Integration of Brain Tissue Saturation Monitoring in Cardiopulmonary Exercise Testing in Patients with Heart Failure

Cerebral hypo-oxygenation during rest or exercise negatively impacts the exercise capacity of patients with heart failure with reduced ejection fraction ...

Chang Gung Memorial Hospital, Linkou

Chang Gung University

Prostaglandin D(2) synthase (PGDS) is a glycoprotein that is exclusively brain derived and is one of the most abundant proteins in the cerebrospinal fluid (CSF). Due to its high CSF specificity, it can be used as a tool for the diagnosis of central nervous system (CNS) disorders. However, several studies have yielded contradictory CSF PGDS concentrations in various CNS neurodegenerative disorders. Sheep CSF samples from different ages were used in this study and 2-dimensional electrophoresis (2-DE) was applied in PGDS identification and concentration calculation. SYPRO Ruby Protein Gel Stain was the staining method used to stain the 2-DE gel protein spots. Pro-Q Emerald 488 Staining for Glycoproteins was used for the staining of glycoproteins. A total of nine PGDS isoforms were identified and CSF total PGDS concentration was calculated to increase linearly by 44% from young (0.9323+/-0.0637mgdL(-1)) to old (1.3669+/-0.0558mgdL(-1)). However, the proportion of CSF total PGDS as a percentage of CSF total protein was discovered to decrease exponentially with age. This was due to the influence of larger age-related increase in CSF albumin concentration (>200% from young to old) as albumin is the most abundant protein in the CSF (>60% of total CSF proteins). Active deglycosylation was not observed in PGDS isoforms during healthy ageing. Some PGDS isoforms were observed to have age-related increase in glycation. These findings suggest that CSF PGDS concentration is increased during healthy ageing and must be taken into consideration when using PGDS as a potential biomarker in diagnosing CNS neurodegenerative disorders. Whether age-related increase in the glycation of some CSF PGDS isoforms will result in detrimental effects on the PGDS protein function needs further investigations.

Age-related increase of prostaglandin D(2) synthase concentration and glycation in ovine cerebrospinal fluid.

Studies have shown that ageing and several neurological diseases of the central nervous system are often accompanied with increase in concentrations of many cerebrospinal fluid (CSF) proteins. However, few studies have actually looked into the mechanisms behind the increase in CSF protein concentrations. In this study, CSF secretion rates and turnovers were measured using the in situ perfused choroid plexus (CP) technique in a group of sheep between 1 and 10 years of age. CSF protein concentrations were determined using quantitative proteomic techniques. CSF turnover in hours correlated significantly with age, changing from 10.5+/-2.7h in the young to 17.1+/-2.4h in the old. The amount of CSF replaced per hour decreased from 2.46+/-0.42mL in the young to 1.17+/-0.16mL in the old. The age-related reduction in CSF turnover was calculated to have a concentrating effect of approximately 1.32 times in middle-aged and 2.10 times in old CSF proteins. After CSF turnover normalization, CSF albumin (a plasma-derived protein) concentration still increased significantly with age; however, both brain-derived and partially brain-derived protein concentrations in the CSF decreased with age after normalization. Regression analysis between turnovers and albumin concentrations has shown that reduced CSF turnover was the cause of increased CSF albumin concentrations with age. Therefore, CSF protein concentrations should be normalized according to their age-specific turnovers first before their concentrations can be compared logically between different ages.

The influence of cerebrospinal fluid turnover on age-related changes in cerebrospinal fluid protein concentrations.

Studies have shown that ageing alone can cause increases in the concentrations of many cerebrospinal fluid (CSF) proteins. Therefore, CSF protein concentrations must be interpreted with caution before concluding that the increased concentrations of certain proteins can be used as disease-specific biomarkers. Age-related reduction in CSF turnover has been shown to have a significant concentrating effect on CSF proteins from young to old. As a result, CSF protein concentrations need to be corrected with age-specific turnovers first before performing any data comparisons between different ages. This study applied the concept of CSF/plasma concentration ratios of plasma-derived proteins that is frequently used in the investigation of brain barrier integrity to calculate the amount of protein that enters the CSF from the plasma side in different age groups. Based on our calculations, proteins with molecular weights greater than 91.92 kDa for the young, 109.51 kDa for the middle-aged and 120 kDa for the old should not be able to cross the brain barriers of the blood-brain and blood-CSF barriers to enter the CSF from the plasma side. For proteins that can be derived from the choroid plexus (CP), brain, and plasma, the amount that crosses the barriers to enter the CSF from the plasma side will contribute to their measured total protein concentrations in the CSF. CP and brain production of these proteins can be calculated when turnover corrected CSF protein concentrations are further corrected by the amount of protein that crosses the barriers. In this study, CP and brain produced concentrations of transthyretin, retinol binding protein, alpha-1-antitrypsin, gelsolin, and lactotransferrin were calculated. The production of these proteins decreased with age with alpha-1-antitrypsin protein revealing the most substantial decrease of 86% from young (0.14±0.01 mg·dL(-1)) to old (0.02 mg·dL(-1)). In conclusion, measured CSF protein concentrations for proteins that can be derived from the CP, brain, and plasma need to be corrected by age-specific CSF turnovers and by the amount of protein that crosses the brain barriers first before their concentrations can be compared logically between different ages.

