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1.
Rheumatol Ther ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33687687

RESUMO

INTRODUCTION: We assessed patient-reported outcomes from a multicenter, randomized, double-blind, placebo-controlled study of repository corticotropin injection (RCI; Acthar® Gel) in patients with persistently active systemic lupus erythematosus (SLE) despite treatment with moderate-dose glucocorticoids. METHODS: The trial enrolled adults with active SLE and moderate-to-severe rash and/or arthritis despite use of stable glucocorticoids (7.5 mg/day to 30 mg/day prednisone equivalent), antimalarials, and nonsteroidal anti-inflammatory drugs for ≥ 4 weeks and/or immunosuppressants for ≥ 8 weeks before screening. Patients were randomly assigned to 80 U of RCI or placebo subcutaneously every other day through week 4, then twice weekly through week 24. Primary analyses evaluated the change from baseline to week 24 in the Lupus Quality of Life (QoL) and Work Productivity and Activity Impairment (WPAI)-Lupus questionnaires. Post hoc analyses stratified results by baseline disease activity (SLE Disease Activity Index-2000 [SLEDAI-2K] < 10 or ≥ 10; Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI]-Activity < 11 or ≥ 11; and British Isles Lupus Assessment Group [BILAG]-2004 < 20 or ≥ 20) and by BILAG-based Combined Lupus Assessment (BICLA) response at weeks 20 and 24. RESULTS: RCI treatment resulted in greater improvement in the LupusQoL pain domain at week 16 and planning domain at week 24 compared with placebo. Post hoc analyses demonstrated greater improvements with RCI in the pain, planning, and fatigue domains than with placebo at multiple time points in patients with higher disease activity by baseline SLEDAI-2K ≥ 10, CLASI-Activity ≥ 11, and BILAG-2004 ≥ 20 and/or in BICLA responders. Compared with placebo, RCI also resulted in greater improvements in percentage work time missed at week 24 in patients with baseline CLASI-Activity < 11 and in percentage impairment while working at week 16 in BICLA responders. CONCLUSIONS: RCI may improve QoL and work productivity in patients who have persistently active SLE despite treatment with standard SLE therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02953821.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33644992

RESUMO

OBJECTIVE: Responsive assessment of disease activity in patients with rheumatoid arthritis (RA) is necessary to evaluate therapeutic efficacy and guide treatment. We compared the utility of the multi-biomarker disease activity (MBDA) score in assessing RA disease activity with that of the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) and the Clinical Disease Activity Index (CDAI) in a multicenter, randomized, placebo-controlled trial of repository corticotropin injection (RCI) in patients with persistently active RA. METHODS: Patients received 80 U of RCI twice weekly during a 12-week open-label period; those who achieved low disease activity at week 12 were randomly assigned to receive either 80 U of RCI or placebo twice weekly during a 12-week double-blind period. Changes in disease activity (measured by DAS28-ESR, CDAI, and MBDA) and correlations between MBDA scores and both DAS28-ESR and CDAI scores were assessed. RESULTS: Changes from baseline in DAS28-ESR and CDAI scores suggested that RCI therapy led to clinically meaningful improvements in disease activity, but improvements from baseline in MBDA scores were below the minimally important difference threshold. For the DAS28-ESR and CDAI, correlations with total MBDA and individual component scores were generally low (r≤0.3), occasionally moderate (r>0.3 but <0.5). CONCLUSION: Our results suggest overall MBDA scores are not sufficiently responsive for assessing RA disease activity after RCI therapy. These findings are consistent with those seen with other RA drugs and, although they are from a clinical trial, suggest the MBDA should not be a preferred disease activity measure in clinical practice.

