídeos , Síndrome do Desconforto Respiratório , Animais , Feminino , Albuminas/toxicidade , Biomarcadores/sangue , Lavagem Broncoalveolar/efeitos adversos , Lavagem Broncoalveolar/métodos , Ácido Clorídrico/toxicidade , Mediadores da Inflamação/sangue , Infusões Intravenosas , Lipopolissacarídeos/toxicidade , Estudos Prospectivos , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/patologia , Ovinos , Traqueia/efeitos dos fármacos , Traqueia/patologia
5.
Neurourol Urodyn ; 39(8): 2089-2110, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32949220

RESUMO

AIM: To perform a systematic review summarizing the knowledge of genetic variants, gene, and protein expression changes in humans and animals associated with urgency urinary incontinence (UUI) and to provide an overview of the known molecular mechanisms related to UUI. METHODS: A systematic search was performed on March 2, 2020, in PubMed, Embase, Web of Science, and the Cochrane library. Retrieved studies were screened for eligibility. The risk of bias was assessed using the ROBINS-I (human) and SYRCLE (animal) tool. Data were presented in a structured manner and in the case of greater than five studies on a homogeneous outcome, a meta-analysis was performed. RESULTS: Altogether, a total of 10,785 records were screened of which 37 studies met the inclusion criteria. Notably, 24/37 studies scored medium-high to high on risk of bias, affecting the value of the included studies. The analysis of 70 unique genes and proteins and three genome-wide association studies showed that specific signal transduction pathways and inflammation are associated with UUI. A meta-analysis on the predictive value of urinary nerve growth factor (NGF) levels showed that increased urinary NGF levels correlate with UUI. CONCLUSION: The collective evidence showed the involvement of two molecular mechanisms (signal transduction and inflammation) and NGF in UUI, enhancing our understanding of the pathophysiology of UUI. Unfortunately, the risk of bias was medium-high to high for most studies and the value of many observations remains unclear. Future studies should focus on elucidating how deficits in the two identified molecular mechanisms contribute to UUI and should avoid bias.


Assuntos
Variação Genética , Incontinência Urinária de Urgência/genética , Disuria/genética , Disuria/urina , Estudo de Associação Genômica Ampla , Humanos , Fator de Crescimento Neural/urina , Incontinência Urinária de Urgência/urina
6.
Cereb Cortex ; 28(10): 3445-3456, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28968768

RESUMO

The organization of the human insular cortex has traditionally been considered as an anterior-posterior dichotomy, where anterior and posterior subdivisions have unique structural and functional connections. However, recent functional neuroimaging research proposes a tripartite organization where insular subdivisions have both unique and overlapping functional profiles. Studies examining unique profiles show that the dorsal anterior insula (dAI) has connections with frontal areas supporting higher-level cognitive processes, the ventral anterior insula (vAI) has connections with limbic areas supporting affective processes, and the posterior insula (PI) has connections with sensorimotor areas supporting interoceptive processes. Studies examining overlapping profiles demonstrate that all 3 subdivisions can also have similar functional profiles. The structural organization supporting a functional tripartite insula organization presenting with overlapping and unique connections is currently unknown. We used a large HARDI diffusion magnetic resonance imaging (MRI) dataset (n = 199) to demonstrate novel visualizations of insula white matter tracts supporting a tripartite structure-function insula organization. Overlapping connections of all 3 insula subdivisions consisted of association pathways (inferior fronto-occipital fasciculus, uncinate fasciculus, arcuate fasciculus) while unique connections included the corona radiata, subcortical-cortical tracts, and horizontal and u-shaped tracts. These results generally support a tripartite structure-function organization of the insular cortex, with subdivisions that exhibit both overlapping and unique connectivity profiles.


