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1.

Background

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for severe aplastic anemia (SAA). However, graft failure and graft-versus-host disease (GVHD) are major causes of the early morbidity in Allo-HSCT.

Methods

To reduce graft failure and GVHD, we treated fifteen patients with SAA using high- dose of HSCT with both G-CSF mobilized PB and BMSCs from HLA-identical siblings to treat patients with SAA.

Results

All patients had successful bone marrow engraftment. Only one patient had late rejection. Median time to ANC greater than 0.5 × 109/L and platelet counts greater than 20 × 109/L was 12 and 16.5 days, respectively. No acute GVHD was observed. The incidence of chronic GVHD was 6.67%. The total three-year probability of disease-free survival was 79.8%.

Conclusion

HSCT with both G-CSF mobilized PB and BMSCs is a promising approach for heavily transfused and/or allo-immunized patients with SAA.
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2.

Background

Despite the high prevalence of insomnia in patients with advanced cancer, there are no randomized controlled trials on pharmacological interventions for insomnia in this group of patients. A variety of pharmacological agents is recommended to manage sleep disturbance for insomnia in the general population, but their efficacy and safety in adults with advanced cancer are not established. Thus, there is a need to evaluate the effectiveness of medications for insomnia in order to improve the evidence in patients with advanced cancer. One of the most used sleep medications at present in patients with cancer is zopiclone.

Methods

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 100 patients with metastatic cancer who report insomnia will be randomly allocated to zopiclone or placebo. The treatment duration with zopiclone/placebo is 6 consecutive nights. The primary endpoint is patient-reported sleep quality during the final study night (night 6) assessed on a numerical rating scale of 0–10, where 0?=?Best sleep and 10?=?Worst possible sleep. Secondary endpoints include the mean patient-reported total sleep time and sleep onset latency during the final study night (night 6).

Discussion

Results from this study on treatment of insomnia in advanced cancer will contribute to clinical decision-making and improve the treatment of sleep disturbance in this patient cohort.

Trial registration

ClinicalTrials.gov, NCT02807922. Registered on 21 June 2016.
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3.

Background

Numerous studies suggest that exercise may be an effective adjunct treatment for substance use disorders. It has been suggested that exercise-induced improvements in inhibitory control may reduce craving for the substance of abuse. However, this potential mechanism has seldom been researched.

Objectives

The aim of the ExAlCo Study is to examine how acute bouts of exercise, at varying intensities, impact on craving for cocaine or alcohol. Cerebral haemodynamic responses during cognitive tests of inhibitory control, and exposure to substance-related cue imagery, will also be assessed using functional near-infrared spectroscopy.

Design

The study is a crossover randomised controlled trial. Participants will be recruited from inpatient and outpatient psychiatric treatment centres, on the approval of their treating physician. A healthy control group will be recruited using online advertising. All participants will undergo each of three conditions in randomised order: 20?min of cycle ergometry at 50–60% of maximum heart rate; 20?min of exercise at 70–80% of maximum heart rate; and 20?min of quiet reading. Immediately before and after each condition, participants will be asked to complete a computerised Stroop test, watch a film containing substance-related images and self-report craving levels. During the Stroop test and film viewing, participants’ neural activity will be measured via functional near-infrared spectroscopy.

Outcomes

The primary outcome measures are self-reported craving, inhibitory control and cerebral haemodynamic response to the Stroop test and a substance-related film. It is hoped that the findings from this study will shed more light on the role of exercise in the treatment of substance use disorders, particularly its scope in preventing relapse through reduced craving severity.

Trial registration

ClinicalTrials.gov, NCT03502486. Registered retrospectively on 5 April 2018.
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4.

Background

Software applications (apps) could potentially promote exercise adherence. However, it is unclear whether adolescents with painful hyperkyphosis will use an app designed for a home exercise program. The purpose of this study is to assess factors regarding adherence to an app-based home exercise program in adolescents with hyperkyphosis and back pain who were provided a one-time exercise treatment.

