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1.
J Nutr Biochem ; 75: 108260, 2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31707285

RESUMO

A maternal high-fat (HF) diet sensitizes offspring to the adverse effects of postnatal HF intake and can lead to metabolic dysregulation. Resveratrol, a natural polyphenolic compound found in grapes and red wine, could help to relieve metabolic syndrome dysregulation. Since the gut microbiota is known to be closely related to metabolic homeostasis, this study aimed to investigate the impact of a combination of maternal and postweaning HF diets on the gut microbiota and whether resveratrol could relieve the gut dysbiosis associated with metabolic dysregulation. Sprague-Dawley dams were sustained on either a chow or HF diet before mating, during pregnancy and during lactation. Their offspring were randomly fed chow or a HF diet after weaning. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal HF/postnatal chow diet), CH (maternal chow/postnatal high-fat diet) and HH (maternal/postnatal HF diet). A fifth group consisted of HH with resveratrol treatment. We found that both maternal and postnatal HF exposure has a distinct effect on the gut microbiota metagenome of offspring. Maternal HF diet exposure decreased plasma acetate, propionate and butyrate level, while postnatal HF diet exposure decreased plasma acetate level in adult life. The metabolic dysregulation programed by the maternal and postnatal HF diets was related to the relevant gut microbiota. Resveratrol treatment ameliorated the altered plasma propionate level related to maternal HF and postnatal HF diet treatment. Resveratrol treatment also improved most of the altered metabolic dysregulation and related dysbiosis programmed by maternal and postnatal HF diet exposure.

2.
Neurourol Urodyn ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31584215

RESUMO

OBJECTIVE: To evaluate the histological response to and changes in the biomechanical properties of titanized polypropylene lightweight mesh and conventional polypropylene mesh at 1 and 12 weeks following implantation in the sheep vagina. METHODS: We compared a titanized polypropylene lightweight mesh (TiLOOP Mesh) to a conventional polypropylene mesh (Gynemesh PS) in a sheep vagina model. Explants were harvested after 1 and 12 weeks (n = 6/mesh type/time point) for histological observation. After 12 weeks, mesh-tissue complex specimens were biomechanically assessed by a uniaxial tension system. RESULTS: One week after implantation, there was no significant difference in the inflammatory response between the two groups. Twelve weeks after implantation, the TiLOOP light mesh elicited a lower inflammatory response than was observed for the Gynemesh PS (1.44 ± 0.61 vs 2.05 ± 0.80, P = .015). Twelve weeks after implantation, the collagen I/III ratio was lower in the TiLOOP light mesh group than in the Gynemesh PS group (9.41 ± 5.06 vs 15.21 ± 8.21, P = .019). The messenger RNA expression levels of the inflammatory factors interleukin 10 and tumor necrosis factor α were lower in the TiLOOP Mesh group than in the Gynemesh PS group at both 1 and 12 weeks (P < .05). There were no significant differences in any of the evaluated biomechanical characteristics between the two meshes (P > .05). CONCLUSION: Although the titanized polypropylene lightweight mesh induces slightly less tissue reactivity and has better in vivo biocompatibility, further studies should be conducted including the complications and the success rate of pelvic organ prolapse in patients before recommending it in pelvic floor reconstruction.

3.
World J Pediatr ; 15(6): 624-625, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446569

RESUMO

In the original publication of the article, "Hainan province" in Fig 1 was missed out. The corrected Fig. 1 is given below.