Assuntos
Córtex Cerebral/anatomia & histologia , Córtex Cerebral/fisiologia , Adulto , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Feminino , Lobo Frontal/anatomia & histologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiologia , Humanos , Masculino , Vias Neurais/anatomia & histologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Córtex Sensório-Motor/anatomia & histologia , Córtex Sensório-Motor/fisiologia , Substância Branca/anatomia & histologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiologia , Adulto Jovem
7.
Int Urogynecol J ; 29(7): 933-942, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29181550

RESUMO

INTRODUCTION AND HYPOTHESIS: The objective was to assess the efficacy of intravesical hyaluronic acid (HA) and chondroitin sulfate (CS), alone or in combination, for recurrent urinary tract infections (RUTIs) in adult female patients using a systematic review and meta-analysis. METHODS: English-language articles were obtained from the MEDLINE, Embase, and Cochrane databases through November 2016, by manual searching and cross-referencing. Randomized and nonrandomized trials of adult female patients with a documented history of RUTIs who received HA, CS or HA plus CS were included. The random effects model was applied to all pooled analyses. Risk of bias was assessed for individual studies and across studies. RESULTS: Two randomized (n = 85) and six nonrandomized (n = 715) studies met the inclusion criteria. These studies assessed HA ± CS; studies of CS alone were not identified in the search. HA ± CS decreased the UTI rate per patient-year (pooled mean difference [MD] -2.56; 95% confidence interval [CI] -3.86, -1.26; p < 0.001) and increased the time to first UTI recurrence (pooled MD 130.05 days; 95% CI 5.84, 254.26; p = 0.04). There was heterogeneity in most outcomes considered, and publication bias in many studies. The standard of trial reporting was low. The patient population size, and the number of studies included, were small. CONCLUSIONS: HA ± CS appears to reduce the rate of UTI and increase the time to recurrence in women with RUTI. As randomized controlled studies are available only for HA plus CS, the quality of evidence is higher for the combination than for HA alone.


Assuntos
Sulfatos de Condroitina/administração & dosagem , Ácido Hialurônico/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Administração Intravesical , Adulto , Sulfatos de Condroitina/uso terapêutico , Feminino , Humanos , Ácido Hialurônico/uso terapêutico , Resultado do Tratamento
8.
Int J Immunogenet ; 45(3): 95-101, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29575597

RESUMO

We reported previously on the widespread occurrence of anti-HLA alloantibodies of the IgA isotype (anti-HLA IgA) in the sera of solid-organ re-transplantation (re-tx) candidates (Arnold et al., ). Specifically focussing on kidney re-tx patients, we now extended our earlier findings by examining the impact of the presence and donor specificity of anti-HLA IgA on graft survival. We observed frequent concurrence of anti-HLA IgA and anti-HLA IgG in 27% of our multicenter collective of 694 kidney re-tx patients. This subgroup displayed significantly reduced graft survival as evidenced by the median time to first dialysis after transplantation (TTD 77 months) compared to patients carrying either anti-HLA IgG or IgA (TTD 102 and 94 months, respectively). In addition, donor specificity of anti-HLA IgA had a significant negative impact on graft survival (TTD 74 months) in our study. Taken together, our data strongly indicate that presence of anti-HLA IgA, in particular in conjunction with anti-HLA-IgG, in sera of kidney re-tx patients is associated with negative transplantation outcome.


Assuntos
Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Imunoglobulina A/imunologia , Isoanticorpos/imunologia , Transplante de Órgãos , Transplantados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Especificidade de Anticorpos/imunologia , Criança , Pré-Escolar , Feminino , Antígenos HLA/genética , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Isoanticorpos/sangue , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Prognóstico , Retratamento , Adulto Jovem
11.
Pflugers Arch ; 468(10): 1741-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27491796