The influence of ageing in the cerebrospinal fluid concentrations of proteins that are derived from the choroid plexus, brain, and plasma.

Knee pain is commonly seen in orthopedic and rehabilitation outpatient clinical settings, and in the aging population. Bursitis of the knee joint, especially when the volume of the synovial fluid is large enough, can compress and distend the nearby soft tissues, causing pain in the knee joint. Out of all the bursae surrounding the knee joint, supra-patellar bursitis is most often associated with knee pain. Treatment strategies in managing supra-patellar bursitis include the aspiration of joint synovial fluid and then followed by steroid injection into the bursa. When supra-patellar bursitis is caused by degenerative disorders, the concept of viscosupplementation treatment may be effective by injecting hyaluronic acid into the bursa. However, the rheology or the changes in the concentrations of proteins (biomarkers) that are related to the development of bursitis in the synovial fluid is virtually unexplored. Therefore, this study aimed to identify the concentration changes in the synovial fluid total protein amount and individual proteins associated with supra-patellar bursitis using the Bradford protein assay and western immunoglobulin methods. A total of 20 patients were divided into two groups with 10 patients in each group. One group received the high molecular weight hyaluronic acid product of Synvisc Hylan G-F 20 and the other group received the low molecular weight hyaluronic acid product of Hya-Joint Synovial Fluid Supplement once per week injection into the bursa for a total of 3 weeks. Significant decreases in the synovial fluid total protein concentrations were observed after the second dosage of high molecular weight hyaluronic acid injections. Apolipoprotein A-I, interleukin 1 beta, alpha 1 antitrypsin, and matrix metalloproteinase 1 proteins revealed a trend of decreasing western immunoblotting band densities after hyaluronic acid injections. The decreases in apolipoprotein A-I and interleukin 1 beta protein band densities were significant in the high molecular weight hyaluronic acid injection group. Transthyretin, complement 5, and matrilin 3 proteins revealed a trend of increasing western immunoblotting band densities after hyaluronic acid injections. Transthyretin revealed significant increases in protein band densities in both the high and low molecular weight hyaluronic acid injection groups. This study may provide the rationale for targeting several biomarkers associated with lipid transport, inflammation, and anti-aging as possible disease modifying therapies for the treatment of supra-patellar bursitis and even degenerative joint disorders.

Changes of synovial fluid protein concentrations in supra-patellar bursitis patients after the injection of different molecular weights of hyaluronic acid.

Knee pain caused by osteoarthritis (OA) is commonly seen in geriatric patients. Patients with knee OA are often complicated with joint pain, soreness, and weakness. The injection of autologous platelet rich plasma (aPRP) has been proven to be effective in treating mild knee OA. The effect of injecting aPRP in treating moderate to severe degrees of knee OA remains controversial. This study aimed to evaluate the effectiveness of aPRP in treating patients with at least grade 2 on the Kellgren and Lawrence system for the classification of knee OA using a proteomic approach and clinical evaluation tool of Lequesne index. Musculoskeletal ultrasound was used for accurate needle placement into the knee joint, and to the perimeniscal soft tissue for the injection of aPRP. Three monthly aPRP injections were performed. Group 1 patients received intra-articular (IA) injection only, while group 2 received simultaneous IA and pes anserinus aPRP injections. After two monthly aPRP injections, both groups revealed significant drops in average SF total protein concentrations, and increases in the protein concentrations associated with chelation and anti-aging (eg/transthyretin, matrilin, and complement). However, it is group 2 that revealed significant decreases in the protein concentrations associated with inflammation (eg/immunoglobulin and apolipoprotein), and improved knee functional status. SF appeared to become less susceptible to degeneration after aPRP injections in group 2. As a result, at least 2 monthly injection of IA aPRP in conjunction with accurate injection of aPRP to the perimeniscal soft tissue structure such as the pes anserinus may be a viable option in treating patients with moderate to severe degrees of knee OA.

Injecting autologous platelet rich plasma solely into the knee joint is not adequate in treating geriatric patients with moderate to severe knee osteoarthritis.

Carl PC Chen

Department of Physical Medicine and Rehabilitation

Chang Gung Memorial Hospital, Linkou

Integration of Brain Tissue Saturation Monitoring in Cardiopulmonary Exercise Testing in Patients with Heart Failure

Carl PC Chen

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Physical Medicine and Rehabilitation

Chang Gung Memorial Hospital, Linkou

Integration of Brain Tissue Saturation Monitoring in Cardiopulmonary Exercise Testing in Patients with Heart Failure

Department of Physical Medicine and Rehabilitation