Methods

Twenty-one participants were instructed in a one-time exercise treatment and asked to complete a home exercise program 3 times a week for 6 months using an app called PT PAL. At a 6-month follow-up, 14 participants completed a survey assessing factors related to their experiences using the app and their treatment engagement.

Results

Although most participants did not use the app, they reported performing their exercises a few times per week. The adolescent participants considered the app to be more of a barrier than a supportive measure for promoting exercise adherence. Most participants still reported bothersome back pain.

Conclusions

Although adherence to the 6-month app-based home exercise program was not successful, adolescents still viewed technology support such as text reminders as a potential solution.

Trial registration

ClinicalTrials.gov Identifier: NCT03212664. Registered 11 July 2017. Retrospectively registered.
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5.

Background

Immediate and exclusive initiation of breastfeeding after delivery has been associated with better neonatal survival and child health and are recommended by the WHO. We report its impact on early infant feeding practices from the PROMISE-EBF trial.

Methods

PROMISE-EBF was a cluster randomised behaviour change intervention trial of exclusive breastfeeding (EBF) promotion by peer counsellors in Burkina Faso, Uganda and South Africa implemented during 2006-2008 among 2579 mother-infant pairs. Counselling started in the last pregnancy trimester and mothers were offered at least five postnatal visits. Early infant feeding practices: use of prelacteal feeds (any foods or drinks other than breast milk given within the first 3 days), expressing and discarding colostrum, and timing of initiation of breastfeeding are presented by trial arm in each country. Prevalence ratios (PR) with 95% confidence intervals (95%CI) are given.

Results

The proportion of women who gave prelacteal feeds in the intervention and control arms were, respectively: 11% and 36%, PR 0.3 (95% CI 0.2, 0.6) in Burkina Faso, 13% and 44%, PR 0.3 (95% CI 0.2, 0.5) in Uganda and 30% and 33%, PR 0.9 (95% CI 0.6, 1.3) in South Africa. While the majority gave colostrum, the proportion of those who expressed and discarded it in the intervention and control arms were: 8% and 12%, PR 0.7 (95% CI 0.3, 1.6) in Burkina Faso, 3% and 10%, PR 0.3 (95% CI 0.1, 0.6) in Uganda and 17% and 16%, PR 1.1 (95% CI 0.6, 2.1) in South Africa. Only a minority in Burkina Faso (<4%) and roughly half in South Africa initiated breastfeeding within the first hour with no large or statistically significant differences between the trial arms, whilst in Uganda the proportion of early initiation of breastfeeding in the intervention and control arms were: 55% and 41%, PR 0.8 (95% CI 0.7, 0.9).

Conclusions

The PROMISE-EBF trial showed that the intervention led to less prelacteal feeding in Burkina Faso and Uganda. More children received colostrum and started breastfeeding early in the intervention arm in Uganda. Late breastfeeding initiation continues to be a challenge. No clear behaviour change was seen in South Africa.

Trial registration

NCT00397150.
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6.

Background

The aim of this study was to explore the characteristics and prognostic information of estrogen receptor-positive/progesterone receptor-negative (ER+/PR?) male breast cancer.

Methods

Using the US National Cancer Institute’s Surveillance, Epidemiology, and End Results database, we compared the demographics, clinical characteristics, and outcome of estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) patients with ER+/PR? male breast cancer patients from 1990 to 2010. Two thousand three hundred twenty-two patients with ER+/PR+ tumors and 355 patients with ER+/PR? tumors were included in our study.

Results

ER+/PR? patients were younger (P?=?0.008) and more likely to be African American (P?<?0.001) while presented with higher histological grade (P?<?0.001), larger tumor size (P?=?0.010), and more invasion to the lymph nodes (P?=?0.034) and distant sites (P?<?0.001), thus later stage (P?=?0.001). Despite higher chance of receiving chemotherapy (51.0% vs 36.5%, P?<?0.001), ER+/PR? patients experienced significantly worse breast cancer-specific survival (BSCC) (P?<?0.001) and shorter overall survival (OS) (P?=?0.003). Multivariate Cox model confirmed that tumor size, lymph node invasion, metastasis, and surgery were independent prognostic factors of both BSCC and OS for ER+/PR? male breast cancer. Age at diagnosis and chemotherapy were significantly associated with OS but not with BSCC.

