Effects of xenon and isoflurane on apoptosis and inflammation in a porcine myocardial infarction model.

Volatile anaesthetics can reduce the infarction size in myocardial tissue when administered before and during experimentally induced ischaemia. The aim of this study was to investigate whether xenon is beneficial compared to isoflurane in limiting myocardial tissue apoptosis and inflammation induced by experimental ischaemia-reperfusion injury in a porcine right ventricular infarction model. Twenty-one animals used for this study randomly received isoflurane, xenon or thiopental, (n=6-8 per group). Myocardial infarction was induced for 90min, followed by reperfusion for 120min. Tissues from the left and right ventricles were removed from the sites of infarction, reperfusion and remote areas, and processed for immunohistochemistry. Apoptosis (caspase-3 staining) and neutrophilic infiltration (naphthol AS-D chloroacetate-specific esterase) were assessed and evaluated. Statistical analysis was performed using an ANOVA of repeated measures. Density of apoptotic cells were higher in tissues from animals that were anesthetized with xenon. This effect was significant in comparison to isoflurane (p=0.0177). Neutrophilic infiltration was significantly higher in the right compared to the left ventricle (p<0.001), whereas no significant differences in the number of granulocytes based on the anaesthetic regime or the different tissue areas were found. We conclude that xenon, in the early phase of ischaemia and reperfusion, induces a significant increase in apoptosis compared to isoflurane. Therefore, clinical use of this anaesthetic in cardiocompromised patients should be taken with care until more long-term studies have been carried out. The increased neutrophilic infiltration in the right vs. the left ventricle indicates the right ventricle being more susceptible to ischaemia-reperfusion injury.

Effects of antipsychotic treatment on psychopathology and motor symptoms. A placebo-controlled study in healthy volunteers.

RATIONALE: There is increased interest in elucidating the range of symptoms of schizophrenia and their response to treatment with medications. Particularly negative and cognitive symptoms are often resistant to the therapy with currently available antipsychotics. There are even similarities between negative symptoms in psychosis and the side effects of antidopaminergic antipsychotic drugs. OBJECTIVES: The aim of this randomized, single-blinded, placebo-controlled study was to investigate the influence of a subchronic, prolonged neuroleptic-induced dopamine deficit on psychopathology and subjective well-being in healthy subjects. METHODS: Seventy-two healthy volunteers without history of psychiatric diseases were included. A 7-day antidopaminergic intervention was provided with aripiprazole, haloperidol, and reserpine. For the clinical assessment, structured interviews and psychopathology and extrapyramidal symptom scales were used. RESULTS: Seven out of 18 participants (38.9%) randomized to the haloperidol group terminated the study ahead of schedule. In the reserpine and the haloperidol group, significantly higher levels of negative and positive symptoms (PANSS scale) were documented. Depressive symptoms predominantly occurred in the reserpine group. Among all participants experiencing the antidopaminergic intervention, the subgroup with positive family history among first and second-generation relatives developed more pronounced depressive symptoms. Concerning extrapyramidal motor symptoms, the haloperidol group had significantly more severe manifestations than all three other groups. CONCLUSION: Antidopaminergic modulation in healthy subjects induced substantial impairments in several domains of subjective well-being. In particular an association between hypodopaminergic states and depressive symptoms was observed which may be amplified by a genetic predisposition.

Impact of different antidopaminergic mechanisms on the dopaminergic control of prolactin secretion.

Antipsychotics are the most common cause of pharmacologically induced hyperprolactinemia. Although this adverse effect was the subject of numerous observations, the mechanisms and promotive factors were not completely investigated yet. Increased awareness of clinical consequences of hyperprolactinemia implicates the necessity for further examinations. The aim of this randomized, single-blinded, placebo-controlled study was to do a systematic examination of the effects of different antidopaminergic mechanisms on prolactin secretion in healthy volunteers. A 7-day intervention was performed with aripiprazole, haloperidol, or reserpine. Prolactin levels changed significantly in the haloperidol (from 177.2 ± 74.6 to 350.7 ± 202.6 mU/L; P < 0.0001) and in the reserpine groups (from 149.6 ± 80.2 to 540.3 ± 280.8 mU/L; P < 0.0001) but not after aripiprazole (from 160.9 ± 65.0 to 189.6 ± 209.6 mU/L; P = 0.69) or placebo (from 211.6 ± 113.4 mU/L to 196.1 ± 85.6 mU/L; P = 0.8). After haloperidol and reserpine, increases in prolactin were significantly more pronounced in women than in men. Furthermore, in women using hormonal contraception, the increase in prolactin was significantly greater than in those without additional estrogen supply. These results demonstrate that the effect of antipsychotic drugs on prolactin levels strongly depends on their mechanism of action. Reserpine, a vesicular monoamine transporter type 2 blocker, causes the most distinct increase. This implies that D2 receptor blockade on the lactotrophs is not the sole major cause leading to hyperprolactinemia. The partial agonistic effect of aripiprazole was sufficient to maintain prolactin on physiologic levels. The strong influences of sex and hormonal contraception underline the sensitizing effect of estrogens to the antipsychotic-induced prolactin increase.

Effects of controlled released BMP-7 on markers of inflammation and degradation during the cultivation of human osteoarthritic chondrocytes.

