Patient-rated long-term results after complete denervation of the wrist.

The aim of this study was to examine the long-term results after the denervation of the wrist. Between 1977 and 2001, we treated 375 patients in our clinic. The mean age was 43.5 years; 81% were male and 19% female. The long-term results were assessed by a questionnaire assessing pain on a visual analog scale and patient satisfaction and by the DASH questionnaire. After a mean follow-up of 12.23 years, we found an overall pain reduction of 52.1%. In 67.7% of the patients, we found a relief of pain: of these, 44% are free of pain until today and 56% were temporarily asymptomatic. Patients with a painful osteoarthritic condition without dynamic instability and good range of motion are ideal candidates to benefit from the denervation. The complete denervation of the wrist is an effective treatment option in patients with painful wrist conditions to reduce pain and improve the overall function.

Aß Induces Excitotoxicity Mediated by APC/C-Cdh1 Depletion That Can Be Prevented by Glutaminase Inhibition Promoting Neuronal Survival.

The E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is activated by the fizzy-related protein homolog/CDC20-like protein 1 (cdh1) in post-mitotic neurons. Growing evidence suggests that dysregulation of APC/C-Cdh1 is involved in neurodegenerative diseases. Here we show in neurons that oligomers of amyloid beta (Aß), a peptide related to Alzheimer's disease, cause proteasome-dependent degradation of cdh1. This leads to a subsequent increase in glutaminase (a degradation target of APC/C-Cdh1), which causes an elevation of glutamate levels and further intraneuronal Ca(2+) dysregulation, resulting in neuronal apoptosis. Glutaminase inhibition prevents glutamate excitotoxicity and apoptosis in Aß treated neurons. Furthermore, glutamate also decreases cdh1 and leads to accumulation of glutaminase, suggesting that there may be a positive feedback loop of cdh1 inactivation. We confirmed the main findings in vivo using microinjection of either Aß or glutamate in the CA1 region of the rat hippocampus. We show here for the first time in vivo that both Aß and glutamate cause nuclear exclusion of cdh1 and an increase in glutaminase. These results show that maintaining normal APC/C-Cdh1 activity may be a useful target in Alzheimer's disease treatment.

Reductive Stress: A New Concept in Alzheimer's Disease.

Reactive oxygen species play a physiological role in cell signaling and also a pathological role in diseases, when antioxidant defenses are overwhelmed causing oxidative stress. However, in this review we will focus on reductive stress that may be defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. This may occur in hypoxia and also in several diseases in which a small but persistent generation of oxidants results in a hormetic overexpression of antioxidant enzymes that leads to a reduction in cell compartments. This is the case of Alzheimer's disease. Individuals at high risk of Alzheimer's (because they carry the ApoE4 allele) suffer reductive stress long before the onset of the disease and even before the occurrence of mild cognitive impairment. Reductive stress can also be found in animal models of Alzheimer's disease (APP/PS1 transgenic mice), when their redox state is determined at a young age, i.e. before the onset of the disease. Later in their lives they develop oxidative stress. The importance of understanding the occurrence of reductive stress before any signs or symptoms of Alzheimer's has theoretical and also practical importance as it may be a very early marker of the disease.

[Decompression of Peripheral Nerves in the Treatment of Diabetic Polyneuropathy]. / Dekompression peripherer Nerven als Behandlungskonzept der diabetischen Polyneuropathie.

Polyneuropathy causing ulceration and amputation as a long-term consequence of diabetes mellitus is analysed for its pathophysiology, socioeconomic and medical relevance. Outcomes of decompression of peripheral nerves on the lower extremity regarding sensation, pain, development, and recurrence of ulceration, and amputation is evaluated by a systematic literature review in pubmed, medline and embase. Decompression of peripheral nerves in diabetic peripheral neuropathy seems to be a good treatment option for restoring sensation, decreasing pain, as well as for avoiding the development and recurrence of ulceration and amputation.

Molecular mechanisms linking amyloid ß toxicity and Tau hyperphosphorylation in Alzheimer׳s disease.

Neurofibrillary tangles (aggregates of cytoskeletal Tau protein) and senile plaques (aggregates mainly formed by amyloid ß peptide) are two landmark lesions in Alzheimer׳s disease. Some researchers have proposed tangles, whereas others have proposed plaques, as primary lesions. For a long time, these were thought of as independent mechanisms. However, experimental evidence suggests that both lesions are intimately related. We review here some molecular pathways linking amyloid ß and Tau toxicities involving, among others, glycogen synthase kinase 3ß, p38, Pin1, cyclin-dependent kinase 5, and regulator of calcineurin 1. Understanding amyloid ß and Tau toxicities as part of a common pathophysiological mechanism may help to find molecular targets to prevent or even treat the disease.

Aß and tau toxicities in Alzheimer's are linked via oxidative stress-induced p38 activation: protective role of vitamin E.

Oxidative stress is a hallmark of Alzheimer's disease (AD). We propose that rather than causing damage because of the action of free radicals, oxidative stress deranges signaling pathways leading to tau hyperphosphorylation, a hallmark of the disease. Indeed, incubation of neurons in culture with 5 µM beta-amyloid peptide (Aß) causes an activation of p38 MAPK (p38) that leads to tau hyperphosphorylation. Inhibition of p38 prevents Aß-induced tau phosphorylation. Aß-induced effects are prevented when neurons are co-incubated with trolox (the water-soluble analog of vitamin E). We have confirmed these results in vivo, in APP/PS1 double transgenic mice of AD. We have found that APP/PS1 transgenic mice exhibit a high level of P-p38 in the hippocampus but not in cortex and this is prevented by feeding animals with a diet supplemented with vitamin E. Our results underpin the role of oxidative stress in the altered cell signaling in AD pathology and suggest that antioxidant prevention may be useful in AD therapeutics.

[Acute and chronic calcium pyrophosphate dihydrate deposition disease in young patients]. / Das akute und chronische Kalksalzdepot der Hand beim Jugendlichen.

The acute calcium deposit belongs to the group of calcium pyrophosphate dihydrate deposition disease (CPPD). It occurs in adults. To our knowledge there is no report on an acute or chronic calcium deposit in children or adolescents. We report on 2 cases of acute and chronic calcium deposit in young patients.

Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment.

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.

[Current therapy of patients with dementia]. / Aktuelle Antidementiva. Demenzkranken steht eine moderne Therapie zu.

In recent years, the efficacy of symptomatic treatment in patients with Alzheimer's disease has repeatedly been demonstrated in a number of multicenter studies. Such treatment aims both to improve the patient's cognitive abilities and to preserve his or her quality of life and ability to cope with the activities of daily life. In this way the burden on relatives and caregivers is reduced, and the need for home or institutionalized care delayed. Causally effective therapeutic strategies resulting in a cure or the delaying of pathophysiological progression are currently not available, but are being investigated in ongoing clinical and experimental studies. Presently available treatments should be initiated early on, and applied as long as needed, which requires the earliest possible clinical diagnosis by the primary-care physician. The results of initial studies reveal an effect of antidementia agents also in mixed Alzheimer's and vascular dementia, as well as vascular and lewy-body dementia. Efforts to obtain approval for these indications are underway.