Endoplasmic reticulum stress is accompanied by activation of NF-κB in amyotrophic lateral sclerosis.

BACKGROUND: Recent studies have indicated that endoplasmic reticulum (ER) stress is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, cells activate the unfolded protein response (UPR). Accumulating evidence from non-neuronal cell models suggests that there is extensive cross-talk between the UPR and the NF-κB pathway. METHODS: Here we investigated the expression of NF-κB and the main UPR markers X-box binding protein 1 (XBP1), basic leucine-zipper transcription factor 6 (ATF6) and phosphorylated eukaryotic initiation factor-2α (p-eIF2) in mutated SOD1(G93A) cell models of ALS, as well as their modulation by lipopolysaccharide and ER-stressing (tunicamycin) stimuli. RESULTS: Expression of NF-κB was enhanced in the presence of SOD1(G93A). Lipopolysaccharide did not induce the UPR in NSC34 cells and motor neurons in a mixed motor neuron-glia coculture system. The induction of the UPR by tunicamycin was accompanied by activation of NF-κB in NSC34 cells and motor neurons. CONCLUSION: Our data linked two important pathogenic mechanisms of ALS, ER stress and NF-κB signalling, in motor neurons.

The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis.

Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1(G93A) NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1(G93A) NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1(G93A) motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1(G93A) , providing evidence that ER stress plays a major role in ALS.

Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients.

We investigated the efficacy and tolerability of short-term treatment with tropisetron, a selective, competitive 5-HT3-receptor antagonist in fibromyalgia. The trial was designed as a prospective, multicenter, double-blind, parallel-group, dose-finding study. We randomly assigned 418 patients suffering from primary fibromyalgia to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily for 10 days. Clinical response was measured by changes in pain score, visual analog scale, tender point count and ancillary symptoms. Responders were prospectively defined as patients showing a 35% or higher reduction in pain score. Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) than placebo (26.2%) (p < 0.05). In the visual analog scale, the group administered 5 mg tropisetron showed a significant improvement (p < 0.05) and the group administered 10 mg tropisetron showed a nonsignificant clinical benefit. The number of painful tender points was significantly reduced (p = 0.002) in the 5 mg tropisetron group. Regarding ancillary symptoms, the 5 mg tropisetron group showed a significant improvement (p < 0.05) in sleep and dizziness. The patients' overall assessment of efficacy was significantly higher for 5 mg (p = 0.016) and 10 mg (p = 0.002) tropisetron than for placebo. The safety and tolerability of tropisetron was good; gastrointestinal tract symptoms were the most frequently reported adverse events. Short-term treatment of fibromyalgia patients with 5 mg tropisetron for 10 days proved to be efficacious and well tolerated. In this study a bell-shaped dose-response curve was seen.

Present state of medication therapy in fibromyalgia syndrome.

For the treatment of primary fibromyalgia syndrome (FMS) the low dose application of tri- and tetracyclic antidepressive drugs was often studied. Up to now from all those drugs the effects of amitriptyline (AMI) are best documented. Because of its sedative properties it doesn't only influence pain but also improves the often disturbed sleep. Its use in patients with FMS is limited by the occurrence of side effects and the lack of response in a substantial number of patients. Serotonin reuptake inhibitors alone seem to be of little value. Nevertheless there is evidence that they may improve pain in combination with other antidepressive agents. Regarding pain moclobemide a reversible inhibitor of monoamine oxidase seems to be inferior to AMI. In controlled studies corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) also failed to improve FMS. The combination of NSAIDs with benzodiazepines gave inconsistent results. Although often used, we have only small information about the effectiveness of opioids. No beneficial effect could be attributed to the muscle relaxant chlormezanone. In conclusion, although only about 1/3 of the patients respond, AMI remains the drug of first choice in the conventional medication treatment of FMS.

Efficacy and tolerability of tropisetron in primary fibromyalgia--a highly selective and competitive 5-HT3 receptor antagonist. German Fibromyalgia Study Group.

OBJECTIVE: Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. METHODS: In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. RESULTS: Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p=0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p<0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p<0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p=0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. CONCLUSIONS: This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen.

[Comparative evaluation of a German version of the Health Assessment Questionnaire and the Hannover Functional Capacity Questionnaire]. / Vergleichende Evaluation einer deutschen Version des Health Assessment Questionnaires (HAQ) und des Funktionsfragebogens Hannover (FFbH).

