Potential adverse events with biologic response modifiers

In recent years, an explosion of biologic response modifiers has entered the market to combat a variety of immune-mediated diseases. These can be in the form of recombinant cytokines, as in the case of interferon beta in the treatment of multiple sclerosis, or novel engineered antibodies constructed by combining non-human determinants with a human immunoglobulin scaffold, as in the case of omalizumab in the treatment of allergic asthma. More recently, completely human monoclonal antibodies have also been constructed. Adverse reactions related to these agents can be classified as expected or unexpected events. A number of case studies and a handful of randomized trials have demonstrated the potential toxicities with the use of biologic response modifiers. This article aims to review adverse event profiles of select biologic response modifiers for which the most data is available and are common to a rheumatology, allergy/immunology, and dermatology patient population.     

Mold and Human Health: Separating the Wheat from the Chaff

The term “mold” is utilized to define the ubiquitous fungal species commonly found in household dust and observed as visible multicellular filaments. Several well-defined human diseases are known to be caused or exacerbated by mold or by exposure to their byproducts. Among these, a solid connection has been established with infections, allergic bronchopulmonary aspergillosis, allergic fungal rhinosinusitis, hypersensitivity pneumonitis, and asthma. In the past decades, other less-defined and generally false conditions have also been ascribed to mold. We will herein review and critically discuss the available evidence on the influence of mold on human health.     

Die Rolle des TSH für Psychische VerÄnderungen und BefindlichkeitsverÄnderungen bei Schilddrüsenfunktionsstörungen

Summary The characteristic psychic and somatic features found in patients with overt hyper- or hypothyroidism are usually attributed to elevated or diminished levels, respectively, of thyroid hormones. This concept does not sufficiently explain our previous investigations in which the same symptoms, albeit attenuated, were also seen in patients suffering from so-called latent disturbances of thyroid function. This state of disorder, however, exhibits normal concentrations of peripheral thyroid hormones. Only the response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH) stimulation is in accordance with the behaviour of the overt thyroid dysfunction and enables its differentiation from the euthyroid state. In this context, we investigated the question as to whether pathologic signs in thyroid disorders are correlated to alterations of peripheral thyroid hormones or to changes in the hypothalamus pituitary axis. Therefore, we investigated two groups of ten patients each who suffered from latent hyper- or hypothyroidism, respectively, and ten euthyroid controls. All were matched from sex and age. Endocrine function was estimated by TRH testing, TT3, TT4 and thyroxine binding globuline (TBG). Psychologic testing was performed by questionnaires concerning subjective somatic symptoms, emotional disturbances, psychomotoric performance, cognitive impairment and personality. Patients with latent hyperthyroidism were more subject to somatic symptoms and affective complaints than were those who had latent hypothyroidism. As compared with controls, there were significant differences in exhaustion and pain in the limbs and heart. In terms of affective complaints, patients were more depressive, anxious, touchy and irritable; their personalities showed a higher degree of emotional lability, excitement and irritability. Many symptoms described in overt thyroid dysfunction could be found in latent metabolic disturbances. Therefore, we conclude that the alterations of health in thyroid disorders are more likely to be caused by hypothalamic pituitary impairment than by changes in peripheral hormone levels. The stronger symptoms occurring in overt thyroid dysfunction as compared with latent metabolic disturbances may reflect the degree of hypothalamic pituitary dysfunction.

Diese Arbeit wurde erstellt im Rahmen des Sonderforschungsbereichs 258 der UniversitÄt Heidelberg, gefördert von der DFG     

Colorimetric activity measurement of a recombinant putrescine N-methyltransferase from Datura stramonium

Putrescine N-methyltransferase (PMT, EC 2.1.1.53) catalyses the S-adenosyl- L-methionine (SAM or AdoMet)-dependent methylation of putrescine to N-methylputrescine within the biosynthetic pathways of calystegines, nicotine, and tropane alkaloids in medicinal plants and produces S-adenosyl- L-homocysteine (SAH or AdoHcy). Determination of PMT activity was time-consuming and hardly reproducible in the past because it required tedious separation steps after chemical derivatisation or radioactive labelling of N-methylputrescine. A convenient and accurate enzyme-coupled colorimetric assay is based on the conversion of SAH to homocysteine by 5'-methylthioadenosine/ S-adenosylhomocysteine nucleosidase (MTAN/SAHN, EC 3.2.2.9) and S-ribosylhomocysteine lyase (LuxS, EC 4.4.1.21). Homocysteine is quantified by 5,5'-dithiobis-2-nitrobenzoic acid. Putrescine was shown not to interfere with MTAN or LuxS. The colorimetric assay was validated by HPLC analysis. K(m) values determined by the assay, 108 microM for putrescine and 42 microM for SAM, are lower than the previously reported values, due to alleviation of PMT inhibition by SAH. DTNB:5,5'-dithiobis-2-nitrobenzoic acid LuxS: S-ribosylhomocysteine lyase MTAN:5'-methylthioadenosine nucleosidase PMT:putrescine N-methyltransferase SAH: S-adenosyl- L-homocysteine SAM: S-adenosyl- L-methionine TNB:2-nitro-5-thiobenzoic acid.     

