Brain imaging of chill reactions to pleasant and unpleasant sounds.

The term 'chill' refers to a short-term bodily event of high arousal, which marks an emotional peak experience when occurring in response to music. Chill responses arise in a clearly circumscribed time frame and can also be reliably elicited by unpleasant sounds. Previous research, however, mostly focused on individually selected stimuli and positive contexts, thus, limiting the scope of interpretation. Hence, we developed a standardized chill paradigm and used fMRI to test neural responses of 16 healthy volunteers to pleasant and unpleasant emotional sound material while collecting subjective reports of chill intensity and skin conductance response data. As predicted, we found chill-associated increases in autonomic arousal regardless of the valence of the sound material. Apart from activity in primary and higher auditory cortices, both pleasant and unpleasant chills were associated with anterior insula, thalamus and basal ganglia activity. In contrast, amygdala responses were observed only in association with chills elicited by unpleasant sounds. Thus, chills elicited by pleasant and unpleasant sounds share activity in a neural network that may be specifically involved in the arousal component of an emotional experience.

MRI Biomarkers for Hand-Motor Outcome Prediction and Therapy Monitoring following Stroke.

Several biomarkers have been identified which enable a considerable prediction of hand-motor outcome after cerebral damage already in the subacute stage after stroke. We here review the value of MRI biomarkers in the evaluation of corticospinal integrity and functional recruitment of motor resources. Many of the functional imaging parameters are not feasible early after stroke or for patients with high impairment and low compliance. Whereas functional connectivity parameters have demonstrated varying results on their predictive value for hand-motor outcome, corticospinal integrity evaluation using structural imaging showed robust and high predictive power for patients with different levels of impairment. Although this is indicative of an overall higher value of structural imaging for prediction, we suggest that this variation be explained by structure and function relationships. To gain more insight into the recovering brain, not only one biomarker is needed. We rather argue for a combination of different measures in an algorithm to classify fine-graded subgroups of patients. Approaches to determining biomarkers have to take into account the established markers to provide further information on certain subgroups. Assessing the best therapy approaches for individual patients will become more feasible as these subgroups become specified in more detail. This procedure will help to considerably save resources and optimize neurorehabilitative therapy.

Interleukin-13 acts as an apoptotic effector on lung epithelial cells and induces pro-fibrotic gene expression in lung fibroblasts.

BACKGROUND: IL-13 promotes acute allergic asthma and is discussed to play a role in late asthmatic features such as fibrotic processes and airway remodelling. The contributions of IL-13-mediated mechanisms to subepithelial events related to fibrosis are not yet settled. OBJECTIVE: We investigated the impact of IL-13 on lung epithelial cells as apoptotic effector and on lung fibroblasts as inducer of pro-fibrotic gene expression. METHODS: Using the two lung epithelial cell lines A549 and BEAS-2B as well as primary lung epithelial cells, we investigated the capability of IL-13 to induce apoptosis by both flow-cytometry and ELISA. The ability of IL-13 to increase the expression of pro-fibrotic genes and to exert influence on the expression of its own receptor was investigated by real-time quantitative PCR measurement of mRNAs encoding collagen I, collagen III, basic fibroblast growth factor (bFGF), alpha-smooth muscle actin (alpha-SMA) and the IL-13 receptor alpha1 (IL-13Ralpha1) chain in human primary lung fibroblasts. The specificity of IL-13-mediated cellular responses was confirmed by means of an inhibitory monoclonal antibody directed to the IL-13 receptor. RESULTS: IL-13 induces apoptosis in lung epithelial cell lines as well as in primary lung epithelial cells. Furthermore, IL-13 increases the expression of mRNA for alpha-SMA and collagen III, but not for bFGF in human primary lung fibroblasts. The susceptibility of lung fibroblasts to IL-13-induced up-regulation of pro-fibrotic genes is associated with the regulation of IL-13 receptor expression. IL-13-dependent fibrosis-associated effects could be inhibited by antibody-mediated blockade of the IL-13Ralpha1 subunit. CONCLUSION: Our findings indicate a function of IL-13 as a mediator in fibrotic processes leading to loss of functional airway tissue in asthma. They also highlight the therapeutic potential of specifically targeting the interaction between IL-13 and its receptor.