RESUMO

The role of transient receptor potential vanilloid subtype 4 (TRPV4) channels in urinary bladder afferent neural pathways was investigated using spinal c-fos measurements in mice. Anesthetized wild type and TRPV4 knockout (-/-) mice underwent noxious bladder distention and treatment with either intravesical instillation with lipopolysaccharide (LPS), or the TRPV1 agonist resiniferatoxin (RTX), vehicle or an intraperitoneal injected TRPV4 antagonist (HC067047). Mice underwent paraformaldehyde perfusion for rapid fixation and L6-S1 spinal cord sections were removed followed by immunohistochemical staining for c-fos. A number of c-fos expressing neurons in the dorsal horns of L6-S1 spinal cord transections were quantified. Groups were compared using univariate ANOVA. Even with the absence of bladder inflammation on H&E, the TRPV4 -/- mice still have a significant twofold higher c-fos expression (n = 39, SD 2) after noxious bladder distention compared to wild type mice (n = 20, SD 3). A twofold increase in c-fos expression was observed after LPS treatment in wild types (n = 42, SD 5), but no increase was seen in TRPV4 -/- mice (n = 42, SD 2). After desensitization of primary afferent C-nerve fibers with RTX, c-fos expression in TRPV4-/- mice decreased significantly (threefold) (n = 12, SD 4). Results imply that TRPV4 channels are important for bladder afferent signaling. TRPV4 -/- mice bladders generate more noxious sensory output, which is predominantly mediated through TRPV1 expressing high threshold nerve fibers. This study reveals TRPV1 related adaptive changes in afferent pathways of the TRPV4 -/- mouse. We propose that this effect is caused by a congenital impairment of low threshold nerves that mediate normal bladder filling sensations.


Assuntos
Células do Corno Posterior/metabolismo , Canais de Cátion TRPV/metabolismo , Bexiga Urinária/metabolismo , Adaptação Fisiológica , Vias Aferentes , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade , Células do Corno Posterior/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Canais de Cátion TRPV/genética , Bexiga Urinária/inervação , Bexiga Urinária/fisiologia
12.
Pharmacogenomics J ; 16(1): 71-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25850030

RESUMO

Treatment of carriers of the CYP2C19*2 allele and ABCB1 TT genotype with clopidogrel is associated with increased ischemic complications after percutaneous coronary intervention (PCI). We sought to evaluate a pharmacogenomic strategy among patients undergoing PCI for ST-elevation myocardial infarction (STEMI), by performing a randomized trial, enrolling 102 patients. Point-of-care genetic testing for CYP2C19*2, ABCB1 TT and CYP2C19*17 was performed with carriers of either the CYP2C19*2 allele or ABCB1 TT genotype randomly assigned to a strategy of prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg daily for 6 days then 75 mg daily). The primary end point was the proportion of at-risk carriers exhibiting high on-treatment platelet reactivity (HPR), a marker associated with increased adverse cardiovascular events, after 1 month. Fifty-nine subjects (57.8%) were identified as carriers of at least one at-risk variant. Treatment with prasugrel significantly reduced HPR compared with clopidogrel by P2Y12 reaction unit (PRU) thresholds of >234 (0 vs 24.1%, P=0.0046) and PRU>208 (3.3 vs 34.5%, P=0.0025). The sensitivity of point-of-care testing was 100% (95% CI 88.0-100), 100% (86.3-100) and 96.9% (82.0-99.8) and specificity was 97.0% (88.5-99.5), 97.1% (89.0-99.5) and 98.5% (90.9-99.9) for identifying CYP2C19*2, ABCB1 TT and CYP2C19*17, respectively. Logistic regression confirmed carriers as a strong predictor of HPR (OR=6.58, 95% CI 1.24-34.92; P=0.03). We confirmed that concurrent identification of three separate genetic variants in patients with STEMI receiving PCI is feasible at the bedside. Among carriers of at-risk genotypes, treatment with prasugrel was superior to an augmented dosing strategy of clopidogrel in reducing HPR.


Assuntos
Citocromo P-450 CYP2C19/genética , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Ticlopidina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Clopidogrel , Feminino , Testes Genéticos , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Sistemas Automatizados de Assistência Junto ao Leito , Estudos Prospectivos , Ticlopidina/uso terapêutico
13.
Am J Transplant ; 15(1): 251-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25534449