Comparative Evaluation of the Datex-Ohmeda S/5 Entropy Module and the Bispectral Index® Monitor during Propofol-Remifentanil Anesthesia

Background: Different analytical concepts were introduced to quantify the changes of the electroencephalogram. The Datex-Ohmeda S/5 Entropy Module (Datex-Ohmeda Division, Instrumentarium Corp., Helsinki, Finland) was the first commercial monitor based on the entropy generating two indices, the state entropy (SE) and the response entropy (RE). The aim of the current study was to compare the accuracy of SE and RE with the Bispectral Index(R) monitor (BIS(R); Aspect Medical Systems, Newton, MA) during propofol-remifentanil anesthesia.

Methods: The authors investigated 20 female patients during minor gynecologic surgery. SE, RE, BIS, mean arterial blood pressure, heart rate, and sedation level were recorded every 20 s during stepwise increase (target-controlled infusion, 0.5 [mu]g/ml) of propofol until the patients lost response. Five minutes after loss of response, remifentanil infusion (0.4 [mu]g [middle dot] kg-1 [middle dot] min-1) was started. Spearman correlation coefficient and prediction probability were calculated for sedation levels with SE, RE, BIS, mean arterial blood pressure, and heart rate. The ability of the investigated parameters to distinguish between the anesthesia steps awake versus loss of response, awake versus anesthesia, anesthesia versus first reaction, and anesthesia versus extubation was analyzed with the prediction probability.

Results: SE correlates best with sedation levels, but no significant differences of the prediction probability values among SE, RE, and BIS were found. The prediction probability for all investigated steps of anesthesia did not show significant differences among SE, RE, and BIS. SE, RE, and BIS were superior to mean arterial blood pressure and heart rate.     

Hepatic hydrothorax

Hepatic hydrothorax is a rare complication of portal hypertension secondary to liver cirrhosis affecting approximately 5-10% of cirrhotic patients with ascites. Hepatic hydrothorax results from an accumulation of fluid migrating through a diaphragmatic defect from the abdominal cavity into the pleural cavities. The effusion of hepatic hydrothorax is typically transudative whereas the effusion of spontaneous bacterial empyema (SBEM) is exudative. The clinical management of hepatic hydrothorax is equivalent to that of ascites. Patients with persistent hepatic hydrothorax despite fluid and sodium restriction as well as the use of maximally tolerable doses of diuretics and repeated thoracentesis are considered to have refractory hepatic hydrothorax. SBEM is a frequent underlying condition. SBEM occurs in up to 13% of patients with hepatic hydrothorax and should be treated by antibiotic therapy. Refractory hydrothorax is observed in 10% of patients with hepatic hydrothorax. These patients should be considered for transjugular intrahepatic portal systemic shunt (TIPS) placement which is the most effective option for refractory hepatic hydrothorax with response rates ranging up to 80% in most studies. Suitable patients with hepatic hydrothorax should be considered as candidates for liver transplantation. TIPS may help to bridge the time to liver transplantation.     

Ses i 6, the sesame 11S globulin, can activate basophils and shows cross-reactivity with walnut in vitro

BACKGROUND: Sesame allergy is increasingly being reported, and multi-sensitization to peanut and tree nuts has been described. The clinical relevance and cross-reactivity of many sesame proteins, such as Ses i 6, are unknown. OBJECTIVE: The aims of this study were to perform a preliminary examination of the cross-reactivity of Ses i 6 in vitro, examine the ability of Ses i 6 to activate basophils in a modified basophil activation test (mBAT), and assess whether such an assay may help to distinguish between potentially relevant and irrelevant IgE reactivity towards 11S globulin proteins. METHODS: Inhibition immunoblotting and chicken anti-rJug r 4 antibodies were used to determine the cross-reactivity of rSes i 6. Basophils from atopic donors were stripped of resident IgE before passive sensitization with food-allergic sera and challenged with protein extracts or recombinant protein. Basophil activation was measured using two activation markers, CD203c and CD63, via flow cytometry. RESULTS: IgE immunoblotting showed cross-reactivity between rJug r 4 and rSes i 6 using sera from two human donors and chicken IgY. Additionally, rSes i 6 activated basophils passively sensitized with sesame-allergic sera. Cross-reactive serum from a sesame-allergic but walnut-tolerant donor was not able to activate basophils when challenged by walnut extract despite IgE reactivity to walnut determined by immunoblotting. CONCLUSIONS: The sesame 11S globulin shows partial immunological cross-reactivity with walnut, and although it is classified as a minor allergen, activated basophils sensitized with serum from seven out of eleven sesame-allergic donors. Additionally, the mBAT may help distinguish between clinically relevant and irrelevant in vitro IgE cross-reactivity of seed storage proteins in nuts and seeds and thus warrants use in further studies.