Modifiable Risk Factors for Accelerated Decline in Processing Speed: Results from Three Dutch Population Cohorts.

BACKGROUND: Several lifestyle, cardiovascular and psychosocial factors are associated with risk of cognitive decline and dementia. We studied the independent associations of a broad set of modifiable risk factors with decline in processing speed in three large population-based cohorts with up to 23 years of follow-up. METHODS: We used data of 9,666 participants from the Doetinchem Cohort Study, the Longitudinal Aging Study Amsterdam, and the Maastricht Aging Study. Decline in processing speed was measured with the letter digit substitution task or the alphabet coding task and modeled using quadratic latent growth curves. Associations of modifiable risk factors with level and rate of decline in processing speed were investigated by estimating associations with level of processing speed at different centering ages. RESULTS: Latent growth curves showed that decline in processing speed accelerated with age. Smoking, not drinking alcohol and depressive symptoms were associated with a lower level of processing speed in all cohorts. In two of the cohorts, more physical activity, drinking more than two glasses of alcohol per day, higher BMI and diabetes were associated with a lower level of processing speed. Depressive symptoms and diabetes were also associated with faster decline in processing speed. CONCLUSION: Several modifiable risk factors are associated with the level of processing speed in older age, while few are also related to the rate of decline.

Cognitive Functioning in Survivors of Hematopoietic Stem Cell Transplantation Compared With a Matched General Population Sample-The Maastricht Observational Study of Late Effects After Stem Cell trAnsplantation Study.

Although cognitive problems can recover over time, a subgroup of hematopoietic stem cell transplantation (HCT) survivors experience persistent cognitive problems in the long term. Despite these implications, studies assessing cognitive functioning in HCT survivors are limited. The aim of the present study was (1) to quantify the prevalence of cognitive impairment in patients treated with HCT who survived at least 2 years and to compare these with a matched reference group representing the general population; (2) to identify potential determinants of cognitive functioning within the HCT survivor group. Within the single-center Maastricht Observational study of late effects after Stem cell trAnsplantation, cognitive performance was assessed by a neuropsychological test battery divided into 3 cognitive domains: memory, information processing speed, and executive function and attention. An overall cognition score was calculated as the average of the domain scores. A total of 115 HCT survivors were group-matched on a 1:4 ratio to the reference group by age, sex, and level of education. Regression analyses adjusted for different sets of covariates including demographic and health- and lifestyle-related factors were used to test for differences in cognition between HCT survivors and the reference group resembling the general population. A limited set of clinical characteristics (diagnosis, type of transplant, time since treatment, conditioning regimen with total body irradiation and age at time of transplantation) were assessed as potential determinants of neurocognitive dysfunction among HCT survivors. Cognitive impairment was defined as scores in the cognitive domains < -1.5 standard deviation (SD) from what can be expected based on someone's age, sex, and education. The mean age at time of transplantation was 50.2 (SD ± 11.2) years, and the mean number of years after transplant was 8.7 (SD ± 5.7) years. The majority of HCT survivors were treated with autologous HCT (n = 73 [64%]). The prevalence of cognitive dysfunction was 34.8% in HCT survivors and 21.3% in the reference group (p = .002.) When adjusted for age, sex, and level of education, HCT survivors had a worse overall cognition score (b = -0.35; 95% confidence interval [CI], -0.55 to -0.16; p < .001), translating into 9.0 years of higher cognitive age. Analyses of specific cognitive domain scores showed that HCT survivors scored worse on memory (b = -0.43; 95% CI, -0.73 to -0.13; p = .005), information processing speed (b = -0.33; 95% CI, -0.55 to -0.11; p = .003), and executive function and attention (b = -0.29; 95% CI, -.55 to -.03; p = .031) than the reference group. The odds of cognitive impairment were on average 2.4 times higher among HCT survivors than the reference group (odd ratio = 2.44; 95% CI, 1.47-4.07; p = .001). Within the HCT survivor group none of the tested clinical determinants of cognitive impairment were significantly associated with cognition. This cohort study showed evidence for worse cognitive functioning in HCT survivors encompassing all three cognitive domains, respectively memory, information processing speed, and executive and attention compared to a reference group that represents the general population translating into nine years of faster cognitive ageing in HCT survivors than can be expected based on their chronological age. It is important to increase awareness for signs of neurocognitive dysfunction after HCT in clinicians and HCT survivors.

