Karl-Heinz Schulz

Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis

In recent years it has become clear that multiple sclerosis (MS) patients benefit from physical exercise as performed in aerobic training but little is known about the effect on functional domains and physiological factors mediating these effects. We studied immunological, endocrine and neurotrophic factors as well as coordinative function and quality of life during an 8-week aerobic bicycle training in a waitlist control design. In the immune-endocrine study (1) 28 patients were included, the coordinative extension study (2) included 39 patients. Training was performed at 60% VO(2)max after determining individual exertion levels through step-by-step ergometry. Metabolic (lactate), endocrine (cortisol, adrendocortico-releasing hormone, epinephrine, norepinephrine), immune (IL-6, soluble IL-6 receptor), and neurotrophic (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF)) parameters were compared from a prestudy and a poststudy endurance test at 60% VO(2)max for 30 min. In study (1), lowered lactate levels despite higher workload levels indicated a training effect. Disease-specific quality of life (as measured by the Hamburg Quality of Life Questionnaire for Multiple Sclerosis, HAQUAMS) significantly increased in the training group. No significant training effects were seen for endocrine and immune parameters or neurotrophins. In study (2), two out of three coordinative parameters of the lower extremities were significantly improved. In summary, low-level aerobic training in MS improves not only quality of life but also coordinative function and physical fitness.

Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls

Neurotrophins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are thought to play an important role in neuronal repair and plasticity. Recent experimental evidence suggests neuroprotective effects of these proteins in multiple sclerosis (MS). We investigated the response of serum NGF and BDNF concentrations to standardized acute exercise in MS patients and controls. Basal NGF levels were significantly elevated in MS. Thirty minutes of moderate exercise significantly induced BDNF production in MS patients and controls, but no differential effects were seen. We conclude that moderate exercise can be used to induce neutrophin production in humans. This may mediate beneficial effects of physical exercise in MS reported recently.

Evolution of Donor Morbidity in Living Related Liver Transplantation: A Single-Center Analysis of 165 Cases

Objective:During the last 14 years, living donor liver transplantation (LDLT) has evolved to an indispensable surgical strategy to minimize mortality of adult and pediatric patients awaiting transplantation. The crucial prerequisite to performing this procedure is a minimal morbidity and mortality risk to the healthy living donor. Little is known about the learning curve involved with this type of surgery. Patients and Methods:From January 1991 to August 2003, a total of 165 LDLTs were performed in our center. Of these, 135 were donations of the left-lateral lobe (LL, segments II and III), 3 were of the left lobe (L, segments II–IV), 3 were full-left lobes (FL, segments I–IV), and 24 were of the full-right lobe (FR, segments V–VIII). We divided the procedures into 3 periods: period 1 included the years 1991 to 1995 (LL, n = 49; L, n = 2; FR, n = 1), period 2 covered 1996 to 2000 (LL, n = 47), and period 3 covered 2001 to August 2003 (LL, n = 39; FR, n = 23; FL, n = 3; L, n = 1). Perioperative mortality and morbidity were assessed using a standardized classification. Length of stay in intensive care unit, postoperative hospital stay, laboratory results (bilirubin, INR, and LFTs), morbidity, and the different types of grafts in the 3 different periods were compared. Results:One early donor death was observed in period 1 (03/07/93, case 30; total mortality, 0.61.%). Since 1991, the perioperative morbidity has continually declined (53.8% vs. 23.4% vs. 9.2%). In period 1, 28 patients had 40 complications. In period 2, 11 patients had 12 complications, and in period 3, 6 patients had 9 complications. Within the first period, 1 donor underwent relaparotomy because of bile leakage. Postoperative hospital stay was 10 days, 7 days, and 6 days, respectively. Donation of the full right lobe, in comparison with that of the left lateral lobe, resulted in a significantly diminished liver function (bilirubin and INR) during the first 5 days after donation but did not increase morbidity. One donor from period 1 experienced late death caused by amyotrophic lateral sclerosis. Conclusions:In a single center, morbidity after living liver donation strongly correlates to center experience. Despite the additional risks associated with temporary reduction of liver function, this experience enabled the team to bypass part of the learning curve when starting right lobe donation. Specific training of the surgical team and coaching by an experienced center should be implemented for centers offering this procedure to avoid the learning curve.

Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial:

Background: Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. Objective: To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. Methods: Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4–6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8–10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. Results: A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. Conclusion: This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. Trial Registration: ISRCTN (trial number 76467492) http://isrctn.org

Physical exercise in multiple sclerosis: supportive care or a putative disease- modifying treatment

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease affecting young adults and leading to considerable disability. For many years, patients have been advised to avoid physical activity. Today, however, an increasing number of studies have shown beneficial effects of exercise training in MS. It has been reported that such programs not only improve fitness parameters but can also enhance quality of life and beneficially affect some suggestive disability measures. Pilot studies even indicate a neuroprotective potential. This review summarizes the findings of the major clinical trials on exercise in MS. Possible biological effect mediators, such as neurotrophic factors or anti-inflammatory cytokines, will be discussed. Exercise management guidelines will be proposed and possible further research strategies are presented.

Correlates of cognitive dysfunction in multiple sclerosis

Cognitive impairment is one of the most frequent symptoms in patients with multiple sclerosis (MS) but its underlying mechanisms are poorly understood. A number of pathogenetic correlates have previously been proposed including psychosocial factors (such as depression and fatigue), inflammation, neurodegeneration, and neuroendocrine dysregulation. However, these different systems have never been studied in parallel and their differential contributions to cognitive impairment in MS are unknown. We studied a well-characterized cohort of cognitively impaired (CI, n=25) and cognitively preserved (CP, n=25) MS patients based on a comprehensive neuropsychological testing battery, a test of hypothalamo-pituitary-adrenal axis functioning (dexamethasone-corticotropin-releasing hormone suppression test, Dex-CRH test) as well as peripheral blood and MRI markers of inflammatory activity. CI patients had significantly higher disability. In addition, CI patients showed higher levels of fatigue and depression. Fatigue was more closely associated with measures of attention while depression showed strongest correlations with memory tests. Furthermore, percentage of IFNγ-positive CD4+ and CD8+ T cells showed modest correlations with processing speed and working memory. MRI markers of inflammation or global atrophy were not associated with neuropsychological function. Compared to previous studies, the number of patients exhibiting HPA axis hyperactivity was very low and no correlations were found with neuropsychological function. We conclude that fatigue and depression are the main correlates of cognitive impairment, which show domain-specific associations with measures of attention and memory.

Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression

Objective Depression and fatigue are among the most common symptoms of multiple sclerosis (MS). These symptoms frequently co-occur and partially overlap in MS but their underlying biological substrates are unclear. In this study, the relative role of cytokines and hypothalamic–pituitary–adrenal (HPA) axis activity in depression and fatigue were examined in patients with relapsing–remitting MS (RRMS). Methods HPA axis function and frequency of stimulated cytokine (interferon γ (IFNγ) and tumour necrosis factor α (TNFα)) producing T cells was measured cross sectionally in 44 female patients with RRMS. All subjects completed a neurological examination, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and self-report questionnaires. Results 10 patients met diagnostic criteria for major depressive disorder (MDD). MS patients with comorbid MDD showed normal morning but elevated evening salivary cortisol levels, resulting in a flattened slope. While a higher frequency of cytokine producing CD8+ T cells was also seen in MS patients with MDD, these markers were more closely associated with fatigue than depression. Conclusions This study supports a role for HPA axis hyperactivity in major depression in MS. In addition, inflammatory and neuroendocrine factors may differentially mediate fatigue and depressive symptoms.