4.
Biomed Res Int ; 2019: 8921284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467917

RESUMO

Ideal animal models are needed to reflect the changes in the biochemical and biomechanical properties of the vagina that occur in pelvic organ prolapse (POP). In this study, we aimed to demonstrate the short and long-term effect of menopause on the biochemical and biomechanical properties of rat anterior vaginas. Here, Sprague-Dawley rats were bilaterally ovariectomized to induce menopause. Rats without ovariectomy served as the normal control group (n=12). The histology changes and the expression of collagen I, III, and a-SMA were assessed to indicate the biochemical changes in the vagina 2 weeks, 4 weeks, and 16 weeks after ovariectomy (n=6 for 2 and 4 weeks, n=12 for 16 weeks). Uniaxial biomechanical testing was conducted in the control group and ovariectomized rats 16 weeks after ovariectomy. Compared with the control group, the ovariectomy group showed a significant increase in the expression of collagen I 2 weeks after ovariectomy, while collagen III showed a declining trend. Two weeks after ovariectomy, the smooth muscle bundles began to become disorganized, and the fraction of smooth muscle in the nonvascular muscularis of the proximal vagina was significantly decreased (P<0.001). However, there was no difference in the expression of a-SMA in the distal vagina. Compared with the control group, the ovariectomy group had stiffer vaginas with a declining trend in the ultimate load 16 weeks after ovariectomy. In conclusion, surgically induced menopause had a significant short- and long-term impact on tissue composition and biomechanical properties of the rat vagina, which may lead to increased susceptibility to POP development.

5.
MBio ; 10(3)2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213566

RESUMO

Gene loss and genome reduction are defining characteristics of endosymbiotic bacteria. The most highly reduced endosymbiont genomes have lost numerous essential genes related to core cellular processes such as replication, transcription, and translation. Computational gene predictions performed for the genomes of the two bacterial symbionts of the cicada Diceroprocta semicincta, "Candidatus Hodgkinia cicadicola" (Alphaproteobacteria) and "Ca Sulcia muelleri" (Bacteroidetes), have found only 26 and 16 tRNA genes and 15 and 10 aminoacyl tRNA synthetase genes, respectively. Furthermore, the original "Ca Hodgkinia cicadicola" genome annotation was missing several essential genes involved in tRNA processing, such as those encoding RNase P and CCA tRNA nucleotidyltransferase as well as several RNA editing enzymes required for tRNA maturation. How these cicada endosymbionts perform basic translation-related processes remains unknown. Here, by sequencing eukaryotic mRNAs and total small RNAs, we show that the limited tRNA set predicted by computational annotation of "Ca Sulcia muelleri" and "Ca Hodgkinia cicadicola" is likely correct. Furthermore, we show that despite the absence of genes encoding tRNA processing activities in the symbiont genomes, symbiont tRNAs have correctly processed 5' and 3' ends and seem to undergo nucleotide modification. Surprisingly, we found that most "Ca Hodgkinia cicadicola" and "Ca Sulcia muelleri" tRNAs exist as tRNA halves. We hypothesize that "Ca Sulcia muelleri" and "Ca Hodgkinia cicadicola" tRNAs function in bacterial translation but require host-encoded enzymes to do so.IMPORTANCE The smallest bacterial genomes, in the range of about 0.1 to 0.5 million base pairs, are commonly found in the nutritional endosymbionts of insects. These tiny genomes are missing genes that encode proteins and RNAs required for the translation of mRNAs, one of the most highly conserved and important cellular processes. In this study, we found that the bacterial endosymbionts of cicadas have genomes which encode incomplete tRNA sets and lack genes required for tRNA processing. Nevertheless, we found that endosymbiont tRNAs are correctly processed at their 5' and 3' ends and, surprisingly, that mostly exist as tRNA halves. We hypothesize that the cicada host must supply its symbionts with these missing tRNA processing activities.