Iatrogenesis and neurological manifestations in the elderly.

Older people are often exposed to polypharmacy in a multimorbidity context. Inappropriate polypharmacy is often harmful, increasing the risk of inappropriate prescriptions and therefore adverse drug events (ADEs). Five to 20% of all hospital admissions are related to ADE in older people, among which 40 to 70% could be prevented. However, identifying ADEs and drug-related admissions in the elderly is challenging because ADEs often present as common geriatric problems such as falls, delirium, which might be due to the aging process, underlying diseases, and/or medications. In the pharmacovigilance database of the World Health Organization, drug-related neurological manifestations are the third reported cause of ADEs in the elderly, and neurological drugs are the third leading class of medications involved in ADEs. We must therefore be particularly vigilant, both in our prescriptions but also in our diagnoses to avoid prescribing inappropriate treatments and detect ADEs. Even though multiple pharmacologic changes occur in the elderly (absorption, distribution, drug metabolism and excretion), most of medications are still often prescribed at the same daily dosage as in young adults. When prescribing any drug for old patients, we should remember that daily intake should be adapted to these specificities, keeping in mind the old well-known aphorism "start low, go slow". In this review, we describe the main drug-related neurological manifestations (drug-induced movement disorders, falls, seizures, delirium, hypoglycemia, stroke, hyponatremia, peripheral neuropathy and myopathy, and serotonin syndrome) and the main drugs associated with neurological manifestations (dopamine receptor blocking agents, antithrombotics, anticholinergics, beta-lactams, antidepressants, benzodiazepines, mood stabilizers).

Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling.

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1nih ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17ß-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Arginase 1 deletion in myeloid cells affects the inflammatory response in allergic asthma, but not lung mechanics, in female mice.

BACKGROUND: (Over-)expression of arginase may limit local availability of arginine for nitric oxide synthesis. We investigated the significance of arginase1 (ARG1) for the development of airway hyperresponsiveness (AHR) and lung inflammation in female mice with ovalbumin (OVA)-induced allergic asthma. METHODS: Arg1 was ablated in the lung by crossing Arg1 fl/fl and Tie2Cre tg/- mice. OVA sensitization and challenge were conducted, and AHR to methacholine was determined using the Flexivent system. Changes in gene expression, chemokine and cytokine secretion, plasma IgE, and lung histology were quantified using RT-qPCR, ELISA, and immunohistochemistry, respectively. RESULTS: Arg1 ablation had no influence on the development of OVA-induced AHR, but attenuated OVA-induced increases in expression of Arg2 and Nos2, Slc7a1, Slc7a2, and Slc7a7 (arginine transporters), Il4, Il5 and Il13 (TH2-type cytokines), Ccl2 and Ccl11 (chemokines), Ifng (TH1-type cytokine), Clca3 and Muc5ac (goblet cell markers), and OVA-specific IgE. Pulmonary IL-10 protein content increased, but IL-4, IL-5, IL-13, TNFα and IFNγ content, and lung histopathology, were not affected. Arg1 elimination also decreased number and tightness of correlations between adaptive changes in lung function and inflammatory parameters in OVA/OVA-treated female mice. OVA/OVA-treated female mice mounted a higher OVA-IgE response than males, but the correlation between lung function and inflammation was lower. Arg1-deficient OVA/OVA-treated females differed from males in a more pronounced decline of arginine-metabolizing and -transporting genes, higher plasma arginine levels, a smaller OVA-specific IgE response, and no improvement of peripheral lung function. CONCLUSION: Complete ablation of Arg1 in the lung affects mRNA abundance of arginine-transporting and -metabolizing genes, and pro-inflammatory genes, but not methacholine responsiveness or accumulation of inflammatory cells.