High volumetric yields of functional dimeric miniantibodies in Escherichia coli, using an optimized expression vector and high-cell-density fermentation under non-limited growth conditions.

Functional bivalent miniantibodies, directed against the epidermal growth factor receptor, accumulated to more than 3 gl-1 in high-cell-density cultures of Escherichia coli RV308(pHKK) on a pilot scale. The miniantibodies consist of scFv fragments with a C-terminal hinge followed by a helix-turn-helix motif, which homodimerizes in vivo. The improved expression vector pHKK is characterized by the hoklsok suicide system, improving plasmid maintenance, and the inducible lac pl o promoter system with the very strong T7g10 Shine-Dalgarno sequence. The expression unit is flanked by terminators. The prototrophic RV308 cells were cultivated in glucose mineral salt medium and reached a cell density of 145 g dry biomass l-1 after 33 h. After induction, growth continued almost unchanged for a further 4 h with concomitant miniantibody formation. In the fedbatch phase, the concentration of glucose was kept almost constant at the physiological level of approximately 1.5 gl-1, using on-line flow injection analysis for control. Surprisingly, E. coli RV308(pHKK) did not accumulate significant amounts of the metabolic by-product acetate under these unlimited aerobic growth conditions.

[Sarcoidosis. Case report of a patient with isolated sarcoidosis of the breast]. / Sarkoidose der Mamma. Fallbericht einer Patientin mit isolierter Sarkoidose der Mamma.

The case of a 41-year-old woman with sarcoidosis of the breast without evidence of disease elsewhere is reported. The diagnosis was established histologically, and other causes of the sarcoid-like granulomatous lesions could be excluded.

[Relationship between chemical structure and toxicologic-pharmacokinetic properties of new ampicillin derivatives]. / Beziehungen zwischen chemischer Struktur und toxikologisch-pharmakokinetischen Eigenschaften neuer Ampicillin-Derivate.

The toxicity and the bioavailability of new ampicillin derivatives with glyoxylic acid benzhydrazones as site chain depend on the hydrophobic properties of the site chain. Substituents with lower hydrophobicity (expressed by the hydrophobic substituent constant pi according to Hansch) show a lower toxicity (maximal tolerated doses) and also a lower bioavailability.

[2-Amino-oxazoles as potential H-bonding agents in virostatic research. 4. Pharmacokinetics and pharmacologic-toxicologic profile of 2-guanidino-4,5-dipropyloxazole hydrochloride]. / 2-Amino-oxazole als potentielle H-Brückenbildner in der Virostatika-Forschung. 4. Mitteilung: Pharmakokinetik und pharmakologisch-toxikologisches Wirkprofil von 2-Guanidino-4,5-dipropyloxazol-hydrochlorid.

Out of the group of 2-amino-oxazoles 1 was found to be the most potent antiviral compound. Following p.o. or s.c. administration to rats, the 14C-labeled 1 was quickly and completely absorbed. The TRA was eliminated mainly via the kidneys and the liver with half-lives between 32 and 42 h. The acute pharmacodynamic effects of 1 were decrease of blood pressure, bradycardia, and inhibition of both gastric emptying and acid secretion. On smooth muscles spasmolytic and alpha-anti-adrenergic actions were predominant. After single administration the following MTD's were determined: 30 (mouse), 20 (rat), 10 mg/kg i.v. (pig), and 500 (mouse, rat), greater than 100 mg/kg p.o. (pig), respectively. In a subchronic toxicity study in rats, oral doses of 1 between 15 and 240 mg/kg given daily for 4 weeks were tolerated without any severe alterations related to the drug.

Immunohistochemistry of amyloid-related neuropathies.

