Comparison of adverse events of biologicals for treatment of juvenile idiopathic arthritis: a systematic review.

Objectives: Treatment of juvenile idiopathic arthritis has changed rapidly since the introduction of various biologics almost twenty years ago. Many clinical trials have been performed to monitor efficacy and safety of new agents. The aim of this review is to summarize safety concerns, which were observed during prospective clinical trials. Methods: Since etanercept was the first biologic approved and remains the most frequently used, as first biologic in polyarticular JIA patients, the authors calculated the relative risk of the adverse events for all examined biologicals and compared the values with the value of etanercept. Results: Relative rates for all adverse events showed similar rates for etanercept, infliximab, golimumab, and tocilizumab, whereas adalimumab showed higher rates and abatacept lower rates. Comparison of rates for serious adverse events demonstrated, that rates seemed comparable for etanercept, adalimumab, infliximab, and tocilizumab. Again, abatacept showed a lower rate, whereas golimumab seems to have a higher relative risk for serious adverse events. Rate of infection was lowest in patients treated with abatacept or tocilizumab, patients treated with etanercept, adalimumab and Infliximab again had similar rates. Conclusion: The safety profiles of actually approved biologics are highly acceptable. However, further observation, especially long-term observation through registry studies, is required.

Neural reward processing in individuals remitted from major depression.

BACKGROUND: Dysfunctional behavioural and neural processing of reward has been found in currently depressed individuals. However, little is known about altered reward processing in remitted depressed individuals. METHOD: A total of 23 medication-free individuals with remitted major depressive disorder (rMDD) and 23 matched healthy controls (HCs) performed a reward task during functional magnetic resonance imaging. We also investigated reward dependence, novelty seeking and harm avoidance using the Tridimensional Personality Questionnaire and their association with neural responses of reward processing. RESULTS: Compared to HCs, individuals with rMDD exhibited enhanced responses to reward-predicting cues in the hippocampus, amygdala and superior frontal gyrus. When reward was delivered, rMDD subjects did not significantly differ from HCs. In both groups neural activity during reward anticipation was negatively correlated with harm avoidance. CONCLUSIONS: Our results show that rMDD is characterized by hyperactivation in fronto-limbic regions during reward anticipation. Alterations in neural activation during reward processing might reflect an increased effort in remitted depressed individuals to allocate neural activity for executive and evaluative processes during anticipatory reward processing.

Rationale and design of INTERSTROKE: a global case-control study of risk factors for stroke.

UNLABELLED: Stroke is a major global health problem. It is the third leading cause of death and the leading cause of adult disability. INTERHEART, a global case-control study of acute myocardial infarction in 52 countries (29,972 participants), identified nine modifiable risk factors that accounted for >90% of population-attributable risk. However, traditional risk factors (e.g. hypertension, cholesterol) appear to exert contrasting risks for stroke compared with coronary heart disease, and the etiology of stroke is far more heterogeneous. In addition, our knowledge of risk factors for stroke in low-income countries is inadequate, where a very large burden of stroke occurs. Accordingly, a similar epidemiological study is required for stroke, to inform effective population-based strategies to reduce the risk of stroke. METHODS: INTERSTROKE is an international, multicenter case-control study. Cases are patients with a first stroke within 72 h of hospital presentation in whom CT or MRI is performed. Proxy respondents are used for cases unable to communicate. Etiological and topographical stroke subtype is documented for all cases. Controls are hospital- and community-based, matched for gender, ethnicity and age (+/-5 years). A questionnaire (cases and controls) is used to acquire information on known and proposed risk factors for stroke. Cardiovascular (e.g. blood pressure) and anthropometric (e.g. waist-to-hip ratio) measurements are obtained at the time of interview. Nonfasting blood samples and random urine samples are obtained from cases and controls. Study Significance: An effective global strategy to reduce the risk of stroke mandates systematic measurement of the contribution of the major vascular risk factors within defined ethnic groups and geographical locations.

Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression and dysthymia.