6.
Neurourol Urodyn ; 38(7): 1852-1858, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236976

RESUMO

AIMS: To evaluate and compare the clinical outcomes of the transobturator sling with the single-incision sling, for the treatment of stress urinary incontinence at a long-term follow-up. METHODS: From October 2008 to October 2010, 94 patients who were enrolled and underwent either TVT-O, one of standard mid-urethral sling or TVT-S, one of single-incision mini-sling (SIMS) procedure. The study population was followed until February 2019. Surgical outcomes were analyzed by subjective and objective evaluations and Chinese version questionnaires. Data were analyzed by IBM 23.0 SPSS Statistics. The level of statistical significance was set at P < 0.05. RESULTS: At the 10-year follow-up, 31(64.6%) TVT-O patients and 33(71.7%) TVT-S patients were still available. Objective cure and subjective satisfaction rate were not significantly different for TVT-O compared with TVT-S (P > 0.05). However, TVT-S showed a greater drop in success from the second to the tenth year compared with TVT-O (15.1% vs 0% and 9.2% vs 3.2%, respectively). Both groups experienced significantly improved quality of life in the TVT-O group and in the TVT-S group (P < 0.05). The total PISQ-12 scores at 10 years postoperatively of the TVT-O and TVT-S groups were 33.4(4.7) compared with 33.6(3.9) before surgery (P = 0.67 > 0.05) and 35.5(5.9) compared with 31.5(6.3) before surgery (P = 0.045 < 0.05). CONCLUSIONS: It is difficult to state that there is superiority of one sling over another sling without a significant difference. But TVT-O showed superior objective cure and subjective satisfaction rates and a less decline in success during 10 years compared with TVT-S.

7.
Lancet ; 393(10189): 2416-2427, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31104833

RESUMO

BACKGROUND: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Estatura , Criança , Desenvolvimento Infantil , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Feminino , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Resultado do Tratamento
8.
Sci Rep ; 9(1): 6452, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015608

RESUMO

We aimed to evaluate the alteration of diagnosis of individual expert and multidisciplinary discussion (MDD) team in the longitudinal diagnostic assessment of idiopathic interstitial pneumonia (IIP). The retrospective analysis included 56 patients diagnosed as IIP by The First Affiliated Hospital of Guangzhou Medical University with follow-up visits during Jan 1st to Aug 31st 2014. Each expert was provided information in a sequential manner and was asked to assign an individual diagnosis and an MDD diagnosis after group discussion. The level of agreement among individual experts and between different visits was calculated by kappa and the agreement between individual specialist and MDD team with different consensus levels was measured by weighted-kappa coefficients. Follow-up data changed the original clinical diagnosis and MDD diagnosis in 24.1% and 10.7% of all cases, respectively, and clinician and MDD consensus level in 55.4% and 25.0%, respectively. The diagnostic performance of individual clinicians or radiologist was closer to that of the MDD compared with the pathologist, and follow-up further increased the agreement. The longitudinal evaluation of patients with IIP improved the inter-observer agreement in a multidisciplinary team. The performance of individual clinicians or radiologist was approaching the accuracy of multidisciplinary team when provided with follow-up data.

9.
Mol Nutr Food Res ; : e1801385, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31004461

RESUMO

SCOPE: Prenatal high-fat (HF) and postnatal HF diet are both associated with obesity and metabolic disturbances in adults. Leptin resistance induced by obesity limits its biological effects. The anti-obesity mechanism of resveratrol in visceral adiposity is investigated here. METHODS AND RESULTS: During mating and lactation, Sprague-Dawley dams are fed either control or a HF diet. Subsequently, the offspring are fed chow or an HF diet. A fifth group that received maternal/postnatal HF diet and resveratrol after weaning (HHR) is used to study the effects of resveratrol treatment. Resveratrol treatment alleviates adiposity programed by maternal and postnatal HF diet by decreasing feed intake or inducing metabolic changes. Resveratrol treatment is also found to ameliorate the decrease in SIRT1 abundance observed in retroperitoneal adipose tissue, programed by maternal and postnatal HF diet. Moreover, resveratrol therapy decreases plasma leptin level and increases leptin receptor expression in retroperitoneal adipose tissue through DNA methylation modification. CONCLUSION: These results suggest that resveratrol can alleviate peripheral leptin resistance programed by the combined effect of prenatal and postnatal HF diet through epigenetic regulation of genes coding leptin and its receptor. It provides insights into a novel mechanism explaining the beneficial effects of resveratrol in obesity management.

