Prenatal immune activation potentiates endocannabinoid-related plasticity of inhibitory synapses in the hippocampus of adolescent rat offspring

There is strong evidence that immune activation from prenatal infection increases the risk for offspring to develop schizophrenia. The endocannabinoid (eCB) system has been implicated in the pathophysiology of schizophrenia while models of cortical dysfunction postulate an imbalance between neuronal excitation and inhibition in the disorder. The current study examined the impact of prenatal immune activation on eCB-mediated inhibitory mechanisms. We compared two forms of eCB-related plasticity of evoked inhibitory postsynaptic currents, namely depolarization-induced suppression of inhibition (DSI) and metabotropic glutamate receptor-induced long term depression (mGluR-iLTD), in both the dorsal and ventral hippocampus between adolescent offspring from rat dams that received either saline or bacterial lipopolysaccharide (LPS) during pregnancy. Compared to prenatal saline offspring, prenatal LPS offspring displayed prolonged DSI and stronger mGluR-iLTD in the dorsal and ventral hippocampus, respectively. The sensitivity of mGluR-iLTD to the CB1 receptor antagonist AM251 was also lower in the dorsal hippocampus of prenatal LPS compared to prenatal saline offspring. Testing whether changes in eCB receptor signaling or levels could contribute to these changes in inhibitory transmission, we found region specific increases in 2-arachidonoylglycerol-stimulated signaling and in basal and mGluR-induced levels of anandamide in prenatal LPS offspring when compared to prenatal saline offspring. Our findings indicate that prenatal immune activation can lead to long-term changes in eCB-related plasticity of hippocampal inhibitory synaptic transmission in adolescent rat offspring. Perturbation of the eCB system resulting from prenatal immune activation could represent a mechanism linking early life immune events to the development of psychopathology in adolescence.     

Conduct Disorder Symptoms and Illicit Drug Use in Juvenile Justice Involved Youth: The Reciprocal Relationship Between Positive Illicit Drug-Use Attitudes and Illicit Drug Use

Conduct disorder (CD) symptoms cooccur at high rates with illicit drug use in juvenile justice involved youth, which results in poorer outcomes; however, research has not identified where best to intervene in this relationship, limiting the identification of modifiable risk factors to reduce negative effects of CD symptoms. Two mediation models were examined to investigate the potential for CD symptoms to influence a reciprocal relationship between illicit drug use and positive drug attitudes, controlling for age, gender, and race. Data were examined for 245 juvenile justice involved youth (mean age = 15.46, SD = 1.30, range 12–18, 64.9% Black, 80.4% male) who completed court-ordered psychological assessments. Findings indicate: (1) Positive attitudes toward illicit drug use significantly mediated the relationship between CD symptoms and illicit drug use (β = 0.16, CI 0.09–0.27; test for indirect effect z = 4.17, p < .001) and (2) illicit drug use significantly mediated the relationship between CD symptoms and positive attitudes toward illicit drug use (β = 0.20, CI 0.12–0.32; test for indirect effect z = 4.87, p < .001). Overall, the present study suggests that CD symptoms impart risk for illicit drug use both indirectly, through more positive attitudes toward illicit drug use, and directly, which further strengthens positive attitudes toward illicit drug use.     

Action verb comprehension in amyotrophic lateral sclerosis and Parkinson’s disease

Patients with amyotrophic lateral sclerosis (ALS) have a motor disorder and cognitive difficulties, including difficulty with action verbs. However, the basis for the action verb impairment is unknown. Thirty-six participants with ALS and 22 with Parkinson’s disease (PD) were assessed on a simple, two-alternative forced-choice associativity judgment task, where performance was untimed and did not depend on motor functioning. We probed 120 frequency-matched action verbs, cognition verbs, concrete nouns and abstract nouns. Performance was related to T1 MRI imaging of gray matter atrophy. Patients with ALS were significantly impaired relative to healthy senior control participants only for action verbs. Patients with PD did not differ from controls for all word categories. Regression analyses related action verb performance in ALS to motor-associated cortices, but action verb judgments in PD were not related to cortical atrophy. These findings are consistent with the hypothesis that action verb difficulty in ALS is related in part to the degradation of action-related conceptual knowledge represented in motor-associated cortex.     