BACKGROUND: The experience of uncontrollability and helplessness in the face of stressful life events is regarded as an important determinant in the development and maintenance of depression. The inability to successfully deal with stressors might be linked to dysfunctional prefrontal functioning. We assessed cognitive, behavioural and physiological effects of stressor uncontrollability in depressed and healthy individuals. In addition, relationships between altered cortical processing and cognitive vulnerability traits of depression were analysed. METHOD: A total of 26 unmedicated depressed patients and 24 matched healthy controls were tested in an expanded forewarned reaction (S1-S2) paradigm. In a factorial design, stressor controllability varied across three consecutive conditions: (a) control, (b) loss of control and (c) restitution of control. Throughout the experiment, error rates, ratings of controllability, arousal, emotional valence and helplessness were assessed together with the post-imperative negative variation (PINV) of the electroencephalogram. RESULTS: Depressed participants showed an enhanced frontal PINV as an electrophysiological index of altered information processing during both loss of control and restitution of control. They also felt more helpless than controls. Furthermore, frontal PINV magnitudes were associated with habitual rumination in the depressed subsample. CONCLUSIONS: These findings indicate that depressed patients are more susceptible to stressor uncontrollability than healthy subjects. Moreover, the experience of uncontrollability seems to bias subsequent information processing in a situation where control is objectively re-established. Alterations in prefrontal functioning appear to contribute to this vulnerability and are also linked to trait markers of depression.

Development of alcohol-associated cues and cue-induced brain activation in alcoholics.

The objective of this study was to develop new standardized alcohol-associated cues and assess their effects on brain activation with functional magnetic resonance imaging (fMRI). Pictures of alcoholic and neutral beverages and affectively neutral pictures were presented to 44 abstinent alcoholics and 37 age-matched healthy control subjects. We assessed the skin conductance response, and the elicited arousal and valence. Alcoholics and control subjects did not differ in arousal, valence or skin conductance response evoked by alcohol-associated and affectively neutral stimuli, while nonalcoholic beverages were rated as more unpleasant and arousing by alcoholics compared with control subjects. In the fMRI pilot study, alcohol and abstract pictures were presented to six abstinent alcoholics and induced a significant activation of brain areas associated with visual emotional processes such as the fusiform gyrus, parts of the brain reward system (basal ganglia and orbitofrontal gyrus) and further brain regions in the frontal and parietal cortices associated with the attention network. These observations suggest that standardized pictures of alcoholic beverages can be used to assess brain circuits involved in the processing and evaluation of alcohol cues.

cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein.

The receptor for advanced glycation end products (RAGE) has been proposed as a cell surface receptor that binds amyloid-beta protein (Abeta), thereby triggering its cytotoxic effects [S.D. Yan, X. Chen, J. Fu, M. Chen, H. Zhu, A. Roher, T. Slattery, L. Zhao, M. Nagashima, J. Morser, A. Migheli, P. Nawroth, D. Stern, A.M. Schmidt, RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease, Nature 382 (1996) 685-691.]. A cDNA library of human lung was screened for RAGE with an appropriate hybridization probe. In addition to cell surface RAGE, one clone was found which encodes a new version of RAGE, termed hRAGEsec, which lacks the 19 amino acids of the membrane-spanning region and is therefore secreted. Comparison with the genomic sequence revealed that the synthesis of the secreted isoform requires alternative splicing. The deduced protein sequence of the mature hRAGEsec consists of 321 amino acids with a predicted molecular mass of 35.66 kDa. The pattern of expression of hRAGEsec in human brain was analyzed by in situ hybridization histochemistry. The most intense expression of the gene in contrast to cell surface RAGE was detected in hippocampal CA3 pyramidal cells, dentate gyrus granule cells, cortical neurons as well as glial cells in white matter. To investigate the interaction between Abeta and RAGE and another scavenger receptor, SRA, under physiological conditions, they were co-expressed with human betaAPP(695)-SFAD in a human cell and the level of Abeta in the condition medium was assessed by immunoprecipitation and enzyme-linked immunosorbent assay (ELISA) analysis. A nearly 100% reduction of Abeta from the conditioned medium of hRAGE cells and approximately 40% reduction from the SRA-cells implied that hRAGE could be a prominent cell surface receptor interacting with Abeta.

Experimental cranial pain elicited by capsaicin: a PET study.