The aim of the present study is to investigate the effects of BMP-7 released from polylactide microspheres on the appearance of various catabolic and inflammatory cytokines secreted by osteoarthritic chondrocytes cultivated in a collagen gel. Articular chondrocytes of 15 patients suffering from osteoarthritis are transferred to a collagen type-I gel. Additionally, BMP-7 encapsulated into polylactide microspheres (50 ng BMP-7/mL gel) is added. After 14 days, gene expression and protein appearance of various genes involved in matrix turnover and inflammation are investigated by immunohistochemical staining and RT-PCR and compared to untreated controls. TNF-α, MMP-13, IL-6, IL-1ß, and VEGF gene expressions are decreased in the treatment group. In contrast, BMP-7-induced matrix synthesis is not affected, leaving collagen type-II (Col-II) gene expression to be elevated, while collagen type-I (Col-I) is decreased. In summary, controlled release of low concentrated BMP-7 from polylactide microspheres leads to a decrease in gene expression of the investigated inflammation and matrix degradation markers whereas matrix synthesis is induced.

Radiofrequency ablation of liver metastases-software-assisted evaluation of the ablation zone in MDCT: tumor-free follow-up versus local recurrent disease.

The purpose of this study was to investigate differences in change of size and CT value between local recurrences and tumor-free areas after CT-guided radiofrequency ablation (RFA) of hepatic metastases during follow-up by means of dedicated software for automatic evaluation of hepatic lesions. Thirty-two patients with 54 liver metastases from breast or colorectal cancer underwent triphasic contrast-enhanced multidetector-row computed tomography (MDCT) to evaluate hepatic metastatic spread and localization before CT-guided RFA and for follow-up after intervention. Sixteen of these patients (65.1 + or - 10.3 years) with 30 metastases stayed tumor-free (group 1), while the other group (n = 16 with 24 metastases; 62.0 + or - 13.8 years) suffered from local recurrent disease (group 2). Applying an automated software tool (SyngoCT Oncology; Siemens Healthcare, Forchheim, Germany), size parameters (volume, RECIST, WHO) and attenuation were measured within the lesions before, 1 day after, and 28 days after RFA treatment. The natural logarithm (ln) of the quotient of the volume 1 day versus 28 days after RFA treament was computed: lnQ1//28/0(volume). Analogously, ln ratios of RECIST, WHO, and attenuation were computed and statistically evaluated by repeated-measures ANOVA. One lesion in group 2 was excluded from further evaluation due to automated missegmentation. Statistically significant differences between the two groups were observed with respect to initial volume, RECIST, and WHO (p < 0.05). Furthermore, ln ratios corresponding to volume, RECIST, and WHO differed significantly between the two groups. Attenuation evaluations showed no significant differences, but there was a trend toward attenuation assessment for the parameter lnQ28/0(attenuation) (p = 0.0527), showing higher values for group 1 (-0.4 + or - 0.3) compared to group 2 (-0.2 + or - 0.2). In conclusion, hepatic metastases and their zone of coagulation necrosis after RFA differed significantly between tumor-free and local-recurrent ablation zones with respect to the corresponding size parameters. A new parameter (lnQ1//28/0(volume/RECIST/WHO/attenuation)) was introduced, which appears to be of prognostic value at early follow-up CT.

Dose reduction for semi-automated volumetry of hepatic metastasis in MDCT studies.

OBJECTIVES: To investigate the performance of semi-automated measurements (RECIST, volume) of hepatic metastases in multidetector-row computed tomography (MDCT) under normal-dose- and simulated low-dose-protocols. MATERIALS AND METHODS: Thirty-five patients (67 +/- 13 years) with a total of 79 hepatic metastases underwent 16-MDCT (120 kv, 160 mAseff, pitch 1, 3 mm slice thickness, 2 mm reconstruction increment, B30f standard soft tissue kernel) for either initial staging or therapy monitoring. Corresponding raw data from these standard-dose scans were simulated at lower radiation doses of 80/60/40 mAseff (Somatom Noise Vers.6.1 beta, Siemens Healthcare, Forchheim, Germany). A semi-automated software tool (SyngoCT Oncology, Siemens Healthcare, Forchheim, Germany) was applied to each dose setting to evaluate size parameters (RECIST, volume). These measurements were compared by applying repeated-measures analysis of variance and displayed graphically. RESULTS: For RECIST measurements no statistically significant differences were found between standard dose (Mean RECIST diameter: 20.46 +/- 8.37 mm) and different simulated low radiation doses (80 mAseff: 20.95 +/- 8.20 mm/60 mAseff: 20.50 +/- 8.35 mm/40 mAseff: 19.95 +/- 8.16 mm): P = 0.0774.Statistically significant differences of volume quantification (P < 0.05) could be found between standard-(3.60 +/- 4.63 mL) and simulated lowest dose of 40 mAseff (3.17 +/- 4.08 mL), whereas there was no difference (P > 0.05) between 160 mAseff- and either 80 mAseff-(3.46 +/- 4.31 mL) or 60 mAseff-protocols (3.44 +/- 4.35 mL). CONCLUSIONS: Software-assisted assessment of RECIST criteria and volume demonstrated valid performances under different dose-settings in MDCT; therefore, substantial radiation dose reduction could be possible with the use of semi-automated measurements in follow-up studies.