OBJECTIVE: To translate the Health Assessment Questionnaire Disability Index (HAQ) into a German version, to validate and to compare its properties with two different versions of the Hannover Functional Ability Questionnaire (HFAQ) in a German speaking population. METHODS: The test-retest reliability was tested by Pearson correlation in 32 outpatients of the Department of Rheumatology of the Medizinische Hochschule Hannover. For retesting, the questionnaire was mailed to them 1 week later. To validate the questionnaire it was administered to 110 inpatients in three different hospitals. All patients fulfilled the American College of Rheumatology 1987 revised criteria of rheumatoid arthritis (RA) or the Rome criteria of definitive inactive RA. The internal consistency was measured by Cronbach's coefficient alpha (CCA). To assess criterion validity we compared the HAQ and the two versions of the HFAQ with Keitel's test (KT) and the modified Steinbrocker classification (mSC). Construct validity was assessed by comparing these instruments with different clinical and laboratory variables. A multivariate analysis was used to identify the most important factors that are influencing the HAQ- and HFAQ-scores. RESULTS: Test-retest reliability of the HAQ was r = 0.94. CCA was 0.91 (HAQ), 0.90 (HFAQ-P) and 0.93 (HFAQ-PR). The KT Pearson correlation coefficients reached r = -0.73 (HAQ), r = +0.74 (HFAQ-P) and r = +0.71 (HFAQ-PR). The mSC correlated r = +0.75 (HAQ), r = -0.72 (HFAQ-P) and r = -0.70 (HFAQ-PR). The correlation coefficients of HAQ/HFAQ-P was r = -0.87 and of HAQ/HFAQ-PR r = -0.88. The correlations between other clinical and laboratory variables reached from r = +/-0.58 (pain/HAQ) to r = +/-0.11 (number of swollen joints/HFAQ-PR). In backward multiple regression analysis 59-64% of the variance of disability measured by the questionnaires was explained predominantly by pain (32-33%) and by range of motion (16-21%). CONCLUSION: The German version of the HAQ presented here and the two versions of the HFAQ are reliable and valid instruments for measuring functional disability in a German-speaking population with RA. The construct measured by the HAQ and both versions of the HFAQ showed a high degree of correspondence.

[Acupuncture in treatment of inflammatory rheumatic diseases]. / Akupunktur bei der Behandlung entzündlich-rheumatischer Erkrankungen.

Seventeen studies were examined with regard to efficacy and scientific quality of acupuncture in rheumatoid arthritis, spondarthropathy, lupus erythematosus, local and progressive systemic scleroderma. Acupuncture cannot be recommended for treatment of these diseases. By far, the most studies examined failed to show sufficient quality.

Detecting malnutrition at age 6-12 months: international comparisons of arm circumference v. standard anthropometry.

Growth faltering, which may herald protein-energy malnutrition (PEM) usually begins between ages 6 and 12 months. However, arm circumference (AC or MUAC) has mainly been used to screen for PEM between 12 and 60 months of age, when AC is age-independent. This study of 378 infants aged 6-12 months in Pakistan, Nepal, Sierra Leone, and Papua New Guinea showed that a cut-off 12.5 cm AC selects infants < 80 per cent weight-for-age (WA) with 76 per cent sensitivity and 90 per cent specificity. Of the 378 infants studied 131 (35 per cent) had WA < 80 per cent and 126 (33 per cent) had AC < 12.5 cm. Weight-for-length agreed less well with AC. The inter-regional prevalence range of AC < 12.5 cm was 29-40 per cent, while the WA < 80 per cent range was 27-45 per cent. When AC is plotted against age, a flat 'plateau' (slope = 0.04) shows age-independence between 6 and 12 months in these 378; this contrasts to the 10 per cent AC increase in European reference populations. Because this AC plateau parallels the WA plateau seen between 6 and 12 months of age in most developing nations, AC < 12.5 cm may provide a simple and valid screening test for early PEM in this crucial age bracket. Conformatory studies elsewhere are indicated.

Comparisons of spontaneous pain and tenderness in patients with primary fibromyalgia.

Pain was assessed in 47 patients with fibromyalgia in the University Rheumatology Clinic in Basle with the aid of three different techniques. First, a simple visual analog scale was used, later a body diagram on which patients could indicate pain separately in different regions of the body (pain score) and, finally, dolorimetric measurements at 56 typical PFS tender points. After four weeks of therapy, pain was again scored by patients using these techniques. The changes in assessment were compared with the aid of Spearman correlation. Data recorded with the aid of the body diagram correlated better with dolorimetric findings than did the results obtained from a simple visual analog scale. The severity of the disease can be more objectively assessed using these three techniques than it can using only the visual analog scale. In particular, the pain score and dolorimetry make possible a clear assessment of the value of therapeutic regimens.

