Paulien H. Goossens

Feasibility of Adenovirus-Mediated Nonsurgical Synovectomy in Collagen-Induced Arthritis-Affected Rhesus Monkeys

Gene transfer to synovial tissue by adenoviral vectors (Ad) was studied in vitro in cultured human synoviocytes and in vivo in seven primates with arthritis. Hyperplastic synovium was efficiently transduced with Ad.lacZ in vitro and in vivo in rhesus monkeys with collagen-induced arthritis, whereas chondrocytes were not transduced. Intraarticular injection of recombinant Ad harboring the luciferase gene showed the presence of reporter gene products only in Ad-injected joints. In addition, the feasibility of synovectomy by Ad harboring the herpes simplex virus thymidine kinase gene (tk) was studied. In vitro infection of synovium from rheumatoid arthritis patients with Ad.TK, followed by administration of ganciclovir, resulted in death of >90% of the synoviocytes. By mixing Ad.TK-infected with noninfected cells, it appeared that the presence of 10% infected synoviocytes resulted in the killing of more than 85% of the synoviocytes, demonstrating a substantial bystander effect. Intraarticular injection of Ad.TK in the knees of rhesus monkeys with arthritis, followed by treatment with ganciclovir for 14 days, resulted in increased apoptotic cell death in the synovium of Ad.TK-injected as compared with noninjected joints and ablation of the synovial lining layer. The procedure revealed no toxic side effects. These data suggest that nonsurgical synovectomy by tK gene therapy is feasible.

Infection efficiency of type 5 adenoviral vectors in synovial tissue can be enhanced with a type 16 fiber

OBJECTIVE To obtain an adenoviral vector with increased infection efficiency in the synovial tissue compared with conventional vectors based on adenovirus serotype 5 (Ad5), without compromising the specificity of infection. METHODS Coxsackie adenovirus receptor (CAR) expression was assessed in cultured synoviocytes. Chimeric adenoviruses based on Ad5 but carrying the DNA encoding the fiber of adenovirus from subgroup B (Adll, 16, 35) or D (Ad24, 28, 33, 45, or 47) were constructed and produced on PER.C6 cells. The gene transfer efficiency of these chimera was tested on cultured synoviocytes and peripheral blood mononuclear cells (PBMC). RESULTS No surface expression of CAR protein was observed on synoviocytes. CAR messenger RNA expression of synoviocytes was found to be low. Of all fiber chimeric vectors tested, vectors carrying the fiber of Ad16 (Ad5.fib16) were most potent, yielding approximately150 times increased transgene expression in cultured synoviocytes compared with those of Ad5. Flow cytometry showed that the increase in transgene expression was caused by the transduction of higher percentages of synoviocytes and higher gene expression per synoviocyte. Experiments with 500 virus particles/cell of Ad5.GFP or Ad5.fib16.GFP resulted in an infection efficiency of 0.6% and 1% in PBMC and 43% and 76% in synoviocytes, respectively. CONCLUSION Synoviocytes hardly express CAR, which hampers Ad5-mediated gene transfer. Ad5.fib16 is superior to Ad5 vectors for transducing synoviocytes, without compromising the specificity of infection. Our data suggest that Ad5.fib16-mediated gene transfer to synovial tissue improves the therapeutic window.

The influence of synovial fluid on adenovirus-mediated gene transfer to the synovial tissue

OBJECTIVE To determine the effect of synovial fluid (SF) from rheumatoid arthritis (RA) patients on adenovirus type 5 (Ad5)-mediated gene transfer to synoviocytes, and to explore new strategies for vector development based on the neutralization data obtained. METHODS SF was derived from 63 randomly selected R4 patients. Ten samples were used to study the effect of SF on Ad5-mediated gene transfer in synoviocytes. IgG and <100-kd fractions were purified from these 10 SF, and their effect on gene transfer was determined. Neutralizing activity against wild-type Ad5 (wt-Ad5), wt-Ad26, wt-Ad34, wt-Ad35, and wt-Ad48 was tested in the SF from the remaining 53 patients. RESULTS Seven of 10 SF samples inhibited Ad5-mediated gene transfer. Purified antibodies exhibited inhibition patterns similar to those seen with unfractionated SF. In 5 of 10 SF samples, low molecular weight fractions inhibited gene transfer at low dilutions. Neutralization of wt-Ad35 by SF from RA patients was less frequent than neutralization of other wt-Ad tested (4% versus 42-72%; n = 53). CONCLUSION SF from 70% of the RA patients contained neutralizing antibodies that hamper Ad5-mediated gene transfer to synoviocytes. The activity of neutralizing antibodies may be circumvented in the majority of RA patients when vectors based on an Ad35 backbone are used.

Cognitive problems in patients in a cardiac rehabilitation program after an out-of-hospital cardiac arrest