10.
Int Urogynecol J ; 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30997545

RESUMO

INTRODUCTION AND HYPOTHESIS: Most synthetic meshes used in transvaginal surgery are made of polypropylene, which has a stable performance, but does not easily degrade in vivo. However, mesh-related complications are difficult to address and have raised serious concerns. A new biomaterial mesh with good tissue integration and few mesh-related complications is needed. To evaluate the effect of a new bacterial cellulose (BC) mesh on pelvic floor reconstruction following implantation in the vagina of sheep after 1 and 12 weeks. METHODS: The meshes were implanted in the submucosa of the posterior vagina wall of sheep. At 1 and 12 weeks after surgery, mesh-tissue complex (MTC) specimens were harvested for histological studies and biomechanical evaluation. At 12 weeks after surgery, MTC specimens were biomechanically assessed by a uniaxial tension "pulley system". RESULTS: The BC mesh elicited a higher inflammatory response than Gynemesh™PS at both 1 and 12 weeks after implantation. Twelve weeks after implantation, the BC mesh resulted in less fibrosis than Gynemesh™PS. Compared with the Gynemesh™PS group, the BC mesh group had increased mRNA expression of MMP-1, MMP-2, and MMP-9 (P < 0.05), but decreased expression of the anti-inflammatory factor IL-4 (P < 0.05). Twelve weeks after implantation, the ultimate load and maximum elongation percentage of the BC mesh were significantly lower than those of Gynemesh™PS. CONCLUSIONS: The BC mesh could not be a promising biomaterial for pelvic floor reconstructive surgery unless the production process and parameters were improved.

11.
Placenta ; 78: 44-53, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30955710

RESUMO

INTRODUCTION: Maternal nutrition is an extremely important health issue. We evaluated the impact of maternal high fat diet (HFD) on pregnancy outcomes, elucidated how the rat placenta and fetus respond to diet manipulation based on fetal sex, and identified candidate genes and pathways. METHODS: Rats were fed a normal or HFD diet for 10 weeks before conception and during gestation. The placenta was collected on gestational day 21 and sexed. Placental histology was analyzed and placental candidate genes and pathways were identified using whole-genome RNA next-generation sequencing. RESULTS: Pup weights in both sexes from HFD dams were reduced. The weight of the placenta from the HFD group was also decreased in both sexes, but changes in placental layer distributions were only significant for female fetuses. Maternal HFD altered the placental transcriptome in a sex-specific manner. Activation of the placental renin-angiotensin system (RAS) by maternal HFD was associated with fetal growth restriction in both fetal sexes. CONCLUSIONS: The placenta reacts to maternal HFD by altering the placental layer distribution and gene expression in a sex-specific manner. The male placenta in late gestation is thought to exhibit greater plasticity relative to the female placenta; however, fetuses of both sexes exhibited similar growth restriction. Our data reveal an association between the placental RAS and HFD-induced fetal growth restriction.

12.
Biomarkers ; 24(4): 309-316, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30821522

RESUMO

Objective: Controversial results exist with respect to the association between elevated homocysteine level and adverse prognosis in acute coronary syndrome (ACS) patients. We performed a meta-analysis to evaluate the prognostic value of homocysteine level on ACS patients. Materials and methods: A comprehensive literature search of PubMed and Embase databases was conducted prior to August 2018. Prospective observational studies reporting the association of baseline homocysteine level with major adverse cardiovascular events (MACE), cardiovascular or all-cause mortality in ACS patients were selected. Pooled risk ratio (RR) and corresponding 95% confidence intervals (CI) were calculated for the highest versus the lowest homocysteine level. Results: Ten studies including 4120 ACS patients were identified. ACS patients with the highest homocysteine level had an increased risk of MACE (RR 2.01; 95% CI 1.53-2.64) and all-cause mortality (RR 2.05; 95% CI 1.50-2.79) after controlling confounding factors. However, the association between elevated homocysteine level and cardiovascular mortality (RR 1.08; 95% CI 0.83-1.39) was not statistically significant. Conclusions: Elevated homocysteine level was associated with an increased risk of MACE and all-cause mortality among ACS patients. However, the association of elevated homocysteine level with cardiovascular mortality in ACS patients should be further confirmed in future studies.