Conclusion

ER+/PR? male breast cancer was more aggressive and experienced shorter survival than ER+/PR+ patients. The prognosis was mainly associated with tumor size, lymph node invasion, metastasis, and surgery.
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7.

Background

Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women.

Methods/design

The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1?g of TXA or matching placebo by intravenous injection immediately (within 15?min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. The main analyses will be on an ‘intention-to-treat’ basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia.

Discussion

The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia.

Trial registration

ISRCTN, ISRCTN62396133. Registered on 7 December 2017;ClincalTrials.gov, ID: NCT03475342. Registered on 23 March 2018.
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8.

Background

Intra-operative urinary catheterization frequently causes postoperative catheter related bladder discomfort (CRBD) during recovery. We conducted this study to evaluate the efficacy of tramadol, which with muscarinic receptor antagonist property, as a treatment for CRBD.

Methods

Ninety patients who underwent elective gynecological surgery and complained of CRBD in the (PACU) were randomized into three groups of 30 each. Group A received normal saline, group B 1?mg/kg tramadol, and group C 1.5?mg/kg tramadol. The medication was administered from the Murphy’s dropper with a slow drip, and the severity of CRBD (none, mild, moderate, and severe) and postoperative pain were assessed after 0, 0.5, 1, 2 and 6?h.

Results

The severity of CRBD was reduced in group C compared with that in groups A and B at 1?h, and in groups C and B compared with that in group A at 2?h. The incidence of CRBD was reduced in group C compared with that in groups A and B at 2?h, and in group C compared with that in group A at 6?h. The visual analog scale (VAS) was reduced in group C compared with that in groups A and B at all time intervals. No differences in adverse effects were observed.

Conclusions

Tramadol 1.5?mg/kg was more effective than tramadol 1?mg/kg in treating CRBD and reducing postoperative pain, without significant side effects.

Trial registration

ChiCTR1800016390. Registered on 30 May 2018.
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9.

Background

The prevalence of atrial fibrillation (AF) is growing as the population ages, and at least 15% of ischemic strokes are attributed to AF. However, many high-risk AF patients are not offered guideline-recommended stroke prevention therapy due to a variety of system, provider, and patient-level barriers.

Methods

We will conduct a pragmatic, cluster-randomized controlled trial randomizing primary care clinics to test a “toolkit” of quality improvement interventions in primary care. In keeping with the recommendations of the chronic care model to simultaneously activate patients and facilitate proactive care by providers, the toolkit includes provider-focused strategies (education, audit and feedback, electronic decision support, and reminders) plus patient-directed strategies (educational letters and reminders). The trial will include two feedback cycles at baseline and approximately 6 months and a final data collection at approximately 12 months. The study will be powered to show a difference of 10% in the primary outcome of proportion of patients receiving guideline-recommended stroke prevention therapy. Analysis will follow the intention-to-treat principle and will be blind to treatment allocation. Unit of analysis will be the patient; models will use generalized estimating equations to account for clustering at the clinical level.

Discussion

Stroke prevention therapy using anticoagulation in patients with AF is known to reduce strokes by two thirds or more in clinical trials, but most studies indicate under-use of this treatment in real-world practice. If the toolkit successfully improves care for patients with AF, stakeholders will be engaged to facilitate broader application to maximize the potential to improve patient outcomes. The intervention toolkit tested in this project could also provide a model to improve quality of care for other chronic cardiovascular conditions managed in primary care.

Trial registration

ClinicalTrials.gov (NCT01927445). Registered August 14, 2014 at https://clinicaltrials.gov/.
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10.