A randomized placebo-controlled trial on the effects of Menthacarin, a proprietary peppermint- and caraway-oil-preparation, on symptoms and quality of life in patients with functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a very common condition affecting more than 10% of the population. While there is no cure, a few drugs have been found to be effective for the relief of symptoms, although most are only effective in a subgroup of patients. We assess and compare the efficacy of a fixed peppermint/caraway-oil-combination (Menthacarin) on symptoms and quality of life (QoL) in patients with FD symptoms consistent with epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). METHODS: In a prospective, double-blind, multicenter trial, 114 outpatients with chronic or recurrent FD were randomized and treated for 4 weeks with the proprietary peppermint- and caraway-oil-preparation Menthacarin or placebo (2×1 capsule/day). Improvement of abdominal pain and discomfort were used as co-primary efficacy measures (scores measured with the validated Nepean Dyspepsia Index). KEY RESULTS: After 2 and 4 weeks, active treatment was superior to placebo in alleviating symptoms consistent with PDS and EPS (P all <.001). After 4 weeks of treatment, pain and discomfort scores improved by 7.6±4.8 and 3.6±2.5 points (full analysis set; mean±SD) for Menthacarin and by 3.4±4.3 and 1.3±2.1 points for placebo, respectively. All secondary efficacy measures showed advantages for Menthacarin. CONCLUSIONS & INFERENCES: Menthacarin is an effective therapy for the relief of pain and discomfort and improvement of disease-specific QoL in patients with FD and significantly improves symptoms consistent with EPS and PDS.

Associations of advanced glycation end-products with cognitive functions in individuals with and without type 2 diabetes: the maastricht study.

CONTEXT: Advanced glycation end-products (AGEs) are thought to be involved in the pathogenesis of Alzheimer's disease. AGEs are products resulting from nonenzymatic chemical reactions between reduced sugars and proteins, which accumulate during natural aging, and their accumulation is accelerated in hyperglycemic conditions such as type 2 diabetes mellitus. OBJECTIVE: The objective of the study was to examine associations between AGEs and cognitive functions. DESIGN, SETTING, AND PARTICIPANTS: This study was performed as part of the Maastricht Study, a population-based cohort study in which, by design, 215 participants (28.1%) had type 2 diabetes mellitus. MAIN OUTCOME MEASURES: We examined associations of skin autofluorescence (SAF) (n = 764), an overall estimate of skin AGEs, and specific plasma protein-bound AGEs (n = 781) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition. RESULTS: After adjustment for demographics, diabetes, smoking, alcohol, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, and lipid-lowering medication use, higher SAF was significantly associated with worse delayed word recall (regression coefficient, b = -0.44; P = .04), and response inhibition (b = 0.03; P = .04). After further adjustment for systolic blood pressure, cardiovascular disease, estimated glomerular filtration rate, and depression, associations were attenuated (delayed word recall, b = -0.38, P = .07; response inhibition, b = 0.02, P = .07). Higher pentosidine levels were associated with worse global cognitive functioning (b = -0.61; P = .04) after full adjustment, but other plasma AGEs were not. Associations did not differ between individuals with and without diabetes. CONCLUSION: We found inverse associations of SAF (a noninvasive marker for tissue AGEs) with cognitive performance, which were attenuated after adjustment for vascular risk factors and depression.

ABO-compatible retransplantation after ABO-incompatible infant heart transplantation: absence of donor specific isohemagglutinins.

Implementation of ABO-incompatible (ABOi) pediatric heart transplantation has contributed to significant reduction in the mortality of infants on the waiting list, without increasing the risk of rejection. This has been attributed to the immature and therefore not fully competent immune system in this population group, which results in lower production of isohemagglutinins compared to older children and adults. Serial evaluations of isohemagglutinin titers in infants revealed cases with absence of donor specific anti-blood group antibodies. However, it is currently unknown whether continuous exposure to donor antigens is necessary to prevent formation of donor specific isohemagglutinins (DSI) in recipients. We are reporting a case of an infant who underwent ABOi heart transplantation, with no evidence of DSI even 4 years after ABO-compatible retransplantation. Hence, temporary exposure to donor antigens in infants may contribute to permanent absence of donor specific anti-blood group antibodies, suggesting the possibility of induced permanent B cell tolerance.