13.
Bone ; 122: 76-81, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30772600

RESUMO

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.

14.
Int Urogynecol J ; 30(7): 1127-1139, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30715576

RESUMO

INTRODUCTION AND HYPOTHESIS: The objective of this study was to translate the short version of the Pelvic Floor Distress Inventory (PFDI-20) into Chinese and to evaluate its psychometric properties in Chinese women with symptomatic pelvic floor dysfunction according to the Consensus-Based Standards for the Selection of Health Status Measurement Instruments (COSMIN) checklist. METHODS: Between October 2017 and May 2018, a cross-sectional analysis of the clinical data of 126 patients who met the inclusion criteria was performed. The patients completed the questionnaires at the baseline (T1), 1-2 weeks later (T2), and 3 months after surgery (T3). Reliability testing included internal consistency, test-retest reliability, and measurement error. The methodical tests for validity were content validity, criterion validity, construct validity, and hypothesis testing. Responsiveness was also taken into consideration. RESULTS: One hundred twenty-six patients completed all questionnaires. Internal consistency, measured by Cronbach's alpha value, was good, and the test-retest reliability was high, with an intraclass correlation coefficient (ICC) of 0.99. Construct validity was verified by factor analysis. All assumptions were confirmed, and there were no ceiling or floor effects in this study. Spearman's correlation coefficient between the PFDI-20 and the Pelvic Floor Impact Questionnaire (PFIQ-7) was 0.867, showing a significant correlation. Furthermore, the minimal important change (MIC) of 50.0 was less than the smallest detectable change (SDC) of 18.36, indicating the sufficient responsiveness. CONCLUSIONS: The Chinese version of the PFDI-20 developed in this study is a reliable and valid instrument that provides good responsiveness to clinical changes.

15.
World J Pediatr ; 15(2): 190-197, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30796730

RESUMO

BACKGROUND: Human milk banks (HMB) have been established for over 100 years in North America and Europe. This study aimed to describe and summarize the operation and characteristics of the HMBs in mainland China since the first nonprofit HMB operated in 2013. METHODS: Operation of HMB in mainland China is based on the standards and guidelines of the Human Milk Banking Association of North America and some countries in Europe and was modified to meet the needs and circumstances in China such as donation only in the local HMB by medical staff. We reviewed the descriptive data of these 14 HMBs and the clinical characteristics of recipients, the eligible milk donors and the donor milk retrospectively. RESULTS: In mainland China, from March 2013 to December 2016, 14 nonprofit HMBs were developed and operational in public hospitals except one and located in the south, east, north and northwest of mainland China. In total, 2680 eligible donors donated 4608.2 L of breast milk. The mean age of these donors was 29.4 years with 60.6% receiving college education and 90.6% term delivery. A total of 4678 recipients including preterm infants (n = 2990, 63.9%), feeding intolerance (n = 711, 15.2%), maternal illness (n = 345, 7.4%), serious infection (n = 314, 6.7%), necrotising enterocolitis (n = 244, 5.2%), post-surgery (n = 38, 0.8%) and others (n = 36, 0.8%). The rate of discarded raw milk was only 4.4% because of hepatitis B and C or cytomegalovirus positivity. CONCLUSIONS: HMB has been developing rapidly in mainland China. Donor human milk was used not only for preterm infants but also for other ill children. But the sustainability of milk banking needs proper management and more financial support by relative health authorities and the government.