[The course and topography of pain in generalized tendomyopathies]. / Schmerzverlauf und -topographie bei generalisierten Tendomyopathien.

The generalized tendomyopathy (fibromyalgia) is characterized by the characteristic picture of multilocular pain symptoms, severe pressure-type pain in the tendon insertions and muscles, vitality deficiency, sleep disturbance and other vegetative disorders as well as functional complaints and is often also characterized by an altered psychological condition. Nevertheless, the disease is often not recognized, resulting in extensive superfluous diagnostic procedures and sometimes invasive and useless therapeutic measures. The disorder develops on average in the 37th year of life and initially affects, mostly monolocular, the cervical and lumbar region. The further course of the disease is progressive or recurrent and extends over years, often over decades. The patients' quality of life is markedly impaired and in many cases they are no longer able to carry out their occupational and household work. The socioeconomic significance of the generalized tendomyopathy probably exceeds that of chronic polyarthritis. One problem is the still poor therapeutic possibilities and also the assessment of the treatment. It is, therefore, of great importance to follow the course of the disease and the pain course via hand measurement methods, so as to enable the evaluation of new, but also known therapies. Measuring instruments, which record the intensity and the topography of the pain, such as dolorimetry and the pain score, will be presented and discussed. One of the newest possibilities is the computerized recording of the current symptoms, which is made by the patient himself by means of an electronic pain diary.

[Generalized tendomyopathy. I: Clinical aspects, follow-up and differential diagnosis]. / Die generalisierte Tendomyopathie (GTM). Teil I: Klinik, Verlauf und Differentialdiagnose.

Generalized tendomyopathy (GTM), or fibromyalgia, is a disorder characterized by diffuse pain in the musculoskeletal apparatus which usually begins at a single site, e.g., as low-back pain or cervical syndrome, and develops into generalized pain over months or years. It is accompanied by increased tenderness at characteristic tender points, although the pain threshold on the whole is reduced. In addition to the main symptoms (pain in the musculoskeletal system, tenderness at the tender points), autonomic and functional symptoms are almost invariably present and are often accompanied by pathological psychological findings such as neuroses and depression. To date, no reliable laboratory parameters or pathognomonic histological findings have been identified. The disorder affects primarily women, beginning around the age of 35 and reaching its peak during or after the menopause. It also affects young people and those over age 60, although it is much less common in these cases. Secondary forms are observed particularly in rheumatoid arthritis. The differential diagnosis must first distinguish primary GTM from the secondary forms. There must also be further differentiation between internal and psychiatric disorders and primary GTM. This can be achieved in many cases by careful clinical diagnosis, although a more complete examination is sometimes required.

[Generalized tendomyopathy. II: Pathogenesis and therapy]. / Die generalisierte Tendomyopathie (GTM). Teil II: Pathogenese und Therapie.

Many factors are known to play a role in the pathogenesis of generalized tendomyopathy (GTM), or fibromyalgia. While the secondary forms develop along with known diseases, particularly rheumatoid arthritis, the cause of primary GTM is often not well understood. The fact that this disorder usually appears first at a single site, e.g., as low-back pain or cervical syndrome in which poor posture or malformation of the spine can be observed, gives rise to the theory that local changes in the spine or the joints are particular underlying causes of the initial manifestation. As the disorder becomes generalized, however, psychological causes predominate. Psychosocial factors in particular seem to further the process of generalization. Therapy can take many forms. Above all, it calls for an understanding attitude on the part of the managing physician and, whenever, possible, elimination of likely causal factors. Analgesics and antiinflammatories are often inadequate; antidepressants and neuroleptics provide more effective relief. Moreover, intensive physiotherapy and psychotherapy are necessary. GTM in many cases is resistant to treatment despite intensive management, although it often subsides naturally after age 60. Recognizing GTM is of great importance in order to initiate appropriate treatment promptly, avoid incorrect diagnoses and their consequences, e.g., repeat surgery, and to prevent premature disability.

[Hyaluronic acid and N-terminal procollagen-III-peptide in the urine in inflammatory and degenerative joint diseases]. / Hyaluronsäure und N-terminales Prokollagen-III-Peptid im Urin bei entzündlichen und degenerativen Gelenkerkrankungen.