3.
Rheumatol Ther ; 7(4): 893-908, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32996096

RESUMO

INTRODUCTION: We assessed the efficacy and safety of repository corticotropin injection (RCI; Acthar® Gel) for persistently active systemic lupus erythematosus (SLE) despite use of moderate-dose glucocorticoids. METHODS: This multicenter, double-blind, randomized, placebo-controlled study enrolled patients ≥ 18 years with active SLE and moderate to severe rash and/or arthritis despite stable glucocorticoid doses (7.5-30 mg/day prednisone equivalent) and antimalarials for ≥ 4 weeks and/or immunosuppressants for ≥ 8 weeks before screening. Stable glucocorticoid doses were required through week 16 with optional taper from weeks 16 to 24. Patients were randomized (1:1) to 80 U RCI subcutaneously or placebo every other day to week 4, then twice weekly to week 24. Endpoints included the proportion of SLE Responder Index (SRI)-4 responders at week 16; changes from baseline to week 16 in 28 Swollen Joint Count/Tender Joint Count (28 SJC/TJC) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-Activity score; and changes from baseline to week 24 in inflammatory cytokines. Safety was assessed by adverse events. RESULTS: In the modified intention-to-treat population (RCI, n = 84; placebo, n = 85), the proportion of SRI-4 responders at week 16 was not significantly different between groups (RCI, 47.6%; placebo, 43.5%; OR [95% CI] 1.2 [0.6 to 2.2]; p = 0.5762). RCI treatment resulted in a reduction from baseline to week 16 in 28 SJC/TJC and CLASI-Activity score and from baseline to week 8 in a proliferation-inducing ligand cytokine. Post hoc analyses demonstrated a greater proportion of BILAG-based Combined Lupus Assessment responders for RCI than placebo at weeks 4, 12, and 20 and greater SRI-4 response in RCI-treated patients with baseline SLE Disease Activity Index-2000 ≥ 10 and CLASI-Activity ≥ 11. No new safety signals were identified. CONCLUSIONS: Despite failure to achieve the primary endpoint, these results support the utility of RCI for treating persistently active SLE. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02953821.

4.
Blood Adv ; 4(13): 3154-3168, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32658986

RESUMO

Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-ß (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.

5.
Lupus Sci Med ; 7(1): e000383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32399253

RESUMO

Objective: SLE is a chronic inflammatory autoimmune disease characterised by the excessive production of autoantibodies, immune complexes and proinflammatory cytokines. Repository corticotropin injection (RCI) is a naturally sourced complex mixture of adrenocorticotropic hormone analogues and other pituitary peptides. RCI is approved by the US Food and Drug Administration for use during an exacerbation or as maintenance therapy in select cases of SLE. This paper discusses the design and baseline characteristics of a multicentre, double-blind, randomised, placebo-controlled, 24-week clinical trial evaluating the effect of RCI in reducing disease activity for patients with persistently active SLE despite moderate-dose corticosteroid use. Methods: Efficacy will be evaluated using the SLE Responder Index-4 (SRI-4), SLE Disease Activity Index-2000 (SLEDAI-2K), British Isles Lupus Assessment Group-2004 (BILAG-2004) and Physician's Global Assessment (PGA). The primary efficacy endpoint will be the proportion of SRI-4 responders at week 16. Secondary and exploratory endpoints will include changes in disease activity scores over time, prednisone dose and biomarkers of inflammation and bone turnover. The safety and tolerability profile of RCI will also be evaluated through adverse event profiles, physical examination, clinical laboratory tests and serum cortisol levels. Results: Target enrolment for this global study is 270 patients, and as of 15 November 2019, the modified intent-to-treat population included 169 patients. The study cohort had 91.7% women, had a mean age of 39.7 years, mean SLEDAI-2K total score of 9.9, mean BILAG-2004 total score of 18.1, mean PGA of 59.7 and mean prednisone or equivalent daily dose of 11.1 mg. A total of 79.3% and 64.5% of patients were receiving concomitant antimalarial or immunosuppressive therapy, respectively. Conclusions: Data from this study will provide valuable insights into the therapeutic role of RCI in refractory SLE, as well as important information regarding its safety profile.