Glucocorticoids in myasthenia gravis - if, when, how, and how much?

Glucocorticoids (GC) are the most commonly used immune-directed therapy in myasthenia gravis (MG). However, to date, GC have not proven their effectiveness in the setting of a randomized clinical trial that complies with currently accepted standards. The rationale for the use of GC in MG is the autoimmune nature of the disease, which is supported by consistent positive results from retrospective studies. Well-defined recommendations for treatment of MG with GC are lacking and further hampered by inter- and intra-individual differences in the disease course and responses to GC treatment. Uncertainties concerning GC treatment in MG encompass the indication for treatment initiation, exact dosage, dose adjustment in specific conditions (e.g., pregnancy, thymectomy), mode of tapering, and surveillance of adverse events (AE). This review illustrates the mode of action of GC in the treatment for MG, presents the currently available data on GC treatment in MG, and attempts to translate the currently available information into clinical recommendations.

Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia.

RATIONALE AND OBJECTIVE: Arginase-1 is an important component of the intricate mechanism regulating arginine availability during immune responses and nitric oxide synthase (NOS) activity. In this study Arg1(fl/fl)/Tie2-Cre(tg/-) mice were developed to investigate the effect of arginase-1 related arginine depletion on NOS2- and NOS3-dependent NO production and jejunal microcirculation under resting and endotoxemic conditions, in mice lacking arginase-1 in endothelial and hematopoietic cells. METHODS AND RESULTS: Arginase-1-deficient mice as compared with control mice exhibited higher plasma arginine concentration concomitant with enhanced NO production in endothelial cells and jejunal tissue during endotoxemia. In parallel, impaired jejunal microcirculation was observed in endotoxemic conditions. Cultured bone-marrow-derived macrophages of arginase-1 deficient animals also presented a higher inflammatory response to endotoxin than control littermates. Since NOS2 competes with arginase for their common substrate arginine during endotoxemia, Nos2 deficient mice were also studied under endotoxemic conditions. As Nos2(-/-) macrophages showed an impaired inflammatory response to endotoxin compared to wild-type macrophages, NOS2 is potentially involved. A strongly reduced NO production in Arg1(fl/fl)/Tie2-Cre(tg/-) mice following infusion of the NOS2 inhibitor 1400W further implicated NOS2 in the enhanced capacity to produce NO production Arg1(fl/fl)/Tie2-Cre(tg/-) mice. CONCLUSIONS: Reduced arginase-1 activity in Arg1(fl/fl)/Tie2-Cre(tg/-) mice resulted in increased inflammatory response and NO production by NOS2, accompanied by a depressed microcirculatory flow during endotoxemia. Thus, arginase-1 deficiency facilitates a NOS2-mediated pro-inflammatory activity at the expense of NOS3-mediated endothelial relaxation.

Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice.

Asthma is a chronic inflammatory disease of the small airways, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. Recent studies suggest a role for arginase in asthma pathogenesis, possibly because arginine is the substrate for both arginase and NO synthase and because NO modulates bronchial tone and inflammation. Our objective was to investigate the importance of increased pulmonary arginase 1 expression on methacholine-induced AHR and lung inflammation in a mouse model of allergic asthma. Arginase 1 expression in the lung was ablated by crossing Arg1(fl/fl) with Tie2Cre(tg/-) mice. Mice were sensitized and then challenged with ovalbumin. Lung function was measured with the Flexivent. Adaptive changes in gene expression, chemokine and cytokine secretion, and lung histology were quantified with quantitative PCR, ELISA, and immunohistochemistry. Arg1 deficiency did not affect the allergic response in lungs and large-airway resistance, but it improved peripheral lung function (tissue elastance and resistance) and attenuated adaptive increases in mRNA expression of arginine-catabolizing enzymes Arg2 and Nos2, arginine transporters Slc7a1 and Slc7a7, chemokines Ccl2 and Ccl11, cytokines Tnfa and Ifng, mucus-associated epithelial markers Clca3 and Muc5ac, and lung content of IL-13 and CCL11. However, expression of Il4, Il5, Il10, and Il13 mRNA; lung content of IL-4, IL-5, IL-10, TNF-α, and IFN-γ protein; and lung pathology were not affected. Correlation analysis showed that Arg1 ablation disturbed the coordinated pulmonary response to ovalbumin challenges, suggesting arginine (metabolite) dependence of this response. Arg1 ablation in the lung improved peripheral lung function and affected arginine metabolism but had little effect on airway inflammation.

Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery: is there an impact of the genomic deletion of exon 3 in the growth hormone receptor (d3-GHR) gene on "safe" GH cut-off values?

BACKGROUND: Acromegaly is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. IGF-1, also known as somatomedin C, mediates several actions of GH. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing. Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. In such patients, GH may not always be a useful marker of disease, and traditional GH cut-offs may be misleading. Recent data suggest that soluble Klotho (sKlotho), besides and in addition to IGF-1, may help monitor the activity of GH-producing adenomas (presumably reflecting GH action on the kidneys) and may be a useful supplementary tool. METHODS: GHR genotyping was performed in 112 patients with acromegaly. IGF-1 and sKlotho levels were measured in the sera of patients before and after transsphenoidal surgery, with emphasis on patients judged inconclusively cured by surgery or with small residual tumour masses shortly after surgery. Patients were assessed for recurrence of acromegaly with GH levels (random or nadir during an oGTT). RESULTS: Of the 48 patients who underwent surgery between 2000 and 2009 and who had well-documented longer term follow-up at our institution, 29 had no biochemical evidence of residual disease activity after transsphenoidal surgery (marked reduction in IGF-1 and sKlotho levels, GH suppressible to <1 ng/ml) and were classified as in remission. 2 of these patients developed recurrent symptoms of acromegaly during follow-up with increasing levels of IGF-1 and sKlotho, and both patients were carriers of the d3-GHR genotype. CONCLUSIONS: Acromegalic patients with the d3-GHR polymorphism might be - for a given low postsurgical GH level - at higher risk for recurrence and may require a lower GH nadir during oGTT to be classified as in remission. Soluble Klotho could be useful in the follow-up of acromegalic patients. The question arises whether sKlotho not only reflects the activity of GH-secreting pituitary adenomas but whether Klotho (ectodomain clipping?) could also mediate selected actions of GH.

[Botulinum toxin for the treatment of spastic entropion. Case report]. / Botulinumtoxintherapie beim spastischen Entropium. Fallbericht.

Spastic entropion is a rare condition that predominantly affects older people. We report on a 74-year-old dementia patient who was successfully treated by botulinum toxin injections into the lower eyelid, thereby avoiding lid correction surgery. For patients with an increased risk of eyelid surgery, symptomatic therapy comprising botulinum toxin injections to the lower eyelid should be considered as an alternative treatment.

[Implant-related fractures of the femoral neck cone adapter of a modular short-stem hip prosthesis - patient management and operative technique]. / Implantatbedingte Brüche des Schenkelhals-Konusadapters einer modularen Kurzschaft-Hüftendoprothese - Patientenmanagement und OP-Technik.

AIM: In cases of unexpected and implant-related mechanical failures, optimal surgical treatment and provident information for the patients are mandatory. We describe the surgical method to revise the hip stem after fracture of the modular cone adapter of a short-stem hip prosthesis and the management of and information for all patients who have received a fracture-prone implant. METHOD: We present two out of four cases in a series of fractures of the femoral neck cone adapter of a modular short-stem hip prosthesis. The patients in our hospital were male, aged 69 and 52 years with a body weight of 73 and 88 kg. Implant failures occurred 18 and 20 months after the index THA. RESULTS: Using special instruments available at short notice, the revision operation can be carried out with a primary implant (case 2) with reasonable technical expenditure, unless pathological-anatomic reasons do not allow it (case 1 with varus-flexion deformity and a rotational deviation that required a revision long-stem with combined correction osteotomy). Once the implants were fully integrated and tightly secured to the bone, they were loosened with flexible thin chisels. Drilling a hole and a thread into the fractured cone adapter allows the connection of a removal instrument for implant extraction. The clinical and radiological examination showed good results with an HSS of 100 points at 24 months follow-up. Our institution decided to inform all 54 patients who had received the failure-prone implant device. The provision of advice to the patients at risk proved to be effective. CONCLUSIONS: When using new implants and procedures, the surgeons must inform the patients of hitherto unknown risks. The recipients of a failure-prone implant must be provided with comprehensive information. It is advisable for both the clinic and the manufacturer to contact the patients and advise them on how to cope with the situation. In most cases, the revision operation of the stem component can be performed with a primary implant without significant additional bone loss.