16.
Lancet Diabetes Endocrinol ; 7(3): 189-199, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30638856

RESUMO

BACKGROUND: Children with X-linked hypophosphataemia have high concentrations of circulating phosphatonin fibroblast growth factor 23 (FGF23), which causes renal phosphate wasting and hypophosphataemia, rickets, skeletal deformities, and growth impairment. Burosumab, a human monoclonal antibody against FGF23, improves phosphate homoeostasis and rickets in children aged 5-12 years with X-linked hypophosphataemia. We aimed to assess the safety and efficacy of burosumab in younger children with X-linked hypophosphataemia. METHODS: In this open-label, phase 2 trial at three hospitals in the USA, children (aged 1-4 years) with X-linked hypophosphataemia received burosumab (0·8 mg/kg) via subcutaneous injection every 2 weeks for 64 weeks. The dose was increased to 1·2 mg/kg if two consecutive pre-dose serum phosphorus concentrations were below 1·03 mmol/L (3·2 mg/dL), serum phosphorus had increased by less than 0·16 mmol/L (<0·5 mg/dL) from baseline, and a dose of burosumab had not been missed. Participants could continue to receive burosumab for up to an additional 96 weeks during the extension period. Key inclusion criteria were age 1-4 years at the time of informed consent; fasting serum phosphorus concentration of less than 0·97 mmol/L (3·0 mg/dL); serum creatinine 8·8-35·4 µmol/L (0·1-0·4 mg/dL); radiographic evidence of rickets (at least five participants were required to have a Thacher Rickets Severity Score of ≥1·5 at the knee); and a confirmed PHEX mutation or a variant of unknown significance in the patient or direct relative also affected with X-linked hypophosphataemia. Conventional therapy was stopped upon enrolment. The coprimary endpoints were safety and change from baseline to week 40 in fasting serum phosphorus concentrations. Changes in rickets severity from baseline to weeks 40 and 64 (assessed radiographically using Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change), and recumbent length or standing height, were key secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02750618, and is ongoing. FINDINGS: Between May 16, 2016, and June 10, 2016, we enrolled 13 children with X-linked hypophosphataemia. All 13 children completed 64 weeks of treatment and were included in the efficacy and safety analysis; none exceeded 70 weeks of treatment at the time of analysis. Serum phosphorus least squares mean increase from baseline to week 40 of treatment was 0·31 mmol/L (SE 0·04; 95% CI 0·24-0·39; 0·96 mg/dL [SE 0·12]; p<0·0001). All patients had at least one adverse event. 14 treatment-related adverse events, mostly injection site reactions, occurred in five children. One serious adverse event considered unrelated to treatment (tooth abscess) occurred in a child with a history of tooth abscess. All other adverse events were mild to moderate, except a severe food allergy considered unrelated to treatment. No instances of nephrocalcinosis or noteworthy changes in the results of a standard safety chemistry panel emerged. Total Thacher Rickets Severity Score decreased by a least squares mean of -1·7 (SE 0·1; p<0·0001) from baseline to week 40 and by -2·0 (SE 0·1; p<0·0001) by week 64. The Radiographic Global Impression of Change score also indicated significant improvement, with a least squares mean score of +2·3 (SE 0·1) at week 40 and +2·2 (0·1) at week 64 (both p<0·0001). Mean length or standing height Z score was maintained from baseline to week 64. INTERPRETATION: Burosumab had a favourable safety profile, increased serum phosphorus, and improved rickets and prevented early declines in growth in children aged 1-4 years with X-linked hypophosphataemia. These findings could substantially alter the treatment of young children with X-linked hypophosphataemia. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.