Studying eight sural nerve biopsy specimens of a biopsied trigeminal ganglions and peripheral nerves from eight autopsies, some of them retrieved 30 years ago, with a panel of antibodies against several types of amyloid revealed the presence of AF, AL of the lambda type, AA and ASs in peripheral nerve specimens while AB, AE, ASc, ASb, ACc, APrP could not be detected. Amyloid of the AF type in the endoneurial space was associated with loss of unmyelinated and small caliber myelinated axons. Availability of antibodies against respective types of amyloid enables retrospective identification of subtypes of amyloid and aids in further investigation and treatment of patients and their families. Thus, immunohistochemical analysis in peripheral nerve specimens is recommended when amyloid is apparent.

Influence of melanoma B16 on the pharmacokinetics of mitoguazone in mice.

In this study, the influence of different stages and transplantation routes of the experimentally widely used solid tumor melanoma B16 on the pharmacokinetics of the antineoplastic agent mitoguazone was investigated in B6D2F1 mice. It could be shown that changes of the pharmacokinetic parameters as well as the distribution pattern of this drug were clearly influenced and dependent on the tumor stage but not by the tumor inoculation route. Advanced melanoma (d16) led to a sharp decrease in the terminal elimination half-life as well as to decreased spleen levels and increased initial liver concentrations of the drug. With respect to the results obtained in leukemia P388-bearing mice it can be concluded that the tumor stage as well as the tumor model are to be considered as important factors in which way and to which extent a tumor may alter the pharmacokinetics of antineoplastic agents.

[Acute and subacute toxicity of antineoplastic Pt(II) and Pt(IV) coordination compounds in laboratory rodents]. / Akute und subakute Toxizität antineoplastisch wirksamer Pt(II)- und Pt(IV)-Koordinationsverbindungen bei Labornagern.

After single i.v. administration of cis-diammine-platinum(II)-lactate cis-diammine-platinum(II)-lactate, L cis-diammine-platinum(II)-dilactate trans-dihydroxy-cis-dichlorodiammine-platinum(IV), the LD50 values have been calculated to range between 80 and 130 mg/kg in mice, and between 22 and 45 mg/kg in rats. The LD50 of cis-DDP amounted to 17 mg/kg and 6.6 mg/kg, respectively. Likewise, the compounds have been found to be about 3 to 5 times less toxic than the standard cis-DDP when administered daily for 5 consecutive days. Since the kidneys, the bone marrow, the lymphatic tissue and the intestinal tract have been proved to be the main target organs, the profile of the toxic action of the Pt(II)-complexes seems to be similar to that of cis-DDP. Additionally, the Pt(IV) compound has been found to be toxic to the pancreas, the liver and the salivary glands. With regard to the antineoplastic activity the more soluble lactates of cis-DDP showed a smaller therapeutic index compared to cis-DDP.

[Nephrotoxicity and myelotoxicity of antineoplastic Pt(II) and Pt(IV) coordination compounds in rats]. / Nephrotoxizität und Myelotoxizität antineoplastisch wirksamer Pt(II)- und Pt(IV)-Koordinationsverbindungen bei Ratten.

In comparison with cis-DDP four new platinum (II) and platinum (IV) complexes were evaluated for their acute nephrotoxic and myelotoxic potency in male rats following i.v. administration of maximum tolerated doses on 5 consecutive days. Parameters for nephrotoxicity determined on day 6, 13 and 22 after the first administration of the drugs included blood, urea nitrogen, serum creatinine, urine volume, urinary glucose and tubule cell excretion. Parameters for myelotoxicity determined on the same days included leucocytes, platelets, hemoglobin and hematocrit. Cis-DDP was found to be the most nephrotoxic compound. The myelotoxicity of the new platinum complexes appeared to be similar to that of cis-DDP with exception of trans-ODDP.

[Non-Hodgkin's lymphoma-like pseudolymphoma in syphilis II]. / Non-Hodgkin-Lymphom-ähnliches Pseudolymphom bei Syphilis II.