In a cross-sectional study of 130 patients (main diagnosis: rheumatoid arthritis, n = 41, osteoarthritis, n = 39; ankylosing spondylitis, n = 28) we measured the concentrations of hyaluronan (HA) and the N-terminal propeptide of type-III collagen (NP III P) in urine and evaluated the relationship with their serum levels. Increased HA levels in serum correlated with increased urinary excretion (r = 0.69 for patients with active rheumatoid arthritis). Only patients with rheumatoid arthritis showed significantly elevated HA concentrations in urine (mean = 1,493 micrograms/mmol creatinine). Because of relatively wide fluctuations in urinary HA in normals (mean = 944, standard deviation 818 micrograms/mmol creatinine) and only modest differences between groups, the diagnostic accuracy of urinary HA measurements is inferior to serum determinations. NP III P showed no significant differences between patients and controls (means 10.5 to 15 micrograms/mmol creatinine). Obviously, renal excretion is of minor importance in the metabolism of HA and NP III P. The possible diagnostic usefulness of determinations of these parameters in serum is not enhanced by measurements in urine.

[Localized pressure pain in the diagnosis of generalized tendomyopathy (fibromyalgia)]. / Lokalisierte Druckschmerzen in der Diagnose der generalisierten Tendomyopathie (Fibromyalgie).

56 tender points were examined in 100 patients and 50 age- and sex-matched healthy volunteers using a dolorimeter. 24 of the 56 points were especially selected according to ability of discrimination, best possible distribution on the body, and easy localization. All 56 points as well as the 24 specially selected points were examined as to their sensitivity and specificity in the diagnosis of generalized tendomyopathy. The sensitivity and the specificity for both point-combinations were acceptable. The sensitivity and specificity of the 24 points were superior to the 56 points in the case of discrimination ability. A 100% sensitivity and specificity could not, however, be achieved. It remains to be considered if functional and vegetative symptoms must still be used to support the diagnosis of generalized tendomyopathy (fibromyalgia).

[Measuring pressure pain of tendons and muscles in healthy probands and patients with generalized tendomyopathy (fibromyalgia syndrome)]. / Die Messung von Druckschmerzen im Bereich von Sehnen und Muskeln bei Gesunden und Patienten mit generalisierter Tendomyopathie (Fibromyalgie-Syndrom).

A newly developed dolorimeter was tested by repeated measurements in 25 healthy volunteers to demonstrate its reliability. Repeated measurements at 12 different points demonstrated good correlation. Measurements at these points gave a highly significant difference between 100 patients with generalized tendomyopathy (fibrositis-syndrome/fibromyalgia) and a group of 50 age- and sex-matched healthy volunteers.

[Serum hyaluronic acid and aminoterminal procollagen III peptide in inflammatory and degenerative joint diseases]. / Serum-Hyaluronsäure und aminoterminales Prokollagen-III-Peptid bei entzündlichen und degenerativen Gelenkerkrankungen.

Serum levels of hyaluronic acid (HA) and the amino-terminal type III procollagen peptide (NP-III-P) were determined simultaneously by specific immunoassays in patients with rheumatoid arthritis (n = 41), osteoarthritis (n = 43), ankylosing spondylitis (n = 7), psoriatic arthritis (n = 6), and reactive arthritis (n = 6). Increased serum levels of both HA and NP-III-P, were found in rheumatoid arthritis and - although less pronounced - in osteoarthritis, differing significantly from age- and sex-matched controls (n = 77). Furthermore, patients suffering from active rheumatoid arthritis showed higher serum levels of both antigens than patients with inactive disease, and significant correlations were found in rheumatoid arthritis between acute phase plasma proteins, HA and NP-III-P, respectively. In contrast, determination of low molecular weight fractions of NP-III-P by Fab- assay proved not to be useful in regard to clinical application. No significant effects of anti-inflammatory treatment were evident in any of the parameters. In rheumatoid patients, the serum concentrations of HA were found to correlate positively with the serum reactivity of NP-III-P related antigens (r = 0.692) and with the excretion of urinary pyridinoline (r = 0.455). Thus, both parameters seem to reflect similar mechanisms of connective tissue activation and may be related to inflammatory activity in joint diseases.

[Accident during local anesthesia in a patient with antiarrhythmic therapy]. / Zwischenfall während der Lokalanästhesie bei einem Patienten unter antiarrhythmischer Therapie

A side reaction of antiarrhythmic treatment in a 18-year-old patient with congestive cardiomyopathy is reported. During treatment with high doses of aprindine cerebral convulsions occurred. After ceasing the medication temporarily, a pacemaker revision was done in local anesthesia. Cerebral convulsions reappeared after injection of the local anesthetic. The patient died due to cardiac arrest. It is discussed that some amount of the local anesthetic agent (mepivacaine) was absorbed from the tissue elevating the blood level of local anesthetic drugs (aprindine and mepivacine) into the toxic range, thus producing cerebral convulsions, augmenting the stimulation threshold and depressing the automaticity of the heart. It is urged that antiarrhythmic treatment should be stopped before local anesthesia will be performed.