6.
PLoS One ; 15(3): e0229070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130228

RESUMO

Acetaminophen is one of the most commonly consumed analgesics world wide. Generally perceived as a safe medication, it is the most common cause of acute liver failure in the United States with inadvertent hepatotoxicity in half of all cases. We therefore conducted a survey on the public perceptions of acetaminophen in patients attending the outpatient clinic in Vancouver, Canada. Among 928 patients who were asked, 765 completed the survey questionnaire. The majority of respondents were female (59%), Caucasian (61%), and educated beyond the secondary school level (81%). 23% reported using acetaminophen at least once a week. A significant minority were unaware of the potential liver toxicity of acetaminophen (24%), and knowledge of hepatotoxicity did not vary with education status. In terms of the medicinal composition of acetaminophen products, over half of the respondents (58%) did not know that extra strength preparations of acetaminophen contained the same drug but in a different dose. This knowledge was more prevalent among those with higher level of education (49% in graduate school educated respondents), but was still low overall. The knowledge that alcohol use with acetaminophen was more harmful was low (43%), but improved with level of education (P for trend 0.03). Among respondents who consumed alcohol regularly, 21% were consuming over 1.5 grams of acetaminophen at a time. These patients had similar harm perception to liver as patients who consumed lower doses of acetaminophen. Overall, in a large, well-educated cohort of patients, knowledge about the adverse effects of acetaminophen, the additional risks with alcohol and composition of various retailed products was suboptimal. We speculate that consumer ignorance is a significant reason why acetaminophen is a leading cause of acute liver failure.


Assuntos
Acetaminofen/efeitos adversos , Conscientização , Doença Hepática Induzida por Substâncias e Drogas , Conhecimentos, Atitudes e Prática em Saúde , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial , Canadá/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Estudos de Coortes , Feminino , Humanos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Opinião Pública , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
7.
Rheumatol Ther ; 7(2): 327-344, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32185745

RESUMO

INTRODUCTION: The objective of this study was to assess efficacy and safety of repository corticotropin injection (RCI) in subjects with active rheumatoid arthritis (RA) despite treatment with a corticosteroid and one or two disease-modifying antirheumatic drugs (DMARDs). METHODS: All subjects received open-label RCI (80 U) twice weekly for 12 weeks (part 1); only those with low disease activity [LDA; i.e., Disease Activity Score 28 joint count and erythrocyte sedimentation rate (DAS28-ESR) < 3.2] were randomly assigned to receive either RCI (80 U) or placebo twice weekly during the 12-week double-blind period (part 2). The primary efficacy endpoint was the proportion of subjects who achieved LDA at week 12. Secondary efficacy endpoints included proportions of subjects who maintained LDA during weeks 12 through 24 and achieved Clinical Disease Activity Index (CDAI) ≤ 10 at weeks 12 and 24. Safety was assessed via adverse event reports. RESULTS: Of the 259 enrolled subjects, 235 completed part 1; 154 subjects (n = 77 each for RCI and placebo) entered part 2, and 127 (RCI, n = 71; placebo, n = 56) completed. At week 12, 163 subjects (62.9%) achieved LDA and 169 (65.3%) achieved CDAI ≤ 10 (both p < 0.0001). At week 24, 47 (61.0%) RCI-treated and 32 (42.1%) placebo-treated subjects maintained LDA (p = 0.019); 66 (85.7%) RCI-treated and 50 (65.8%) placebo-treated subjects maintained CDAI ≤ 10 (p = 0.004). No unexpected safety signals were observed. CONCLUSIONS: RCI was effective and generally safe in patients with active RA despite corticosteroid/DMARD therapy. By week 12, > 60% of patients achieved LDA, which was maintained with 12 additional weeks of treatment. Most patients who achieved LDA maintained it for 3 months after RCI discontinuation. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02919761.

8.
BMC Gastroenterol ; 19(1): 199, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775657

RESUMO

BACKGROUND: Drug induced liver injury (DILI) is an important cause of acute liver injury and accounts for approximately 10% of all cases of acute hepatitis. Both prescription and natural health products (NHPs) have been implicated in DILI. There is a dearth of studies on NHPs induced liver injury. CASE PRESENTATION: A previously healthy 37-year-old female presented with subacute hepatitis, in the context of a previous admission to a separate institution, months prior for undiagnosed acute hepatitis. Importantly, she had disclosed taking complex regiments of natural health products (NHPs) for months. Her only other medication was rivaroxaban for her homozygous Factor V Leiden deficiency. She had an extensive work up for causes of acute and unresolving hepatitis. She discontinued several but not all of her NHPs after her initial presentation for acute hepatitis at the first institution and continued taking NHPs until shortly after admission to our institution. The predominant pathological features were that of drug induced liver injury, although an abnormal amount of copper was noted in the core liver biopsies. However, Wilson's disease was ruled out with normal serum ceruloplasmin and 24-urine copper. After 2 months of stopping all the NHPs, our patient improved significantly since discharge, although there is evidence of fibrosis on ultrasound at last available follow up. CONCLUSION: NHPs are a well-established but poorly understood etiology of DILI. The situation is exacerbated by the unregulated and unpredictable nature of many of the potential hepatotoxic effects of these agents, especially in cases of multiple potential toxic agents. This highlights the importance of acquiring a clear history of all medications regardless of prescription status.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Suplementos Nutricionais/efeitos adversos , Fitoterapia/efeitos adversos , Adulto , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Diagnóstico Diferencial , Feminino , Degeneração Hepatolenticular/diagnóstico , Humanos
9.
J Can Assoc Gastroenterol ; 2(4): 161-169, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31616857