RESUMO

Transplantation utilizing donation after circulatory death (DCD) donors is associated with ischemic cholangiopathy (IC) and graft loss. The University of Washington (UW) DCD experience totals 89 DCD liver transplants performed between 2003 and 2011. Overall outcome after DCD liver transplantation at UW demonstrates Kaplan-Meier estimated 5-year patient and graft survival rates of 81.6% and 75.6%, respectively, with the great majority of patient and graft losses occurring in the first-year posttransplant from IC. Our program has almost exclusively utilized either anti-thymocyte globulin (ATG) or basiliximab induction (86/89) for DCD liver transplantations. Analysis of the differential effect of induction agent on graft survival demonstrated graft survival of 96.9% at 1 year for ATG versus 75.9% for basiliximab (p = 0.013). The improved survival did not appear to be from a lower rate of rejection (21.9% vs. 22.2%) but rather a differential rate of IC, 35.2% for basiliximab versus 12.5% for ATG (p = 0.011). Multivariable analysis demonstrated induction agent to be independently associated with graft survival and IC free graft survival when analyzed against variables including donor age, fWIT, donor cold ischemia time and transplant era.


Assuntos
Doenças dos Ductos Biliares/epidemiologia , Sobrevivência de Enxerto , Imunossupressores/uso terapêutico , Isquemia/epidemiologia , Transplante de Fígado , Adolescente , Adulto , Anticorpos Monoclonais/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Basiliximab , Feminino , Seguimentos , Rejeição de Enxerto/induzido quimicamente , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Incidência , Hepatopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Proteínas Recombinantes de Fusão/uso terapêutico , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos , Obtenção de Tecidos e Órgãos , Estados Unidos/epidemiologia , Adulto Jovem
14.
Tissue Antigens ; 86(3): 178-85, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26204790

RESUMO

Chronic lung allograft dysfunction (CLAD) is a limiting factor for long-term survival in lung transplant recipients. Donor-specific human leukocyte antigen (HLA)-antibodies (DSA) have been suggested as potential risk factors for CLAD. However, their impact on clinical outcome following lung transplantation remains controversial. We performed a single-center study of 120 lung transplant recipients transplanted between 2006 and 2011. Patient sera were investigated before and after transplantation. The sera were screened by means of Luminex(®) technology (Luminex Inc., Austin, TX, USA) for IgG-HLA-class I and class II antibodies (ab). Using single antigen beads, DSA were identified and correlated retrospectively with clinical parameters. After transplantation 39 out of 120 patients (32.5%) were positive for HLA-ab. The incidence of de novo DSA formation was 27 of 120 patients (22.5%). Eleven of 27 (41%) of de novo DSA-positive patients developed BOS compared to 13 of 93 (14%) DSA-negative patients (p = 0.002). Furthermore, the generation of de novo DSA was independently associated with the development of BOS in multivariable analysis [hazard ration (HR) 2.5, 95% confidence interval (CI) 1.0-6.08; p = 0.046). Our results indicate that de novo DSA are associated with the development of BOS after lung transplantation. Monitoring of HLA-ab after transplantation is useful for identifying high-risk patients and offers an opportunity for early therapeutic intervention.


Assuntos
Anticorpos/imunologia , Bronquiolite Obliterante/imunologia , Antígenos HLA/imunologia , Adulto , Feminino , Humanos , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos
15.
Int Ophthalmol ; 35(2): 281-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25708281

RESUMO

Intravenous immunoglobulin (IVIg) therapy has multiple mechanisms of immunomodulatory action. We wished therefore to assess its efficacy in a spectrum of patients with refractory uveitis. Retrospective review of clinical charts was conducted to document response to IVIg treatment in consecutive patients with treatment-refractory uveitis. Main outcome measures were control of intraocular inflammation, visual acuity, progression of the disease, and complications. Four (two male) patients, with a mean age at the beginning of the treatment of 47 years (range: 39-64), were included in the study. Indication for treatment was patients with active non-infectious uveitis refractory to steroids and immunomodulatory therapy. All patients received a course of 0.5 g/kg per day of IVIg for three consecutive days, repeating this course at a mean of 11 week (range: 2-39 weeks) intervals when indicated clinically. The median duration of the IVIg therapy was 7 months (range: 3-14 months). In three patients treatment resulted in stabilisation and prevention of progression of the disease, and additionally in two patients it facilitated a decrease in prednisolone dose. Treatment failed to induce long-term remission in one patient with recurrence of macular oedema. IVIg was well tolerated with neither immediate nor longer-term adverse events observed. In three out of four cases IVIg was an effective adjunctive therapy and well tolerated for the management of treatment-refractory uveitis.