OBJECTIVE Estimate prevalence of cognitive problems due to hypoxic brain injury in out-of-hospital cardiac arrest (OHCA) survivors referred for cardiac rehabilitation and association with quality of life as well as autonomy and participation. DESIGN Prospective cohort study. METHOD/DESIGN Consecutive OHCA patients. The Mini-Mental State Examination (MMSE), Cognitive Failures Questionnaire (CFQ) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were administered 4 weeks after the OHCA. Cognitive problems were defined if MMSE <28, CFQ >32 or IQCODE >3.6. The Impact on Participation and Autonomy Questionnaire (IPAQ) (participation/autonomy), the SF-36 Health Survey (SF-36) (quality of life) and the Hospital Anxiety Depression Scale (HADS) (anxiety/depression) were administered. Correlations between cognitive problems and participation/autonomy and quality of life were calculated. RESULTS 63 of 77 patients were male (82%), median age 59 years (range 15-84). MMSE median 29 (interquartile range 28-30), CFQ mean 20.9 (SD 9.4) and IQCODE mean 3.1 (SD 0.2). Eighteen patients (23%) scored positive for cognitive problems. Significant correlations were found between MMSE and IPAQ: autonomy inside (r = -0.38), family role (r = -0.26), autonomy outside (r = -0.32), social relations (r = -0.38) and social functioning (r = 0.32). MMSE was related to SF-36: social functioning (r = 0.32). The CFQ was related to IPAQ: autonomy outdoors (r = 0.29) and SF-36: bodily pain (r = -0.37), vitality (r = -0.25), mental health (r = -0.35) and role emotional (r = -0.40). The IQCODE was related to IPAQ: autonomy indoors (r = 0.26) and to SF-36: vitality (r = -0.33) and social functioning (r = -0.41). CONCLUSION Twenty-three percent of the patients referred for cardiac rehabilitation showed cognitive problems. Associations were found between cognitive problems and several aspects of participation/autonomy and perceived quality of life.

Rehabilitation after Cardiac Arrest: Integration of Neurologic and Cardiac Rehabilitation

Abstract Cognitive impairments are common after resuscitation. Severe cognitive impairments are easily recognized. Mild cognitive impairments are much more difficult to spot. Given the influence of cognitive problems in daily functioning, it is important to identify cognitive impairments at an early stage. Also, emotional problems, mainly depression and fear, are common in this group of patients. To optimize the care for patients after an out‐of‐hospital cardiac arrest, rehabilitation should focus on the physical approach through cardiac rehabilitation and on brain injury and associated cognitive impairments. The goal of rehabilitation after a cardiac arrest is to provide excellent patient‐centered cardiac and cognitive rehabilitation to all patients and their spouses to achieve optimal participation in society, with minimal burden for spouses and society. To achieve this, cardiac and cognitive rehabilitation need to be coordinated in an integrated care path.

The Longer-term Unmet Needs after Stroke Questionnaire: Cross-Cultural Adaptation, Reliability, and Concurrent Validity in a Dutch Population

BACKGROUND Unmet needs are common after stroke. We aimed to translate the 22-item Longer-term Unmet Needs after Stroke (LUNS) Questionnaire and validate it in a Dutch stroke population. METHODS The LUNS was translated and cross-culturally adapted according to international guidelines. After field testing, the Dutch version was administered twice to a hospital-based cohort 5-8 years after stroke. Participants were also asked to complete the Frenchay Activity Index (FAI) and Short Form (SF)-12. To explore acceptability, the response and completion rates as well as number of missing items were computed. For concurrent validity, the differences in health status (FAI, SF-12) between groups who did and did not report an unmet need were calculated per item. To determine the 14-day test-retest reliability, the percentage of agreement between the first and the second administration was calculated for each item. RESULTS Seventy-eight of 145 patients (53.8%) returned the initial Dutch LUNS (average age 68.3 [standard deviation 14.0] years, 59.0% male); 66 of these patients (84.6%) fully completed it. Of all items, 3.3% were missing. Among completers, the median number of unmet needs was 3.5 (2.0-5.0; 1.0-14.0). For 15 of 22 items, there was a significant association with the FAI or SF-12 Mental or Physical Component Summary scales. The percentage of agreement ranged from 69.8% to 98.1% per item. CONCLUSIONS Among the 53.8% who completed the survey, the LUNS was concluded to be feasible, reliable, and valid; two-thirds of its items were related to activities and quality of life. Its usefulness and acceptability when administered in routine practice require further study.

Out-of-hospital cardiac arrest survivors with cognitive impairments have lower exercise capacity ☆

BACKGROUND Hypoxic brain injury is described in up to 40% of survivors after out-of-hospital cardiac arrest (OHCA). Besides cognitive impairments, lack of circulation may also affect exercise capacity. It is not known if exercise capacity of patients with cognitive impairments differs from other OHCA survivors. METHODS This retrospective cohort study included patients ≥18 years with myocardial infarction (MI) as cause of OHCA admitted for cardiac rehabilitation between February 2011 and April 2014. Data in socio-demographic, OHCA and medical interventions were retrieved. Cognitive functioning was determined with the Mini-Mental State Examination, Cognitive Failures Questionnaire and the Informant Questionnaire on Cognitive Decline in the Elderly. Exercise capacity (VO2peak), workload (Watts) and blood pressure (mmHg) were measured at maximum cardiopulmonary exercise. Heart rate (bpm) was measured at rest and maximum exercise and Metabolic Equivalents of Tasks (MET) were calculated. RESULTS 65 patients after OHCA caused by MI were included (85% male, median age 60years). Of 53 patients Cardio Pulmonary Exercise Test data was available of which nine patients showed cognitive impairments. Significant differences (p<0.05) in exercise capacity were found between patients with and without cognitive impairments: VO2peak (median 14.5 vs 19.7ml/kg/min), workload (median 130.0 vs 143.5W) and METs (median 4.1 vs 5.6). CONCLUSION Based on this small study, there seems to be a correlation between cognitive impairments and lower exercise capacity in patients referred for rehabilitation after OHCA caused by MI. It seems sensible for rehabilitation programs to take the lower exercise capacity of patients with cognitive impairments into account.

Revalidatie na reanimatie? Ja, natuurlijk!

SamenvattingCognitieve klachten komen vaak voor na reanimatie. Ernstige cognitieve problemen worden gemakkelijk onderkend, milde cognitieve klachten zijn echter moeilijker te herkennen. Gezien de grote invloed van cognitieve problemen op het dagelijks functioneren, is het belangrijk om een eenvoudig screeningsinstrument te hebben. Patiënten kunnen dan tijdig worden voorgelicht over hun hersenletsel en, indien nodig, cognitief revalideren.