[Recruitment and activation of members in self-help organisations. Results of a survey of self-help organisations at the national level]. / Mitgliedergewinnung und -aktivierung in Selbsthilfeorganisationen. Ergebnisse einer Befragung von Selbsthilfeorganisationen auf Bundesebene.

The majority of the German population can envisage a membership in self-help groups or organisations when this should become relevant. As a matter of fact, only relatively few people are attending joint self-help activities. However, a significant number of members is important for self-help organisations (SHO) for self-organisation, lobbyism and (political) influence. Many SHOs in Germany are dissatisfied with their membership development and are therefore looking for better recruitment and activation strategies. The project "Activating Potentials for Joint Self-help Activities" (funded by the statutory health insurance fund BKK BV 10/2006-04/2009) is a participative collaboration between scientists, practitioners and SHO representatives to develop strategies and methods to promote access to joint self-help activities. In co-operation with the BAG SELBSTHILFE (a National HCPO Alliance) and the NAKOS (the National Clearing House for the Encouragement and Support of Self-Help Groups) 322 boards of national level SHOs were contacted in late 2007 and asked to complete a questionnaire on membership development, recruitment strategies and measures to activate members for voluntary commitment. 50% returned the questionnaire. The results were fed back in a transfer workshop in August 2008 and discussed with 60 representatives of SHOs. Their views are integrated in this paper. Despite all claimed stagnation or decline in membership development, the results show stability or increases over the last two years. Furthermore, the majority of SHOs was founded from the 1990 s until today, specifically in the areas of rare and chronic diseases. This development is based on a better socio-political recognition and promotion of self-help activities, self-help groups and SHOs as well as in better communication technologies. The views on the co-operation between SHOs and social service and health care providers are controversial: Positive and negative experience is more or less balanced. Then the openness and self-reflection of the workshop and survey participants is remarkable. In the context of a growing patient orientation in the health-care system participative co-operation in research and development will become more meaningful.

E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung.

BACKGROUND: Interactions of endothelial selectins with tumour cell glycoconjugates have been shown to have a major role in tumour cell dissemination in previous experiments. However, experiments validating this observation were limited in value, as 'metastases' in these experiments were artificially induced by i.v. injection rather than developed spontaneously as in true metastases. METHODS: Endothelial (E) and platelet (P)-selectin-deficient severe combined immunodeficient (scid) mice were generated and human HT 29 colon cancer cells were subcutaneously inoculated in these mice and in wild-type scid mice. Tumour growth, spontaneous metastasis formation in the lung and adherence of HT29 cells to E- and P-selectin under flow were determined. RESULTS: The number of metastases decreased by 84% in E- and P-selectin-deficient scid mice, compared with wild-type scid mice. The remaining 16% metastases in the E- and P-selectin-deficient scid mice grew within the pulmonary artery and not in the alveolar septae as they did in wild-type scid mice. Flow experiments indicate that tumour cells roll and tether on an E- and P-selectin matrix similar to leukocytes; however, firm adhesion is mainly mediated in E-selectin. CONCLUSION: Our results indicate that E- and P-selectins have a crucial role in spontaneous metastasis formation. As the human HT 29 colon cancer cells are positive for the lectin Helix pomatia agglutinin (HPA), which identified the metastatic phenotype in earlier clinical studies, these results are of particular clinical relevance.

Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation: a prospective randomized controlled trial.