Assuntos
Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Uveíte/tratamento farmacológico , Adulto , Progressão da Doença , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acuidade Visual
16.
Tissue Antigens ; 83(1): 49-51, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24355008

RESUMO

In this article, we describe a subgroup-specific amplification assay for HLA-DQA1 that encompasses the whole coding region and allows us to sequence full-length HLA-DQA1 genes. We introduce the novel alleles HLA-DQA1*01:10 and HLA-DQA1*01:11. Moreover, we were able to confirm the full-length genomic sequence data of the alleles HLA-DQA1*01:07, HLA-DQA1*03:01:01, HLA-DQA1*03:02, HLA-DQA1*04:01:02, HLA-DQA1*04:02, HLA-DQA1*05:03, HLA-DQA1*05:05:01:02 and HLA-DQA1*06:01:01. A complete genomic overview of all six HLA-DQA1 allele groups is now available from the submission of our data to the IMGT/HLA database. Because our approach facilitates the analysis of all HLA-DQA1 allele sequences, HLA-DQA1 may become the first HLA locus from which all subgroup members will be known in detail in the near future.


Assuntos
Cadeias alfa de HLA-DQ/genética , Teste de Histocompatibilidade , Reação em Cadeia da Polimerase/métodos , Alelos , Primers do DNA/genética , Bases de Dados de Ácidos Nucleicos , Genoma , Genótipo , Humanos , Reprodutibilidade dos Testes
17.
Br J Dermatol ; 171(6): 1347-57, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25078898

RESUMO

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCIs) are keratinization disorders caused by impaired skin barrier function. Mutations in the genes encoding the lipoxygenases 12R-LOX and eLOX-3 are the second most common cause of ARCIs. In recent years, human skin equivalents recapitulating the ARCI phenotype have been established. OBJECTIVES: To develop a murine organotypic tissue culture model for ARCI. METHODS: Epidermal keratinocytes were isolated from newborn 12R-LOX-deficient mice and cocultivated with mouse dermal fibroblasts embedded in a scaffold of native collagen type I. RESULTS: With this experimental set-up the keratinocytes formed a well-organized multilayered stratified epithelium resembling skin architecture in vivo. All epidermal layers were present and the keratinocytes within showed the characteristic morphological features. Markers for differentiation and maturation indicated regular epidermal morphogenesis. The major components of epidermal structures were expressed, and were obviously processed and assembled properly. In contrast to their wild-type counterparts, 12R-LOX-deficient skin equivalents showed abnormal vesicular structures in the upper epidermal layers correlating with altered lipid composition and increased transepidermal water loss, comparable with 12R-LOX-deficient mice. CONCLUSIONS: The mouse skin equivalents faithfully recapitulate the 12R-LOX-deficient phenotype observed in vivo, classifying them as appropriate in vitro models to study molecular mechanisms involved in the development of ARCI and to evaluate novel therapeutic agents. In contrast to existing human three-dimensional skin models, the generation of these murine models is not constrained by a limited supply of material and does not depend on in vitro expansion and/or genetic manipulations that could result in inadvertent genotypic and phenotypic alterations.


Assuntos
Modelos Animais de Doenças , Ictiose Lamelar/genética , Animais , Araquidonato 12-Lipoxigenase/deficiência , Técnicas de Cultura de Células/métodos , Epiderme/fisiologia , Queratinócitos/fisiologia , Lipídeos/fisiologia , Camundongos , Engenharia Tecidual
18.
J Obstet Gynaecol ; 34(4): 350-1, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24484297

RESUMO

Impedance-controlled endometrial ablation (NovaSure) is commonly used to treat premenopausal heavy menstrual bleeding in Lothian, Scotland. Using postal questionnaires, we assessed patient satisfaction, treatment success and post-procedure symptoms in a cohort of women who had NovaSure treatment between January 2007 and May 2009. The response rate was 61.2% (115/188): 90.4% (104/115) of women were satisfied and would recommend the procedure; 36.8% (42/114) of women were amenorrhoeic at follow-up (mean = 497 days) and NovaSure significantly improved levels of both menstrual bleeding and pain (p < 0.01). Of the women, 67.0% (77/115) reported symptoms such as discomfort, vaginal discharge and bleeding/spotting within 6 weeks following NovaSure. A total of 13.9% (16/115) required further treatment following NovaSure, including hysterectomy. Patient satisfaction with NovaSure was high. Preoperative counselling needs to include information on character and duration of postoperative symptoms. Future research could compare patient satisfaction and clinical outcomes between NovaSure and the levonorgestrel-releasing intrauterine system.