Using a positron emission tomography (PET) study it was shown recently that in migraine without aura certain areas in the brain stem were activated during the headache state, but not in the headache free interval. It was suggested that this brain stem activation is inherent to the migraine attack itself and represents the so called 'migraine generator'. To test this hypothesis we performed an experimental pain study in seven healthy volunteers, using the same positioning in the PET scanner as in the migraine patients. A small amount of capsaicin was administered subcutaneously in the right forehead to evoke a burning painful sensation in the first division of the trigeminal nerve. Increases of regional cerebral blood flow (rCBF) were found bilaterally in the insula, in the anterior cingulate cortex, the cavernous sinus and the cerebellum. Using the same stereotactic space limits as in the above mentioned migraine study no brain stem activation was found in the acute pain state compared to the pain free state. The increase of activation in the region of the cavernous sinus however, suggests that this structure is more likely to be involved in trigeminal transmitted pain as such, rather than in a specific type of headache as was suggested for cluster headache.

Factors predicting the subjective well-being of nations.

Subjective well-being (SWB) in 55 nations, reported in probability surveys and a large college student sample, was correlated with social, economic, and cultural characteristics of the nations. The SWB surveys, representing nations that include three fourths of the earth's population, showed strong convergence. Separate measures of the predictor variables also converged and formed scales with high reliability, with the exception of the comparison variables. High income, individualism, human rights, and societal equality correlated strongly with each other, and with SWB across surveys. Income correlated with SWB even after basic need fulfillment was controlled. Only individualism persistently correlated with SWB when other predictors were controlled. Cultural homogeneity, income growth, and income comparison showed either low or inconsistent relations with SWB.

In patients with common variable immunodeficiency, interleukin-6 and expression of its receptor on B-cells are normal.

In a group of patients suffering from common variable immunodeficiency (CVID), levels of interleukin-6 (IL6) were measured and found to be in the normal range or even increased, for single patients. IL6 production of peripheral blood mononuclear cells was shown to be in the normal range when corrected for monocyte number. To exclude the possibility that the Interleukin-6 receptor (IL6R) on B-cells is missing, its expression was measured by assessing the binding of a Phycoerythrin-derivative of IL6 by flow cytometry and correlated with various markers for B-cells and T-cells. As compared with normal controls, no statistically significant deviation of the group as a whole nor for individual patients could be shown. It was concluded that lack of B cell differentiation in the presence of normal to high IL6 as shown for these patients is not due to inability of the B cells to detect IL6 in the serum.

[In vitro IL-6- and immunoglobulin-production in patients with variable immunodeficiency syndrome (CVID)]. / In vitro IL-6- und Immunglobulin-produktion bei Patienten mit variablem Immundefektsyndrom (CVID).

In vitro immunoglobulin and IL-6 synthesis were investigated in patients with CVID and healthy controls. The IL-6 production was increased in CVID patients. However, after calibration to equal monocyte counts in the mononuclear cell population the difference between patients and controls was no longer significant. The immunoglobulin production in CVID was decreased but no correlation between immunoglobulin and IL-6 production was found. From these results we suggest that monocyte activation might be of importance in terms of secondary organ lesions frequently occurring in CVID patients.

Detection of crossreactive determinants in grass pollen extracts using monoclonal antibodies against group IV and group V allergens.

Monoclonal antibodies (MoAb) to defined allergens of P. pratense were raised. Five of them were selected for detailed studies by means of immunoblotting after SDS-PAGE and IEF of extracts from P. pratense and L. perenne. Three antibodies (1D11, 3B2, 2D1) recognize structures with mol. wt of 29 and 34 kD and pI of 4.8-7.6, corresponding to group V allergens. Two other MoAbs (2D8, 3C4) are directed against strong basic structures with a mol. wt of 50 kD and pI of 7.8-9.5 according to group IV allergens. The specificity of antibodies was supported by direct ELISA with purified group V and IV allergens. The isolated allergens were characterized before by SDS-PAGE and CIE and that allergenicity was detected with sera of patients with allergic rhinitis. Using our selected MoAbs crossreactive epitopes on group V and IV allergens have been excluded. Our antibodies have been used to detect crossreactivity in 14 grass pollen extracts. The evaluation of the pollen extracts has been performed by enzyme immunoassay (EIA) inhibition. One MoAb (3C4) is able to recognize group IV allergens in all grass species analysed whereas the MoAb 2D8 seems to identify group IV structures in selected grasses only. Binding to conserved structures of group V has been proved for MoAb 1D11. Other group V specific MoAbs (2D1, 3B2) identify similar, however incomplete, spectra. These results have been confirmed also by the dot immunobinding assay.