17.
Lipids Health Dis ; 18(1): 19, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30658634

RESUMO

BACKGROUND: Prenatal dexamethasone treatment has been shown to enhance the susceptibility of offspring to postnatal high-fat (HF) diet-induced programmed obesity. We investigated the metabolic phenotypes, nutrient-sensing signal and circadian-clock genes in adipose tissue that are programmed by prenatal dexamethasone exposure and postnatal HF diet. METHODS: Male offspring of Sprague-Dawley rats were divided into four experimental groups: normal diet, prenatal dexamethasone exposure, postnatal HF diet, and prenatal dexamethasone plus postnatal HF diet. Postnatal HF diet was prescribed from weaning to 6 months of age. RESULTS: Prenatal dexamethasone and postnatal HF diet exerted synergistic effects on body weight and visceral adiposity, whereas prenatal dexamethasone and postnatal HF diet altered the metabolic profile and caused leptin dysregulation. Prenatal dexamethasone and postnatal HF diet distinctly influenced nutrient-sensing molecules and circadian-clock genes in adipose tissue. The mRNA expression of mTOR, AMPK-α2, PPAR-α, and PPAR-γ was suppressed by prenatal dexamethasone but enhanced by postnatal HF diet. CONCLUSION: Prenatal dexamethasone and postnatal HF treatment cause dysregulation of nutrient-sensing molecules and circadian-clock genes in visceral adipose tissue. Characterizing altered nutrient-sensing molecules and circadian-clock genes has potential therapeutic relevance with respect to the pathogenesis and treatment of prenatal stress and postnatal HF diet-related metabolic disorders.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/genética , Relógios Circadianos/genética , Dexametasona/efeitos adversos , Dieta Hiperlipídica , Gordura Intra-Abdominal/patologia , Obesidade/etiologia , Obesidade/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal , Feminino , Inflamação/genética , Inflamação/patologia , Gordura Intra-Abdominal/metabolismo , Leptina/metabolismo , Tamanho do Órgão , Gravidez , Ratos Sprague-Dawley , Sirtuína 1/metabolismo
18.
Cell Commun Signal ; 16(1): 91, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30497498

RESUMO

BACKGROUND: The link between cardiac diseases and cognitive deterioration has been accepted from the concept of "cardiogenic dementia", which was proposed in the late 1970s. However, the molecular mechanism is unclarified. METHODS: The two animal models used in this study were cardiac-specific overexpression of microRNA-1-2 transgenic (Tg) mice and a myocardial infarction mouse model generated by left coronary artery ligation (LCA). First, we observed the microRNA-1 (miR-1) level and synaptic vesicles (SV) distribution in the hippocampus using in situ hybridization and transmission electron microscopy (TEM) and evaluated the expression of vesicle exocytosis related proteins by western blotting. Second, we used dual luciferase reporter assay as well as antagonist and miRNA-masking techniques to identify the posttranscriptional regulatory effect of miR-1 on the Snap25 gene. Third, FM1-43 staining was performed to investigate the effect of miR-1 on synaptic vesicle exocytosis. Lastly, we used GW4869 to inhibit the biogenesis and secretion of exosomes to determine the transportation effect of exosomes for miR-1 from the heart to the brain. RESULTS: Compared with the levels in age-matched WT mice, miR-1 levels were increased in both the hearts and hippocampi of Tg mice, accompanied by the redistribution of SVs and the reduction in SV exocytosis-related protein SNAP-25 expression. In vitro studies showed that SNAP-25 protein expression was down- or upregulated by miR-1 overexpression or inhibition, respectively, however, unchanged by miRNA-masking the 3'UTR of the Snap25 gene. SV exocytosis was inhibited by miR-1 overexpression, which could be prevented by co-transfection with an anti-miR-1 oligonucleotide fragment (AMO-1). The knockdown of miR-1 by hippocampal stereotaxic injection of AMO-1 carried by a lentivirus vector (lenti-pre-AMO-1) led to the upregulation of SNAP-25 expression and prevented SV concentration in the synapses in the hippocampi of Tg mice. The application of GW4869 significantly reversed the increased miR-1 level in the blood and hippocampi as well as reduced the SNAP-25 protein levels in the hippocampi of both Tg and LCA mice. CONCLUSION: The overexpression of miR-1 in the heart attenuated SV exocytosis in the hippocampus by posttranscriptionally regulating SNAP-25 through the transportation of exosomes. This study contributes to the understanding of the relationship between cardiovascular disease and brain dysfunction.