Assuntos
Técnicas de Ablação Endometrial , Menorragia/cirurgia , Satisfação do Paciente/estatística & dados numéricos , Estudos de Coortes , Feminino , Humanos , Escócia , Autorrelato , Resultado do Tratamento
19.
Eye (Lond) ; 38(5): 871-876, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37848676

RESUMO

OBJECTIVES: To examine the outcome of infliximab treatment in patients with non-infectious paediatric uveitis who have previously failed biologic treatment. METHODS: A retrospective cohort study was performed at Bristol Eye Hospital, UK. Paediatric patients with chronic non-infectious uveitis who had been switched to infliximab due to inadequate uveitis control were identified. Two separate groups were evaluated: group 1 consisted of 20 children (36 eyes) who had been switched to infliximab following treatment failure with adalimumab (=in-class switching), while group 2 (5 patients; 9 eyes) included those who had been switched to infliximab from a non-TNF antagonist after failing several biologics (=across-class switching). The change in anterior chamber (AC) activity between baseline and 6- and 24-months follow-up was the primary outcome measure. RESULTS: A statistically significant reduction in AC activity was found between baseline and 6-months follow-up (RE: p = 0.002; LE: p < 0.001) and between baseline and 24-months follow-up (RE: p = 0.016; LE: p = 0.011) in group 1. No statistically significant difference was found for either eye in the number of steroid eye drops needed between time points or the difference in visual acuity in time. In group 2, analysis of change of AC activity, number of steroid eye drops and visual acuity failed to reach statistical significance. Treatment failure occurred in four patients (20% of group 1) and adverse events developed in six patients including three patients with acute infusion reactions. CONCLUSIONS: This study supports the efficacy and safety of infliximab in adalimumab-refractory patients with paediatric non-infectious uveitis.


Assuntos
Uveíte , Humanos , Criança , Infliximab , Adalimumab , Estudos Retrospectivos , Resultado do Tratamento , Terapia Biológica , Soluções Oftálmicas , Esteroides , Fator de Necrose Tumoral alfa
20.
Healthcare (Basel) ; 12(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38391841

RESUMO

BACKGROUND: Quality of life (QoL)-based outcomes are hardly incorporated into interstitial cystitis/bladder pain syndrome (IC/BPS) guidelines, because studies are limited and outdated. Therefore, guidelines might not reflect the current clinical situation accurately. Secondly, guidelines suggest using a multimodal approach for BPS/IC management, but data on the patient-perceived efficacy of these therapies are limited. The aim of this study is to investigate the perception of IC/BPS patients of their QoL, to determine which treatments they have received, and to examine how they evaluate the efficacy of these various (alternative) therapies. METHODS: A quantitative retrospective database evaluation was performed, with data from an existing IC/BPS patient survey (n = 217) that was conducted in 2021. This survey contained QoL data based on validated questionnaires such as EQ-5D 5L. RESULTS: The QoL of patients is affected significantly by IC/BPS. This is evident from the various affected domains on the EQ-5D 5L. The symptom severity was negatively affected by a delay in diagnosis, and there were clear differences in QoL domains between females and males. Secondly, coagulation therapy and intravesical glycosaminoglycan (GAG) therapy were most appreciated by patients. Other (alternative) treatments were commonly utilized, although some had doubtful results and high discontinuation rates. CONCLUSION: QoL is considerably impaired in IC/BPS patients. The diverse responses and adherence to various treatments warrant a personalized approach (phenotype-oriented therapy). To achieve QoL improvement, it is important to incorporate the patient's perspective in treatment guidelines.

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