Endocrine and cytokine responses to standardized physical stress in multiple sclerosis

Since the earliest descriptions psychological and physical stress has been considered a controversial but potentially important factor in the onset and course of multiple sclerosis (MS). During recent years it has become clear that MS patients benefit from physical exercise as performed in aerobic training. As acute exercise has profound effects on immune and endocrine parameters we studied endocrine and immune response to standardized physical stress in MS within a study of aerobic training. Fifteen MS patients completed an eight-week aerobic training program, 13 patients were part of a wait-control group. Twenty healthy controls were recruited as well. A step-by-step bicycle ergometry was performed to determine individual exertion levels. For the endurance test patients exercised at 60% VO2 max for 30 min. Blood samples were drawn before, directly after and 30 min after completion of the exercise. Heart rate and lactate increased in all groups (p<.0001). We furthermore saw significant increases in endocrine parameters (epinephrine, norepinephrine, ACTH, and beta-endorphin; all p<.0001) in healthy individuals and in MS patients but without a differential effect. Whole-blood stimulated production of IFN-gamma (IFNgamma) was induced similarly in all groups (p<.01). TNF-alpha (TNFalpha) and IL-10 were less inducible in MS patients (trend). From these data we could not demonstrate a proinflammatory immune deviation in response to physical stress in MS. The observed trend of hyporesponsive TNFalpha and IL-10 responses in MS warrants further investigation.

Effects of a Physical Exercise Rehabilitation Group Program on Anxiety, Depression, Body Image, and Health-Related Quality of Life among Breast Cancer Patients

Background: Since physical exercise programs have the potential to help cancer patients regain physical fitness and may exert a range of positive consequences for recovery and psychological well-being, the impact of a physical exercise program was investigated in this prospective study. Patients and Methods: Women with primary nonmetastatic breast cancer after a minimum 4-week period post chemotherapy and/or radiotherapy completion were randomly assigned to one of 2 groups: intervention group (IG) (n = 30) and waiting group (WG) (n = 28). The 10-week twice weekly exercise group program consisted of gymnastics, movement games, relaxation, walking, and jogging. Anxiety, depression, body image, and quality of life were measured using standardized questionnaires. Maximal oxygen uptake (VO2max/kg) was assessed as a measure of physical fitness. Results: Patients in the IG improved significantly over time with regard to anxiety (p = 0.03, d = 0.45), depression (p = 0.05, d = 0.43), individual body image (p = 0.006, d = 0.44), and VO2max/kg (p < 0.001, d = 0.50), whereas no improvements were observed in the WG. However, this randomized controlled trial failed to demonstrate significant intervention effects in quality of life and social body image. Conclusions: This prospective study provided evidence for the effectiveness of a 10-week physical exercise intervention to significantly improve psychosocial wellbeing, individual body image, and physical fitness.

Cognitive abilities in children after liver transplantation

Background. The authors investigated the cognitive status during the late postoperative phase in children who had undergone liver transplantation (LTx). Methods. The authors examined 44 children who had undergone liver transplantation at their center. The children were 8.9±2.3 (mean±SD) years of age and had received the transplant 6.1±2.6 years previously. In 24 of the 44 children, a living-related transplantation had been carried out. Cognitive abilities were assessed with the three subscales of the Kaufman Assessment Battery for Children (K-ABC): the sequential processing scale (SES), the simultaneous processing scale (SIS), and the achievement scale (AS). Results. The children scored below the population mean but within the normal range on all subscales of the K-ABC. In the SIS and the AS, age at transplantation influenced the cognitive outcome, as the children who were younger at transplantation scored significantly better than the older children and their results were within the normal range. However, for the SES, no such differences were found. A multiple regression analysis revealed that duration of illness and height at transplantation predicts the performance in the SIS and the AS. To a lesser degree, type of transplantation (cadaveric vs. living-related) predicts performance in the AS. Performance in the SES was not predicted by any of these variables. Time since LTx and type of immunosuppressive regimen were not associated with the cognitive status after transplantation. Conclusions. Children who are younger, with a shorter duration of illness, and who are more physically developed before LTx have a better prognosis regarding their mental development. However, this result does not hold for sequential processing functions, which showed no relationship with any of these variables. This could indicate differential effects of liver disease and consecutive metabolic derangements on brain development during the preoperative phase.