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Background: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ~50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.Methods: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.Results: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).Conclusions: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC.

Previous models proposed that the subthalamic nucleus (STN) is critical in the early phase of skill acquisition. We hypothesized that subthalamic deep brain stimulation modulates the learning curve in early classification learning. Thirteen idiopathic Parkinson's disease patients (iPD) with subthalamic deep brain stimulation (STN-DBS), 9 medically treated iPD, and 21 age-matched healthy controls were tested with a probabilistic classification task. STN-DBS patients were tested with stimulation OFF and ON, and medically treated patients with medication OFF and ON, respectively. Performance and reaction time were analyzed on the first 100 consecutive trials as early learning phase. Moreover, data were separated for low and high-probability patterns, and more differentiated strategy analyses were used. The major finding was a significant modulation of the learning curve in DBS patients with stimulation ON: although overall learning was similar to healthy controls, only the stimulation ON group showed a transient significant performance dip from trials '41-60' that rapidly recovered. Further analysis indicated that this might be paralleled by a modulation of the learning strategy, particularly on the high-probability patterns. The reaction time was unchanged during the dip. Our study supports that the STN serves as a relay in early classification learning and directs attention toward unacquainted content. The STN might play a role in balancing the short-term success against strategy optimization for improved long-term outcome.

Objectives: To measure maternal serum and amniotic fluid levels of macrophage inhibitory cytokine-1 (MIC-1) in Down syndrome and normal pregnancies, assessing the utility of MIC-1 as a prenatal marker of Down syndrome. Method(s): Stored serum from 64 Down syndrome and 399 control pregnancies, collected at 8 to 17 weeks of pregnancy, and stored amniotic fluid from 17 Down syndrome and 53 controls, collected at 15 to 19 weeks of pregnancy, were retrieved for analysis. MIC-1 was measured using an established in-house ELISA, blinded to sample type. Result(s): In maternal serum, MIC-1 levels are not altered in Down syndrome in either the first or second trimester. Levels, expressed as median (95% CI) multiples of the median (MoM), in the Down syndrome cases and controls were 1.07 (0.9-1.1) MoM and 1.0 (0.95-1.03) MoM respectively. In amniotic fluid, MIC-1 levels were significantly decreased compared to controls, 0.52 (0.44-0.64) MoM versus 1.0 (0.85-1.08) MoM (p < 0.0001). Conclusion(s): MIC-1 is decreased in amniotic fluid but not in maternal serum in Down syndrome pregnancies. MIC-1 will not be useful as a prenatal marker of Down syndrome. Copyright © 2004 John Wiley & Sons, Ltd.

Postural and action tremor in peripheral neuropathy is characteristic of Roussy-Levy syndrome. A patient with a severe demyelinating neuropathy and disabling neuropathic tremor successfully treated by deep brain stimulation (DBS) is reported. Disease onset was at age 63 years with sensory symptoms and slight action tremor. Within the following 9 years a severe, drug resistant, postural and action tremor developed rendering the patient unable to feed himself. At age 72 years the patient was treated by bilateral DBS of the ventral intermediate thalamic nucleus, with a useful 30% reduction in tremor. The clinical benefit of the stimulation remained stable over a 1 year postoperative observation period.

The placenta and fetal membranes are the site of expression of macrophage inhibitory cytokine (MIC-1), a member of the transforming growth factor (TGF)-beta superfamily. We hypothesized that MIC-1 may act as an immune regulator in pregnancy complications associated with intrauterine inflammation. Decidual cells, chorionic trophoblasts and amnion epithelial cells were identified by immunohistochemistry as the predominant MIC-1-containing cell type in term membranes. Amnion and choriodecidual explants all produced MIC-1 in culture, the latter having the greatest production rate (206 +/- 74.5 pg/mg tissue/24 h, n = 6; mean +/- SEM). Production was not responsive to stimulation by pro-inflammatory cytokines. MIC-1 was detectable in 217 transabdominal amniotic fluid (AF) samples taken from 15 to 41 weeks gestation, concentrations ranging from 0.9-51.1 ng/ml. AF MIC-1 concentrations in pregnancies with premature rupture of membranes (PROM) or preterm labour, either with or without microbial invasion of the amniotic cavity, were not significantly different from those delivered at term either with or without labour. Treatment with MIC-1 (0.25-25 ng/ml) did not alter production of interleukin-6 or -8 by amnion or choriodecidual cells in vitro. We conclude that AF MIC-1 is derived from the fetal membranes and decidua, but that MIC-1 is unlikely to be involved in the pathophysiology of preterm birth or PROM.

We investigated the effects of three components of ischemia: external acidosis (pH = 6.0), extracellular hyperkalemia ([K+] = 20 mmol/l), and resting membrane depolarization to -60 mV. on Kv4.3 current stably expressed in Chinese Hamster Ovary cells. We used single electrode whole cell patch clamp techniques to study changes in the current elicited. External acidosis caused a positive shift in the steady state activation curve from -13.4±2.1 mV to -3.3±1.5 mV (n = 8, P = 0.004) and the steady state inactivation curve from -56.5±0.4 mV to -46.7±0.5 mV (n = 14, P<0.0001). Acidosis also caused an acceleration of recovery from inactivation with the t1/2 decreasing from 306 ms (95% CI 287-327 ms) to 194 ms (95% CI 182-207 ms), (n = 14, P<0.05). Hyperkalemia did not affect any of these parameters. Combined acidosis and hyperkalemia produced effects similar to those seen with acidosis. Changing the holding potential from -90 mV to -60 mV with test potentials of +5 and +85 mV decreased the peak currents by 34.1% and 32.4% respectively (n = 14). However, in the presence of external acidosis the decrease in peak currents induced by changing the holding potential was less marked. In acidotic bath the peak current at -60 mV was reduced by only 13.6% at a test potential of +5 mV and 12.3% at a test potential of +85 mV (n = 14). Taken together our data suggest that the membrane depolarization and changes in pH which occur under ischemic conditions would be accompanied by relative preservation of Kv4.3 currents and provide a molecular basis for the observation of preserved epicardial Ito and epicardial action potential duration (APD) shortening in ischemia. © 2002 Elsevier Science Ltd.