Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E₂ (PGE₂) synthesis. Further, we showed that inflammation-induced PGE₂ targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE₂-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.     

Pregnancy-specific beta-1-glycoprotein levels in normal and toxemic pregnancy.

Maternal plasma levels of pregnancy-specific beta-1-glycoprotein (PSBG) in 166 normal and 169 toxemic pregnancies were measured by radioimmunoassay in the third trimester. Individual PSBG levels were studied in 16 women during weeks 7 through 39 of normal pregnancy. The levels were found to increase as pregnancy progressed. During the third trimester neither normal nor toxemic pregnancies showed any circadian rhythm in PSBG levels. In toxemic pregnancies low PSBG values were seen mainly in cases with intrauterine growth retardation (IUGR). Plasma PSBG concentrations at weeks 39-40 in toxemic patients correlated positively with placental weight. No such correlation was found in normal or toxemic pregnancies at 37-38 weeks or in either group between PSBG level and infant birth weight, birth length, or Apgar score. In toxemic pregnancies with low PSBG values during the last trimester, birth weights were somewhat lower than in those with normal levels. Thus, low levels of maternal plasma PSBG may reflect IUGR, but will be of little value for assessment of fetal condition at birth.     

Changes in treatment volume of hormonally treated and untreated cancerous prostate and its impact on rectal dose

Late chronic side effects of the rectum constitute one of the principal limiting factors for curative radiation therapy in patients with prostate cancer. The purpose of the study was to determine the impact of immediate androgen deprivation (IAD) prior to conformal radiotherapy on rectal volume exposed to high doses, as compared with a deferred treatment strategy (DAD). Twenty-five patients (13 in the IAD group and 12 in the DAD group) with bulky tumours of the prostate, T3pN1-2M0 from the prospective EORTC trial 30846 were analysed. Three-dimensional conformal radiation treatment plans (3DCRT) using a 4-field box technique were generated based on the digitized computed tomographic or magnetic resonance findings acquired during the first 9 months after inclusion in the EORTC trial. Dose-volume histograms (DVHs) were calculated for the prostate and rectum. In the DAD group, there was no obvious alteration in the mean size of the prostate or other evaluated structures. In the IAD patients, a statistically significant reduction of approximately 40% of the gross tumour volume (GTV) was reached after a 6 months' course of hormonal treatment (p < 0.001). High-dose rectal volume was correlated with the volume changes of the GTV (p < 0.001). Mean rectal volume receiving 95% or more of the target dose was significantly reduced by 20%. Our study confirms the effect of downsizing of locally advanced prostate tumours following AD treatment and demonstrates the interdependence of the high-dose rectal volume with the volume changes of the GTV. However, the mean beneficial sparing of rectal volume was outweighed in some patients by considerable inter-patient variations.     

Choriocarcinoma: expression of tumor- and trophoblast-associated antigens in patients with low chorionic gonadotropin excretion.

The circulating levels of four tumor- or trophoblast-associated antigens were measured by specific radioimmunoassays in 11 patients with gestational choriocarcinoma. The estimations were carried out at the time when the urinary gonadotropin (hCG) excretion was low or negligible. Gonadotropin, measured as the hCG beta-subunit, was detected in serum of three patients, one of whom also showed a slightly raised level of carcinoembryonic antigen (CEA). All patients had normal serum alpha-fetoprotein (AFP) levels and no trace of human placental lactogen could be demonstrated. Repeat estimation after treatment of patients with raised levels showed a disappearance or a marked decrease of the circulating hCG levels and a return to normal of the elevated serum CEA level. The results show that although CEA levels may occasionally be elevated new information can hardly be expected from markers other than hCG when one is monitoring response to treatment, but AFP may have potential significance in the distinction between pregnancy and a trophoblastic disease. The circulating levels of hCG are of vital importance in the monitoring of choriocarcinoma patients who appear to be in remission by the conventional analysis of urinary hCG excretion.