We report on a patient suffering from early secondary syphilis associated with hepatitis and generalized papular rash which clinically and histologically appeared as non-Hodgkin lymphoma of the centrocytic-centroblastic type. The benign course and the response of the papular rash to penicillin therapy as well as repeated histological examination of many plasma cells and epithelioid cells, however, revealed pseudolymphoma.

Toxicity of the alkylating agent bendamustin.

In acute toxicity studies the maximum tolerated dose (MTD), the LD50 and the LD100 of Bendamustin were determined in rats and mice after i.v. and oral administration. In a subchronic study male rats were given Bendamustin for 28 days at oral dose levels of 5, 10, 20 or 40 mg/kg/day. Chlorambucil was used as a standard at dose levels of 1, 5 and 10 mg/kg/day. Bodyweight gain, food and water intake, hematology, clinical chemistry and histopathology were evaluated. With quantitative differences the main target organs for both compounds were the bone marrow, the kidney, the intestine and the lymphatic system. Additionally, Chlorambucil caused a significant atrophy of the testes and a slight atrophy of the pancreas at a dose of 5 mg/kg/day. In conclusion, the data obtained may be used as a base to evaluate the therapeutic range of Bendamustin compared to Chlorambucil for the oral route.

[Major aspects of direct fetal electrocardiography with regard to the diagnosis of intrauterine fetal status]. / Prinzipielle Aspekte der direkten fetalen Elektrokardiographie im Hinblick auf die intrauterine fetale Zustandsdiagnostik.

The possibilities and limits of direct fetal electrocardiography are described, which result from the estimation and interpretation of only one ECG lead in the diagnostics of disorders in excitation development, conduction and repolarisation and in the as early as possible detection of heart defects.

Long term toxicological studies on the progestin STS 557.

The toxicity of 17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one (STS 557) was studied by its oral administration of 0.1, 1.0 or 10.0 mg/kg/day to Wistar rats for six months, and of 0.01, 0.1 or 1.0 mg/kg/day to beagle dogs for six months, respectively. Levonorgestrel at a dose of 1.0 mg/kg/day was used as the standard in the dog study. With respect to the progestational activity of the compound the main target organs were the hypophysis, the reproductive organs and the adrenals. Mammary hyperplasia was observed in dogs treated with STS 557 or levonorgestrel at the dose of 1.0 mg/kg/day, but in no case mammary nodules could be detected. At the dose of 1.0 mg/kg/day STS 557 and levonorgestrel were found to increase the plasma insulin response to i.v. glucose in bitches, but neither the mean blood glucose levels nor the glucose utilization were affected. Moreover, during administration of both steroids to dogs temporary changes in serum concentrations of triglycerides and total cholesterol were noted. The results obtained in rats and dogs from functional and morphological investigations did not reveal any toxic side effects of STS 557 on the liver, the kidneys, the bone marrow or on blood coagulation. The effects on the reproductive organs observed following STS 557 especially in dogs are related to both the hormonal effects of the compound and the specific response of the dog to potent progestagens.

[Asymptomatic uterus rupture in a patient with placenta percreta--case report (author's transl)]. / Stille Uterusruptur bei Placenta percreta. Fallbericht.

The asymptomatic course of placenta percreta is the most important form of impaired placentation. Early hysterectomy seems to be the optional method on account of high maternal mortality.

Pharmacokinetics of 3-[bis(2-hydroxyethyl)amino]acetophenone [4,5-diphenyloxazolyl-(2)]hydrazone (ZIMET 98/69) in rats.

The pharmacokinetics of 3H-ZIMET 98/69 after i.v. and oral administration to rats was studied. After i.v. administration of 2.5 and 10 mg/kg a biphasic exponential decay of total serum radioactivity was found, so that a two compartment open model could be assumed. Oral administration of 10 mg/kg results only a moderate bioavailability (25%), which further decreased after administration of higher doses. The distribution steady state between serum and tissue is reached rapidly. Elimination proceeds slowly, the serum half-life being 64-84 h.