RESUMO

The incidence of celiac disease has risen quickly and has a worldwide distribution in Europe, North and South America, Asia, the Middle East and Africa. This is attributed in part to increased availability in screening but also to the fast-rising gluten consumption and perhaps unknown environmental factors. In daily practice, this means that more subclinical cases and very young and elderly patients are diagnosed. The pathogenesis of celiac disease is a T-cell driven process initiated by gluten, leading to increased intestinal permeability and villous atrophy. The process requires HLA genotypes DQ2, DQ8 or both. Additional non-HLA alleles have been identified in genome-wide association studies. Serological testing, followed by duodenal biopsies, are still required to confirm the diagnosis. Advances are in the making for novel biomarkers to monitor disease and for pharmacological support of celiac disease. Medical costs and patient-perceived disease burden remain high in celiac disease, which point to the need for ongoing research in drug development to improve quality of daily life. Drugs undergoing phase I and phase II clinical trials include intraluminal therapies and vaccines to restore immune tolerance. These therapies aim to reduce symptoms and mucosal injuries as adjunct therapies to a gluten-free diet.

10.
Menopause ; 26(9): 994-1001, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31453961

RESUMO

OBJECTIVE: To prospectively evaluate the effects of ospemifene on the vulva and vagina in postmenopausal women using vulvar-vestibular photography and direct visual assessments. METHODS: Postmenopausal women (aged 40-80 years) with moderate to severe vaginal dryness as their most bothersome symptom (MBS) were randomized to daily ospemifene 60 mg or placebo in this 12-week, multicenter, double-blind, phase 3 study. Vulvar-vestibular photographic images were captured at baseline and week 12 and were independently assessed with the Vulvar Imaging Assessment Scale (VIAS). Changes from baseline in Vaginal and Vulvar Health Indices (VHI and VuHI) with ospemifene versus placebo were analyzed at weeks 4, 8, and 12. Correlations between VIAS, VHI, and VuHI, with vaginal dryness severity and the Female Sexual Function Index (FSFI) scores were also assessed. RESULTS: In all, 631 eligible participants were randomized (ospemifene 316, placebo 315) and included in the intention-to-treat population. Compared with placebo, ospemifene significantly improved total scores for VIAS (P = 0.0154), VHI (P < 0.0001), and VuHI (P < 0.0001) from baseline to week 12; significant VHI (P < 0.0001) and VuHI (P = 0.002) improvements were observed at week 4. Most VHI and VuHI individual items were significantly better with ospemifene versus placebo at week 12 (P < 0.05). Most correlations between the vulvovaginal assessment total scores versus vaginal dryness severity and FSFI scores were significant (P < 0.05). CONCLUSION: Improvements observed in vulvovaginal health with ospemifene assessed by prospective vulvar-vestibular photography and other direct visual assessments support its efficacy in addition to the treatment of moderate to severe vaginal dryness due to menopause and the use of photographic and direct visual evaluations in future clinical trials. VIDEO SUMMARY: Supplemental Digital Content 1, http://links.lww.com/MENO/A415.