OBJECTIVE: To investigate potential beneficial effects of donor treatment with methylprednisolone on organ function and outcome after liver transplantation. SUMMARY BACKGROUND DATA: It is proven experimentally and clinically that the brain death of the donor leads to increased levels of inflammatory cytokines and is followed by an intensified ischemia/reperfusion injury after organ transplantation. In experiments, donor treatment with steroids successfully diminished these effects and led to better organ function after transplantation. METHODS: To investigate whether methylprednisolone treatment of the deceased donor is applicable to attenuate brain death-associated damage in clinical liver transplantation we conducted a prospective randomized treatment-versus-control study in 100 deceased donors. Donor treatment (n = 50) consisted of 250 mg methylprednisolone at the time of consent for organ donation and a subsequent infusion of 100 mg/h until recovery of organs. A liver biopsy was taken immediately after laparotomy and blood samples were obtained after brain death diagnosis and before organ recovery. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction. Soluble serum cytokines were measured by cytometric bead array system. RESULTS: After methylprednisolone treatment, steroid plasma levels were significantly higher (P < 0.05), and a significant decrease in soluble interleukins, monocyte chemotactic protein-1, interleukin-2, interleukin-6, tumor necrosis factor-alpha, and inducible protein-10 was observed. Methylprednisolone treatment resulted in a significant downregulation of intercellular adhesion molecule-1, tumor necrosis factor-alpha, major histocompatibility complex class II, Fas-ligand, inducible protein-10, and CD68 intragraft mRNA expression. Significantly ameliorated ischemia/reperfusion injury in the posttransplant course was accompanied by a decreased incidence of acute rejection. CONCLUSIONS: Our present study verifies the protective effect of methylprednisolone treatment in deceased donor liver transplantation, suggesting it as a potential therapeutical approach.

12-year results with the cementless Bicontact SD stem in dysplastic and narrow femoral bone conditions.

AIM: The aim of the study was the evaluation of the medium- to long-term results of the cementless Bicontact SD hip arthroplasty, which was designed specially for narrow femoral medullary cavities. METHOD: From February 1992 to December 1996 115 patients (123 joints) were treated with a Bicontact SD stem and various cup implants through a posterior approach. In one third of cases, the indication was dysplastic osteoarthritis of various degrees of severity. RESULTS: Between November 2006 and May 2007 90 patients (98 hip joints) were followed up in a retrospective study after an average of 12.2 (10.1-15.1) years. The average Harris Hip Score was 93 (60-100) points and the Merle d'Aubigné score was 16.7 (5-18) points. A stem implant had to be regarded as loosened according to radiological criteria. One patient died 7 days postoperatively of a pulmonary embolism. CONCLUSION: The clinical and radiological results confirmed the proximal fixation concept in dysplastic femurs and narrow medullary cavities.

[Shoulder arthroplasty for treatment of the sequelae of proximal humerus fractures]. / Schulterendoprothetik bei posttraumatischen Deformitäten durch Frakturfolgen.

The sequelae of fractures of the proximal humerus can be of considerable clinical significance. Careful classification of the sequelae allows precise determination of whether correction osteotomy, reconstruction, or implantation of one of the various prostheses available is indicated. The integrity of the greater tuberosity, its position and continuous osseous integration to the metaphysis of the proximal humerus is the most important predictive factor for a good outcome following implantation of an anatomical shoulder prosthesis. When there is some incongruence of the glenohumeral joint while the greater tuberosity remains intact, shoulder arthroplasty can give a better clinical outcome than is seen after arthroplasty for a primary fracture. In the case of nonunion of subcapital fractures the results achieved by reconstruction, i.e. bone grafting and internal fixation using plates with fixed-angle blades, are superior to those possible with an anatomical prosthesis. Reverse shoulder arthroplasty gives better results than anatomical prostheses in the treatment of severe tuberosity malunion. The results of reverse shoulder arthroplasty for the sequelae of fractures are also influenced by the integrity of or damage to the soft tissues, the muscles of the rotator cuff (teres minor muscle), and bone. Secondary interventions for the sequelae of fractures of the proximal humerus are complex and involve high rates of complications and revisions.