Introduction

Peripheral blood stem cells mobilized by granulocyte colony-stimulating factor (G-CSF) from healthy donors are commonly used for allogeneic stem cell transplantation. The effect of G-CSF administration on global serum metabolite profiles has not been investigated before.

Objectives

This study aims to examine the systemic metabolomic profiles prior to and following administration of G-CSF in healthy adults.

Methods

Blood samples were collected from 15 healthy stem cell donors prior to and after administration of G-CSF 10 µg/kg/day for 4 days. Using a non-targeted metabolomics approach, metabolite levels in serum were determined using ultrahigh performance liquid chromatography-tandem mass spectrometry and gas chromatography/mass spectrometry.

Results

Comparison of the metabolite profiles of donors before and after G-CSF treatment revealed 239 metabolites that were significantly altered. The major changes of the metabolite profiles following G-CSF administration included alteration of several fatty acids, including increased levels of several medium and long-chain fatty acids, as well as polyunsaturated fatty acids; while there were lower levels of other lipid metabolites such as phospholipids, lysolipids, sphingolipids. Furthermore, there were significantly lower levels of several amino acids and/or their metabolites, including several amino acids with known immunoregulatory functions (methionine, tryptophan, valine). Lastly, the levels of several nucleotides and nucleotide metabolites (guanosine, adenosine, inosine) were also decreased after G-CSF administration, while methylated products were increased. Some of these altered products/metabolites may potentially have angioregulatory effects whereas others may suggest altered intracellular epigenetic regulation.

Conclusion

Our results show that G-CSF treatment alters biochemical serum profiles, in particular amino acid, lipid and nucleotide metabolism. Additional studies are needed to further evaluate the relevance of these changes in healthy donors.
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11.

Background

Intrathecally administered morphine is effective as part of a postoperative analgesia regimen following major hepatopancreaticobiliary surgery. However, the potential for postoperative respiratory depression at the doses required for effective analgesia currently limits its clinical use. The use of a low-dose, prophylactic naloxone infusion following intrathecally administered morphine may significantly reduce postoperative respiratory depression. The NAPRESSIM trial aims to answer this question.

Methods/design

‘The use of low-dose, prophylactic naloxone infusion to prevent respiratory depression with intrathecally administered morphine’ trial is an investigator-led, single-centre, randomised, double-blind, placebo-controlled, double-arm comparator study. The trial will recruit 96 patients aged?>?18 years, undergoing major open hepatopancreaticobiliary resections, who are receiving intrathecally administered morphine as part of a standard anaesthetic regimen. It aims to investigate whether the prophylactic administration of naloxone via intravenous infusion compared to placebo will reduce the proportion of episodes of respiratory depression in this cohort of patients.Trial patients will receive an infusion of naloxone or placebo, commenced within 1 h of postoperative extubation continued until the first postoperative morning. The primary outcome is the rate of respiratory depression in the intervention group as compared to the placebo group. Secondary outcomes include pain scores, rates of nausea and vomiting, pruritus, sedation scores and adverse outcomes. We will also employ a novel, non-invasive, respiratory minute volume monitor (ExSpiron 1Xi, Respiratory Motion, Inc., 411 Waverley Oaks Road, Building 1, Suite 150, Waltham, MA, USA) to assess the monitor’s accuracy for detecting respiratory depression.

Discussion

The trial aims to provide a clear management plan to prevent respiratory depression after the intrathecal administration of morphine, and thereby improve patient safety.

Trial registration

ClinicalTrials.gov, ID: NCT02885948. Registered retrospectively on 4 July 2016.Protocol Version 2.0, 3 April 2017.Protocol identification (code or reference number): UCDCRC/15/006EudraCT registration number: 2015-003504-22. Registered on 5 August 2015.
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12.

Background

Panic disorder (PD) is highly prevalent in patients with non-cardiac chest pain (NCCP). This study aims to explore the role of psychological factors (PD intensity, anxiety sensitivity, heart-related fear, attention and avoidance) common to NCCP and PD in predicting chest pain levels in patients with both conditions.