Assuntos
Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/análogos & derivados , Vagina/patologia , Doenças Vaginais/tratamento farmacológico , Vulva/patologia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia/tratamento farmacológico , Estudos Transversais , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Fotografação , Estudos Prospectivos , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/administração & dosagem , Tamoxifeno/uso terapêutico , Resultado do Tratamento , Estados Unidos
11.
Ann Hepatol ; 18(4): 651-654, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31056363

RESUMO

Rapid overcorrection of chronic hyponatremia can lead to osmotic demyelination syndrome or central pontine myelinolysis (CPM), a diagnosis often triggered by observing the characteristics of neurological abnormalities developed as a result of CPM. However, anyone with chronic hyponatremia and overcorrection of serum sodium is at risk of physiological CPM despite the lack of clinical symptoms. We report an adult patient who presented as post-op delirium, had incidental finding of CPM by magnetic resonance imaging (MRI) of the head after a liver transplant. Despite his non-typical presentation, the patient had the typical risk factors of CPM such as chronic hyponatremia, rapid overcorrection of serum sodium and cirrhosis undergoing a transplant. As hyponatremia and neurological disorder such encephalopathy simultaneously affect patients with cirrhosis, CPM may be more common than once thought in the chronic liver disease population and inappropriate hyponatremia management has important medical consequences that can go unnoticed.


Assuntos
Delírio/diagnóstico , Hidratação/métodos , Hiponatremia/terapia , Achados Incidentais , Cirrose Hepática Biliar/cirurgia , Transplante de Fígado , Mielinólise Central da Ponte/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico por imagem , Delírio/complicações , Hidratação/efeitos adversos , Humanos , Hiponatremia/sangue , Cirrose Hepática Biliar/sangue , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mielinólise Central da Ponte/complicações , Mielinólise Central da Ponte/etiologia , Cuidados Pré-Operatórios
12.
Menopause ; 26(6): 611-621, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30694917

RESUMO

OBJECTIVE: To evaluate the safety and efficacy of ospemifene for the treatment of moderate to severe vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA). METHODS: This 12-week, multicenter, double-blind phase 3 study randomized postmenopausal women (aged 40-80 years) with VVA and moderate to severe vaginal dryness as their most bothersome symptom to daily oral ospemifene 60 mg or placebo. Coprimary efficacy endpoints included changes from baseline to week 12 in percentages of vaginal parabasal and superficial cells, vaginal pH, and vaginal dryness severity with ospemifene versus placebo; other secondary endpoints were evaluated (weeks 4, 8, and 12). Safety was assessed by treatment-emergent adverse events (TEAEs) and endometrial biopsies. RESULTS: Women (n = 631; ospemifene [n = 316], placebo [n = 315]) had a mean age of 59.8 years, a mean body mass index of 27.2 kg/m, and most were white. Ospemifene significantly improved (P < 0.0001) the percentages of parabasal and superficial cells, vaginal pH, and severity of vaginal dryness severity compared with placebo at week 12; significant between-group differences were noted by week 4. Secondary endpoints of dyspareunia (P < 0.001), maturation value (P < 0.0001), and the Female Sexual Function Index (P < 0.05) also significantly improved with ospemifene versus placebo at week 12. Significantly more women responded (31.5% vs 6.0%; P < 0.0001) or were satisfied (49.2% vs 33.8%; P = 0.0007) with ospemifene versus placebo at week 12. No unexpected TEAEs, treatment-related serious TEAEs, thrombotic events, or endometrial hyperplasia or carcinoma were observed. CONCLUSIONS: Ospemifene was effective and well tolerated for the treatment of moderate-to-severe vaginal dryness in postmenopausal women with VVA.


Assuntos
Pós-Menopausa/fisiologia , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Índice de Gravidade de Doença , Tamoxifeno/análogos & derivados , Vagina/patologia , Doenças Vaginais/tratamento farmacológico , Vulva/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia/tratamento farmacológico , Método Duplo-Cego , Dispareunia/tratamento farmacológico , Feminino , Fogachos/etiologia , Humanos , Pessoa de Meia-Idade , Satisfação do Paciente , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico , Resultado do Tratamento
13.
Saudi J Gastroenterol ; 25(1): 67-70, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30117491

RESUMO

Acute hepatitis A viral (HAV) infection is rare in the liver transplant population due to recommended pre-transplant vaccinations. We report a case of acute hepatitis A infection in a liver transplant recipient. This individual had immunity to hepatitis A with protective IgG antibodies and presented with abnormal liver biochemistry in the post-transplant in-patient setting. Hepatitis A infection was confirmed by positive HAV IgM whereas other etiologies, including acute cellular rejection, were ruled out by laboratory tests and liver biopsies. He was treated conservatively with supportive care and liver enzymes recovered to normal baseline. Despite adequate pre-transplant immunity, in the post-transplant setting there may be loss of protective immunity due to profound immunosuppression and hence hepatitis A should remain an important differential diagnosis in the setting of acute hepatitis.