Peritonitis caused by Trichomonas--a preliminary case report.

Trichomonas infections of the abdominal cavity are uncommon and case histories have not been published previously. A patient to whom reference is made this paper developed a combined immunodeficiency syndrome and portal hypertension with ascites on the basis of a cirrhosis of the liver. This seems to have been the precondition for a peritonitis caused by a Trichomonas species.

Antisecretory effect of prostaglandin D2 in rat colon in vitro: action sites.

The effect of prostaglandin D2 (PGD2) on colonic ion transport was studied in the Ussing chamber. PGD2 (10(-6) M) decreased baseline short-circuit current (Isc) in two preparations of rat colon descendens, a mucosa-submucosa preparation with and a mucosa preparation without the submucosal plexus. In both preparations, PGD2 inhibited the neuronally mediated secretory responses to electric field stimulation, the sea anemone toxin ATX II, and different cholinergic agents. Unidirectional flux measurements revealed that PGD2 diminished the secretagogue-induced increase in the serosal-to-mucosal flux of Cl- and thereby inhibited net Cl- secretion. PGD2, however, had no effect on the adenosine 3',5'-cyclic monophosphate-mediated response to forskolin or vasoactive intestinal peptide or on guanosine 3',5'-cyclic monophosphate-mediated secretion induced by the heat-stable enterotoxin of Escherichia coli. The PGD2 also blocked the increase in Isc evoked by two neuronally acting inflammatory mediators, i.e., bradykinin and PGI2 in the mucosa-submucosa preparation, but had no effect on the response to PGE2. Consequently, PGD2 exerts an indirect antisecretory effect caused by an inhibition of enteric secretomotor neurons of both the submucosal and the mucosal plexus.

[An avoidable cause of parental anxiety and unnecessary medical workup: diaper crystals (pannolithiasis)]. / Eine vermeidbare Ursache von elterlicher Besorgnis und unnötigen medizinischen Abklärungen: Windelsteine (Pannolithiasis).

Five infants aged 6 to 23 months had a history of passing crystals in urine. They were not ill, but micturition was reported to be associated with pain in two of them. Physical examination was normal, and urinalysis and culture were negative. In one case we observed "jelly-like crystals" of about 2 mm diameter which dissolved spontaneously in tap water. When the parents were re-questioned it became evident that all used a new brand of highly absorbent diapers. "Jelly-like crystals" developed in our laboratory when the absorbent material of the new diapers was put in contact with urine or tap water. The new highly absorbent diapers help to keep the baby dry. However, "jelly-like crystals" may be observed and possibly alarm both parents and physicians. Information for parents and physicians may avoid unnecessary anxiety or medical workup.

[Pollinosis in chrysanthemum growers]. / Pollinosis bei Chrysanthemenzüchtern.

Pollinosis, first of all mugwort pollinosis, due to pollens of wind pollinated Asteraceae is not seldom. On the other hand allergic reactions to pollens of insect pollinated members of this plant family are a rarity. 8 cases of pollinosis to Chrysanthemums in a floriculture farm are offered, caused by the work specific conditions of exposure in artificial pollination. The analysis of allergens and RAST inhibition tests showed us a close relationship of allergens of Chrysanthemum pollens and pollens of mugwort. It was possible to continue cultivating work in all cases because of several protective measures and hyposensitization.

[Clinical and immunologic aspects in patients with agammaglobulinemia]. / Klinische und immunologische Aspekte bei Patienten mit Agammaglobulinämien.

Agammaglobulinemia is a rare disease. The concentration of these patients provides efficacy of diagnosis and treatment. Within this group the "acquired" type in adulthood (CVID, n = 31) can be separated from the X-linked agammaglobulinemia of infants (n = 6). The former is characterized by variable clinical and immunological pictures. Common to both are sinubronchial infections and extremely low levels of all classes of immunoglobulins. IgG-levels below 4 g/l are usually accompanied by a more severe disease. For the first time an osteopathy in most cases of CVID has been described. Patients with agammaglobulinemia should remain under close control with regard to their clinical data as well as to the result of the substitution by adequate preparations of immunoglobulins. A certain association with HLA-B21 could be identified. In 4 families with several afflicted members this has, however, not the case. Immunological screening in first-degree relatives provides information for genetical counseling.