Methods

This association was investigated in emergency department patients with NCCP and PD receiving either evidence-based treatment of PD or treatment as usual. Patients were assessed at baseline and 14 weeks later for post-treatment.

Results

Only heart-focused fear and attention for cardiac sensations independently explained a significant portion of the variance in baseline pain (n?=?66). At 3 months follow-up (n?=?53), changes in heart-related fear was the only factor independently associated with changes in chest pain intensity. Even in patients with PD, fear specific to cardiac sensations seems to play a central role in determining NCCP intensity.

Conclusion

These results suggest that the efficacy of intervention for patients with PD and comorbid NCCP could be improved by targeting heart-related fear and attention.

Trial registration

NCT00736346
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13.

Background

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition affecting men of all ages. Acupuncture may be an effective treatment option for CP/CPPS, but evidence is limited. We propose to evaluate the effectiveness of acupuncture in a rigorously conducted trial.

Methods

Ten hospitals will recruit 440 participants with CP/CPPS in China from October 2017 to December 2019. Participants will be randomly allocated to acupuncture or sham acupuncture with a 1:1 ratio using computerized simple random sampling. The whole study consists of 2-week baseline, 8-week treatment, and 24-week follow up. Twenty 30-mintute sessions of acupuncture or sham acupuncture treatment will be provided between week 1 and 8. The two co-primary outcomes are the proportion of responders at week 8 and week 32. Secondary outcomes include proportion of responders in the two groups at different time points; change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score; change in the NIH-CPSI subscales; change in the International Prostate Symptom Score; change in the Hospital Anxiety and Depression Scale; expectation assessments; proportions of participants in each response category of the Global Response Assessment; change in the International Index of Erectile Function 5; change in the five-level EuroQol five-dimensional questionnaire and a visual analogue scale; and changes in peak and average urinary flow rate.

Discussion

This study will provide robust evidence on whether acupuncture is effective for relieving symptoms of CP/CPPS.

Trials registration

ClinicalTrials.gov, NCT03213938. Registered on 5 July 2017.
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14.

Background

Administration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo.

Methods

We evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice.

Results

We find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation.

Conclusions

Our findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF.
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15.

Background

The aim of this study is to report the outcome after surgical treatment of 32 patients with ampullary cancers from 1990 to 1999.

Methods

Twenty-one of them underwent pancreaticoduodenectomy and 9 local excision of the ampullary lesion. The remaining 2 patients underwent palliative surgery.

Results

When the final histological diagnosis was compared with the preoperative histological finding on biopsy, accurate diagnosis was preoperatively established in 24 patients. The hospital morbidity was 18.8% as 9 complications occurred in 6 patients. Following local excision of the ampullary cancer, the survival rate at 3 and 5 years was 77.7% and 33.3% respectively. Among the patients that underwent Whipple's procedure, the 3-year survival rate was 76.2% and the 5-year survival rate 62%.

Conclusion

In this series, local resection was a safe option in patients with significant co-morbidity or small ampullary tumors less than 2 cm in size, and was associated with satisfactory long-term survival rates.
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16.

Background

Lower urinary tract symptoms related to benign prostatic obstruction (BPO) are frequent in men aged >?50?years. Based on the use of innovative medical devices, a number of transurethral ablative techniques have recently been developed for the surgical treatment of BPO. In recent years, GreenLight photoselective vaporization of the prostate (PVP) has been considered as a non-inferior alternative to transurethral resection of the prostate. The GreenLight PVP is usually considered as an interesting surgical option for patients treated via oral anticoagulants (OACs) with regard to its haemostatic properties. The aim of this study was to assess the impact of maintaining OAC treatment in patients undergoing PVP.