Assuntos
Vírus da Hepatite A Humana/imunologia , Hepatite A/imunologia , Transplante de Fígado/efeitos adversos , Fígado/virologia , Doença Aguda , Diagnóstico Diferencial , Hepatite A/epidemiologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Imunossupressão/efeitos adversos , Fígado/química , Fígado/enzimologia , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos/métodos , Resultado do Tratamento , Vacinação/normas , Cobertura Vacinal/normas
15.
Adv Sci (Weinh) ; 4(2): 1600313, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28251052

RESUMO

A low-cost, solution-processed, versatile, microfluidic approach is developed for patterning structures of highly conductive metals (e.g., copper, silver, and nickel) on chemically modified flexible polyethylene terephthalate thin films by in situ polymer-assisted electroless metal deposition. This method has significantly lowered the consumption of catalyst as well as the metal plating solution.

16.
J Virol Methods ; 202: 73-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24642241

RESUMO

Hybrid Capture 2 (HC2) has been demonstrated to be a feasible screening method for cervical cancer. Based upon HC2 technology, careHPV is a simple, rapid, accurate, and inexpensive screening test for women in low-resource settings. This study aims to characterize both the careHPV test and HC2 test, and to compare careHPV results of specimens stored in careHPV test collection medium (TCM) to HC2 results from partner specimens stored in Qiagen specimen transport medium and TCM. The positive rates of high-risk HPV in careHPV, HC2, and HC2 (TCM) were 13.2% (108/818), 13.2% (108/818), and 13.6% (111/818), respectively. The agreement rates of pairwise tests were 95.8% (95% CI: 94.5-97.2%), 96.7% (95% CI: 95.5-97.9%), and 97.2% (95% CI: 96.1-98.3%), respectively. The Kappa values of the pairwise tests were 0.82 (95% CI: 0.76-0.88), 0.86 (95% CI: 0.81-0.91), and 0.88 (95% CI: 0.83-0.93), respectively. Based on these findings, although careHPV is demonstrated to be a viable alternative to the HC2 test, improvements on the careHPV test are still required prior to its implementation as a suitable screening method for women in low-resource settings. Further studies on the significance and applicability of the careHPV test must be performed.


Assuntos
Detecção Precoce de Câncer/métodos , Técnicas de Diagnóstico Molecular/métodos , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , China , Feminino , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , População Rural , Sensibilidade e Especificidade , Neoplasias do Colo do Útero/virologia , Virologia/métodos
17.
Urol Oncol ; 32(2): 92-100, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23433894

RESUMO

OBJECTIVES: The objectives of this study are to explore the potential benefits of combining AdGlipr1 (or AdGLIPR1) gene therapy with radiotherapy using subcutaneous prostate and bladder cancer models. MATERIALS AND METHODS: Combination adenoviral vector-mediated gene therapy and radiotherapy were applied to 178-2 BMA and TSU-Pr1 cells in vitro and colony formation and apoptosis were analyzed. In addition, combination therapies were administered to mice bearing subcutaneous 178-2 BMA and TSU-Pr1 tumors, and tumor growth suppression and survival extension were compared with the monotherapies (AdGlipr1/AdGLIPR1 and radiotherapy) or control vector Adv/CMV/ßgal, as well as single-cycle treatment with 2-cycle treatment. RESULTS: Combination treatment significantly suppressed colony formation and increased apoptosis in vitro. In vivo, combination therapy produced significant 178-2 BMA and TSU-Pr1 tumor growth suppression and survival extension compared with the monotherapies or the control. Further tumor growth suppression and survival extension were observed after 2 cycles of the combination treatment. CONCLUSIONS: Combining AdGlipr1 (AdGLIPR1) with radiotherapy may achieve additive or synergistic tumor control in selected prostate and bladder tumors, and additional therapeutic effects may result with repeated treatment cycles.


