Beyond the symptom: the biology of fatigue.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.

Dissecting the autocrine and paracrine roles of the CCR2-CCL2 axis in tumor survival and angiogenesis.

The CCL2 CCR2 axis is likely to contributes to the development and progression of cancer diseases by two major mechanisms; autocrine effect of CCL2 as a survival/growth factor for CCR2+ cancer cells and, the attraction of CCR2+ CX₃CR1+tumor associated macrophages that in the absence of CCR2 hardly migrate. Thus far no in vivo system has been set up to differentiate the selective contribution of each of these features to cancer development. Here we employed a chimera animal model in which all non-malignant cells are CCR2-/-, but all cancer cells are CCR2+, combined with an adoptive transfer system of bone marrow (BM) CX₃CR1+ cells from CCR2+ mice harboring a targeted replacement of the CX₃CR1gene by an enhanced green fluorescent protein (EGFP) reporter gene (cx₃cr1(gfp)), together with the CD45.

New horizons for VEGF. Is there a role for nuclear localization?

Angiogenesis, or new blood vessel formation, is a physiological response of tissues to hypoxia or ischemia. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that is up-regulated by hypoxia. The mechanisms responsible for hypoxic induction of VEGF are still not completely understood, though both transcriptional and post-transcriptional mechanisms are involved.

Peripheral noradrenergic function during chronic lithium treatment in the rat.

Noradrenergic function was evaluated in the rat vas deferens following chronic treatment with lithium (30 mM in the diet for 2 weeks followed by 50 mM for 1 week). No alteration could be detected in: a) 3H-noradrenaline release evoked by electrical field stimulation, b) alpha 1-adrenoceptor function as assessed by contractile response to noradrenaline, c) active neuronal uptake of 3H-noradrenaline, d) alpha 2-adrenoceptor activity, as assessed by yohimbine-enhancement of evoked release of 3H-noradrenaline. The data argue against a primary action of lithium on the noradrenergic nerve.

Patterns of spontaneous pulsatile secretion of human chorionic gonadotropin and pregnancy specific beta 1 glycoprotein by superfused placental explants in first and last trimester. Lack of episodic human placental lactogen secretion.

We have recently reported that during superfusion of placental explants, human chorionic gonadotropin secretion is episodic. In the present work we have examined, using the superfusion model, the pattern of secretion of other glycoprotein hormones, pregnancy specific beta 1 glycoprotein and human placental lactogen, in the first trimester and term placenta. This was done by evaluating the pulsatile pattern by two different computerized programmes.

In vitro vascular responsiveness to norepinephrine in experimental portal hypertension.

It has been postulated that loss of response to norepinephrine accounts in part for the portal hypertension, systemic hypotension, and generalised vascular dilatation of chronic liver disease. The in vitro vascular responsiveness to norepinephrine was measured in aortic rings and portal veins excised from four different rat models of hepatic disease with and without portal hypertension, hepatocellular damage, and hyperbilirubinemia--the carbon tetrachloride (CCl4) cirrhotic rat with portal hypertension, the five-week chronic bile duct ligated and resected (CBDL) cirrhotic rat with portal hypertension and hyperbilirubinemia, the 10-day partial ligated portal vein (PVL) portal hypertensive rat without hepatocellular damage and hyperbilirubinemia, and the three-day bile duct ligated (ABDL) rat with acute hepatocellular damage and hyperbilirubinemia but without portal hypertension. Sham-treated or operated groups for each model were also prepared.

New directions in monoamine oxidase A and B selective inhibitors and substrates.

Identification, cellular localization, and cDNA cloning of MAO subtypes A and B have increased the insight into the pharmacology of these enzymes, whose primary functions are intra- and extraneuronal inactivation of neurotransmitter (dopamine, noradrenaline and serotonin) and other biogenic amines. In addition, MAO oxidizes the inert uncharacteristic tertiary amine, MPTP, to the parkinson inducing dopaminergic neurotoxin, MPP+, and the novel secondary amine anticonvulsant milacemide to the inhibitory amino acid neurotransmitter, glycine. These recent developments have provided new therapeutic perspectives for the management of Parkinson's disease and seizure disorders via the use of selective inhibitors and amino acid amine prodrug substrates of MAO-B.

The dual effect of epidermal growth factor upon human chorionic gonadotropin secretion by the first trimester placenta in vitro.

Epidermal growth factor (EGF) is believed to play an important role in the regulation of placental function. We have examined the effect of EGF upon first trimester (7-10 gestational weeks) placental hCG secretion and cellular differentiation using both static (explants and isolated cells) and kinetic (superfusion of explants) culture methods. In superfused explants, short (1-4 min) pulses of EGF increased both the rate and amplitude of spontaneous pulsatility of hCG.

Anesthesia and pressor responsiveness in chronic bile-duct-ligated dogs.

Cardiovascular homeostasis is comprised under general anesthesia and in jaundice. Because surgery is often performed on jaundiced patients, it is not altogether surprising that the incidence of perioperative complications is higher in such patients than in nonjaundiced ones. In this study we assessed the potential synergistic effects of anesthesia and jaundice on cardiovascular responsiveness of chronic bile-duct-ligated dogs.

Angiotensin-converting enzyme activity in the isolated perfused guinea pig lung.

We have developed a pressure-dependent isolated lung perfusion system that can be used for the determination of pulmonary enzyme activity and kinetics under physiologic conditions. This development was done using two different artificial radiolabeled substrates, glycine-1-hippuryl-L-histidyl-L-leucine and phenyl-4(n)-hippuryl-glycyl-glycine, for the pulmonary enzyme, angiotensin-converting enzyme. With this system, we assessed the effects of different perfusate types upon the stability of the perfusion as well as the independent effects of pressure, flow, and substrate concentration on the activity of this enzyme.