Methods

This study is a multicentre, open-label, randomized controlled trial (RCT) designed to show the non-inferiority of PVP surgery in patients with BPO treated with OACs. This study is designed to enrol 386 OAC-treated patients (treated with vitamin K antagonists and direct oral anticoagulants) who are undergoing PVP for BPO. Patients will be randomized (1:1) to either maintain or stop OAC treatment during the perioperative course. The intervention group will maintain OAC treatment until the day before surgery and resume OAC treatment the day after surgery, whereas the control group will stop OAC treatment (with or without low-molecular-weight heparin bridging therapy) according to the anaesthesia guidelines. The primary outcome of interest to be assessed is the 30-day complications rate according to the Clavien-Dindo classification. The secondary endpoint will examine the 30-day rate of haemorrhagic and thrombotic events. This study will provide 80% power to show non-inferiority, defined as not worse than a 10% (non-inferiority margin) inferior change in the proportion of patients with good outcomes (Clavien-Dindo score?<?2), using two-tailed 95% confidence intervals.

Discussion

This first multicentre RCT in the field is underway to evaluate the safety and efficacy of PVP in patients with ongoing OAC therapy. The study results could influence the perioperative management of OACs in BPO surgery with a high level of evidence.

Trial registration

ClinicalTrials.gov, NCT03297281. Registered on 29 September 2017.
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17.

Introduction

Cornea is the outermost part of the eye supplied mostly by aqueous humor (AH). Therefore, the comparison of the metabolomic compositions of AH and cornea may help to determine which compounds are produced inside the cornea, and which penetrate into cornea from AH for intra-corneal consumption. Keratoconus (KC) is the most common form of the cornea dystrophy, and the analysis of KC corneas can unravel the metabolomic changes occurring in AH and cornea of KC patients.

Objectives

The work is aimed at the determination of concentrations of a wide range of metabolites in the human cornea and AH, the comparison of the metabolomic profiles of cornea and AH, and the comparison of the metabolomic compositions of samples taken from KC patients and normal donors (post-mortem).

Methods

The quantitative metabolomic profiling was carried out with the use of two independent methods—high-frequency 1H NMR spectroscopy and HPLC with high-resolution ESI-MS detection.

Results

The concentrations of 71 most abundant metabolites in cornea and AH from keratoconus patients and from human cadavers have been measured. It is found that the concentrations of purines and organic acids in cornea are significantly higher than in AH. The KC corneas are characterized by the enhanced levels of acetate and citrate, and also by low values of GSH/GSSG ratios.

Conclusion

A significant difference in the metabolomic compositions of the human AH and cornea has been revealed. The concentrations of glucose and some amino acids in cornea are significantly lower than in AH, indicating their fast consumption inside the cornea. The high levels of organic acids, purines and GSH in cornea should be attributed to their production in the cornea. The enhanced levels of acetate and citrate as well as the low values of GSH/GSSG ratios in KC corneas are the indicators of the oxidative stress.
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18.

Introduction

The optical elements of the eye—cornea, lens, and vitreous humor—are avascular tissues, and their nutrition and waste removal are provided by aqueous humor (AH). The AH production occurs through the active secretion and the passive diffusion/ultrafiltration of blood plasma. The comparison of the metabolomic profiles of AH and plasma is important for understanding of the mechanisms of biochemical processes and metabolite transport taking place in vivo in ocular tissues.

Objectives

The work is aimed at the determination of concentrations of a wide range of most abundant metabolites in the human AH, the comparison of the metabolomic profiles of AH and serum, and the analysis of the post-mortem metabolomic changes in these two biological fluids.

Methods

The quantitative metabolomic profiling was carried out with the use of two independent methods—high-frequency 1H NMR spectroscopy and HPLC with high-resolution ESI-MS detection.

Results

The concentrations of 71 most abundant metabolites in blood serum and AH from living patients and human cadavers have been measured. It has been found that the level of ascorbate in AH is by two orders of magnitude higher than that in serum; the levels of other metabolites are either similar to that in serum, or differ from that by a factor of 2–5. The post-mortem metabolomic composition of both serum and AH undergoes rapid and strong changes.