19.
J Cancer Res Ther ; 14(Supplement): S1057-S1062, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30539846

RESUMO

Objective: The objective of this paper was to investigate differential pathways in sporadic amyotrophic lateral sclerosis (SALS) based on pathway network analysis. Materials and Methods: To achieve this goal, first, differentially expressed genes (DEGs) between SALS and normal controls were identified, and a target network was defined as DEGs correlated interactions from the search tool for the retrieval of interacting genes/proteins (STRING). Second, topological centrality analysis was conducted on the target network to identify hub genes and hub network. Third, pathway network was constructed by taking intersections of Reactome database and STRING protein-protein interaction network. Finally, based on extracting the common interactions between target network, hub network and pathway network, we built randomized network, performed randomization test, and denoted differential pathways and hub differential pathways with P < 0.05. Results: There were 485 DEGs and 627 interactions in the target network. The pathway network was comprised 117,370 interactions. What was more, we found that 217 pathways had intersections with the target network. By accessing randomization test and removing the intersected count <10, 21 differential pathways with P values were nearly to be 0 were obtained, of which 6 rightly were the hub differential pathways, such as gene expression, mRNA Splicing, and mRNA splicing-major pathway. Conclusion: We have investigated 217 differential pathways and 21 significant differential pathways between SALS and normal controls based on network strategy. The findings might provide potential biomarkers for detection and therapy of SALS clinically and give great insights to reveal molecular mechanism underlying this disease. However, how these pathways cooperated with each other is still not clear, and future study should focus on this aspect.


Assuntos
Esclerose Amiotrófica Lateral/genética , Biologia Computacional/métodos , Redes Reguladoras de Genes , Mapas de Interação de Proteínas , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/metabolismo , Biomarcadores/metabolismo , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Transdução de Sinais/genética
20.
Medicine (Baltimore) ; 97(45): e12822, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30407282

RESUMO

RATIONALE: Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect (VACTERL) association and Müllerian duct anomalies are rare conditions. We present a rare condition with the co-occurrence of the VACTERL association and Müllerian duct hypoplasia to characterize patients' clinical presentations, outcomes, and treatment. PATIENT CONCERNS: An 11-year-old girl presented to our hospital with severe lower abdominal pain, lower vaginal atresia with enlargement of the upper vagina and a bicornuate uterus with a Y-shaped uterine cavity filled with hematometra on pelvic magnetic resonance imaging. Her medical history included congenital anal atresia with a rectovestibular fistula, congenital right renal deficiency, congenital right thumb malformation, and scoliosis. DIAGNOSES: 1. Congenital genital tract malformations, a partial bicornuate uterus, and distal vaginal atresia (U3aC0V4); 2. VACTERL association (congenital anal atresia with rectovestibular fistula, scoliosis with hemi vertebra and butterfly vertebra, unilateral renal agenesis, and finger defect). INTERVENTIONS: Colpotomy, laparoscopic exploration, pelvic adhesiolysis, and hysteroscopy were performed. OUTCOMES: Two months after surgery, a pelvic examination showed an unobstructed vagina which was 10 cm long and 2 fingers wide, without adhesion or constriction. LESSONS: Clinicians should have a high index of suspicion when evaluating patients with genital malformations associated with VACTERL. Early diagnosis of distal vaginal atresia with appropriate surgical intervention decreases long-term morbidity.


Assuntos
Anormalidades Múltiplas/diagnóstico , Canal Anal/anormalidades , Anus Imperfurado/diagnóstico , Esôfago/anormalidades , Cardiopatias Congênitas/diagnóstico , Rim/anormalidades , Deformidades Congênitas dos Membros/diagnóstico , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Útero/anormalidades , Vagina/anormalidades , Anormalidades Múltiplas/etiologia , Adolescente , Anus Imperfurado/etiologia , Feminino , Dedos/anormalidades , Cardiopatias Congênitas/etiologia , Humanos , Deformidades Congênitas dos Membros/etiologia , Fístula Retal/congênito , Escoliose/congênito , Rim Único/congênito
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