Assuntos
Terapia Genética/métodos , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias da Próstata/terapia , Radioterapia/métodos , Neoplasias da Bexiga Urinária/terapia , Adenoviridae/genética , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Vetores Genéticos/genética , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/efeitos da radiação , Masculino , Proteínas de Membrana , Camundongos , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/terapia , Proteínas do Tecido Nervoso/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Resultado do Tratamento , Carga Tumoral/genética , Carga Tumoral/efeitos da radiação , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
PLoS One ; 7(9): e45183, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23028833

RESUMO

The relatively high co-occurrence of Parkinson's disease (PD) and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR)-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM), the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative stress-induced neuronal injury relevant to PD. SNCA is a PD-causing gene coding for alpha-Synuclein (α-Syn) that expresses not only in brain, but also in skin as well as in tumors, such as melanoma. The findings that α-Syn can interact with tyrosinase (TYR) and inhibit tyrosine hydroxylase (TH), both of which are enzymes involved in the biosynthesis of melanin and dopamine (DA), led us to propose that α-Syn may participate in the regulation of melanin synthesis. In this study, by applying ultraviolet B (UVB) light, a physiologically relevant stimulus of melanogenesis, we detected melanin synthesis in A375 and SK-MEL-28 melanoma cells and in SH-SY5Y and PC12 dopaminergic neuronal cells and determined effects of α-Syn on melanin synthesis. Our results showed that UVB light exposure increased melanin synthesis in all 4 cell lines. However, we found that α-Syn expression reduced UVB light-induced increase of melanin synthesis and that melanin content was lower when melanoma cells were expressed with α-Syn, indicating that α-Syn may have inhibitory effects on melanin synthesis in melanoma cells. Different from melanoma cells, the melanin content was higher in α-Syn-over-expressed dopaminergic neuronal SH-SY5Y and PC12 cells, cellular models of PD, than that in non-α-Syn-expressed control cells. We concluded that α-Syn could be one of the points responsible for the positive association between PD and melanoma via its differential roles in melanin synthesis in melanoma cells and in dopaminergic neuronal cells.


Assuntos
Melaninas/biossíntese , Monofenol Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Dopamina/metabolismo , Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Expressão Gênica/efeitos da radiação , Humanos , Melaninas/genética , Melanoma , Especificidade de Órgãos , Doença de Parkinson , Transdução de Sinais/efeitos da radiação , Neoplasias Cutâneas , Raios Ultravioleta , alfa-Sinucleína/genética
20.
Neurosignals ; 19(3): 163-74, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21778691

RESUMO

Excessive misfolded proteins and/or dysfunctional mitochondria, which may cause energy deficiency, have been implicated in the etiopathogenesis of Parkinson's disease (PD). Enhanced clearance of misfolded proteins or injured mitochondria via autophagy has been reported to have neuroprotective roles in PD models. The fact that resveratrol is a known compound with multiple beneficial effects similar to those associated with energy metabolism led us to explore whether neuroprotective effects of resveratrol are related to its role in autophagy regulation. We tested whether modulation of mammalian silent information regulator 2 (SIRT1) and/or metabolic energy sensor AMP-activated protein kinase (AMPK) are involved in autophagy induction by resveratrol, leading to neuronal survival. Our results showed that resveratrol protected against rotenone-induced apoptosis in SH-SY5Y cells and enhanced degradation of α-synucleins in α-synuclein-expressing PC12 cell lines via autophagy induction. We found that suppression of AMPK and/or SIRT1 caused decrease of protein level of LC3-II, indicating that AMPK and/or SIRT1 are required in resveratrol-mediated autophagy induction. Moreover, suppression of AMPK caused inhibition of SIRT1 activity and attenuated protective effects of resveratrol on rotenone-induced apoptosis, further suggesting that AMPK-SIRT1-autophagy pathway plays an important role in the neuroprotection by resveratrol on PD cellular models.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antioxidantes/uso terapêutico , Autofagia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Estilbenos/uso terapêutico , Animais , Linhagem Celular Transformada , Relação Dose-Resposta a Droga , Doxiciclina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inseticidas/toxicidade , Microscopia Imunoeletrônica/métodos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/genética , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Resveratrol , Rotenona/toxicidade , Fatores de Tempo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
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