Conclusion

The differences between the metabolomic profiles of AH and serum for majority of metabolites can be attributed to the metabolic activity of the ocular tissues leading to the lack or excess of some metabolites, while the high concentration of ascorbate in AH demonstrates the activity of ascorbate-specific pumps at the blood-aqueous border. The post-mortem metabolomic changes are caused by the disruption of the major biochemical cycles and cell lysis. These changes should be taken into account in the analysis of disease-induced changes in post-mortem samples of the ocular tissues.
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19.

Background

Developing non-pharmacological interventions with strong potential to prevent or delay the onset of Alzheimer’s disease (AD) in high-risk populations is critical. Aerobic exercise and cognitive training are two promising interventions. Aerobic exercise increases aerobic fitness, which in turn improves brain structure and function, while cognitive training improves selective brain function intensively. Hence, combined aerobic exercise and cognitive training may have a synergistic effect on cognition by complementary strengthening of different neural functions. Few studies have tested the effects of such a combined intervention, and the findings have been discrepant, largely due to varying doses and formats of the interventions.

Methods/design

The purpose of this single-blinded, 2?×?2 factorial phase II randomized controlled trial is to test the efficacy and synergistic effects of a 6-month combined cycling and speed of processing training intervention on cognition and relevant mechanisms (aerobic fitness, cortical thickness, and functional connectivity in the default mode network) in older adults with amnestic mild cognitive impairment. This trial will randomize 128 participants equally to four arms: cycling and speed of processing, cycling only, speed of processing only, or attention control for 6?months, and then follow them for another 12?months. Cognition and aerobic fitness will be assessed at baseline and at 3, 6, 12, and 18?months; cortical thickness and functional connectivity at baseline and at 6, 12, and 18?months; Alzheimer’s disease (AD) conversion at 6, 12, and 18?months. The specific aims are to (1) determine the efficacy and synergistic effects of the combined intervention on cognition over 6?months, (2) examine the underlying mechanisms of the combined intervention, and (3) calculate the long-term effect sizes of the combined intervention on cognition and AD conversion. The analysis will use intention-to-treat and linear mixed-effects modeling.

Discussion

This trial will be among the first to test the synergistic effects on cognition and mechanisms (relevant to Alzheimer’s-associated neurodegeneration) of a uniquely conceptualized and rigorously designed aerobic exercise and cognitive training intervention in older adults with mild cognitive impairment. It will advance Alzheimer’s prevention research by providing precise effect-size estimates of the combined intervention.

Trial registration

ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.
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20.

Introduction

The analysis of post-mortem metabolomic changes in biological fluids opens the way to develop new methods for the estimation of post-mortem interval (PMI). It may also help in the analysis of disease-induced metabolomic changes in human tissues when the postoperational samples are compared to the post-mortem samples from healthy donors.

Objectives

The goals of this study are to observe and classify the post-mortem changes occurring in the rabbit blood, aqueous and vitreous humors (AH and VH), to identify the potential PMI markers among a wide range of metabolites, and also to determine which biological fluid—blood, AH or VH—is more suitable for the PMI estimation.

Methods

The quantitative metabolomic profiling of samples of the rabbit serum, AH and VH taken at different PMIs has been performed with the combined use of high-frequency NMR and high-resolution LC–MS methods.

Results

The quantitative levels of 61 metabolites in the rabbit serum, AH and VH at different PMIs have been measured. It has been found that the post-mortem metabolomic changes in AH and VH proceed slower than in blood, and the data scattering is lower. Among the metabolites whose concentrations increase with time, the most significant and linear growth is found for hypoxanthine, choline and glycerol.

Conclusion

The obtained results suggest that the ocular fluids AH and VH may have some advantages over blood serum for the search of potential biochemical markers for the PMI estimation. Among the compounds studied in the present work, hypoxanthine, choline and glycerol give the biggest promise as the potential PMI biomarkers.
  相似文献   

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