Recombinant human activated protein C in sepsis: assessing its clinical use

Based on the results of the phase III PROWESS trial, recombinant human activated protein C (rhAPC) was approved by the Food and Drug Administration (FDA) for use in severely septic patients. Concerns regarding rhAPC's inconsistent effects, incomplete understanding of its mechanism of action, and its safety in particular subgroups were raised during the FDA's evaluation. This study attempts to assess the cost-effectiveness rhAPC by comparing its effects during recent clinical use to its prior phase III trial testing and by considering other potentially less expensive treatments with effects that may overlap those of rhAPC. In patients with similar numbers of injured organs, mortality rates may be higher with rhAPC during clinical use compared with the phase III trial. There may also be an increased risk of hemorrhage and other adverse events that necessitate early discontinuation of treatment. Many of the patients receiving rhAPC during clinical use may have otherwise been excluded from its phase III trial testing. Data from several recent phase III trials as well as a recent meta-analysis suggest that heparin and physiologic dose steroids offer substantially less expensive alternatives to rhAPC. Further phase IV testing will be required to confirm such possibilities.     

Sialidosis and galactosialidosis: chromosomal assignment of two genes associated with neuraminidase-deficiency disorders.

The inherited human disorders sialidosis and galactosialidosis are the result of deficiencies of glycoprotein-specific alpha-neuraminidase (acylneuraminyl hydrolase, EC 3.2.1.18; sialidase) activity. Two genes were determined to be necessary for expression of neuraminidase by using human-mouse somatic cell hybrids segregating human chromosomes. A panel of mouse RAG-human hybrid cells demonstrated a single-gene requirement for human neuraminidase and allowed assignment of this gene to the (pter----q23) region of chromosome 10. A second panel of mouse thymidine kinase (TK)-deficient LM/TK- -human hybrid cells demonstrated that human neuraminidase activity required both chromosomes 10 and 20 to be present. Analysis of human neuraminidase expression in interspecific hybrid cells or polykaryocytes formed from fusion of mouse RAG (hypoxanthine/guanine phosphoribosyltransferase deficient) or LM/TK- cell lines with human sialidosis or galactosialidosis fibroblasts indicated that the RAG cell line complemented the galactosialidosis defect, but the LM/TK- cell line did not. This eliminates the requirement for this gene in RAG-human hybrid cells and explains the different chromosome requirements of these two hybrid panels. Fusion of LM/TK- cell hybrids lacking chromosome 10 or 20 (phenotype 10+,20- and 10-,20+) and neuraminidase-deficient fibroblasts confirmed by complementation analysis that the sialidosis disorder results from a mutation on chromosome 10, presumably encoding the neuraminidase structural gene. Galactosialidosis is caused by a mutation in a second gene required for neuraminidase expression located on chromosome 20.     

A 4-kDa maize chloroplast polypeptide associated with the cytochrome b6-f complex: subunit 5, encoded by the chloroplast petE gene.

Four polypeptides, three of which are chloroplast-encoded, have been shown to be associated with the thylakoid membrane cytochrome b6-f complex. In this report, the gene for a fifth polypeptide, which copurifies with the b6-f complex, is identified through the use of an antibody generated against a synthetic decapeptide predicted from a maize chloroplast DNA sequence. The deduced 37-amino acid sequence of the immunoreactive 4-kDa polypeptide is 100% and 86% conserved in the respective similar open reading frames encoded by Nicotiana tabacum and Marchantia chloroplast DNA. The 4-kDa polypeptide is present in both etioplasts and chloroplasts of maize and is found as well in spinach, tobacco, pea, wheat, and rice thylakoids. Similar to the other subunits of the b6-f complex, it is intrinsic to the membrane, and its hydrophilic COOH terminus is located at the stromal thylakoid surface. We propose to call the 4-kDa polypeptide "subunit 5" and the chloroplast gene that encodes it the petE gene.     

Cigarette smoking alters hepatic estrogen metabolism in men: implications for atherosclerosis

Studies of steroids and plasma lipoproteins in male cigarette smokers reveal that smoking is associated with an increase in peripheral estrogens and a decrease in high-density lipoprotein-cholesterol (HDL-C). We hypothesized that the lower HDL-C in this setting results in part from induction of the hepatic metabolic pathway that inactivates estrogen. This pathway, estradiol 2-hydroxylation, produces the peripherally inactive catechol estrogens 2-hydroxyesterone and 2-methoxyestrone. We used an in vivo radiometric method to assess 2-hydroxylation in 20 male smokers and 16 nonsmokers. The extent of the reaction (+/- SEM) was significantly higher among the smokers (43.3% +/- 1.9% v 24.6% +/- 1.9%, P less than .001). Smokers also excreted more urinary 2-hydroxyestrone (10.4 +/- 1.3 micrograms/g creatinine v 6.3 +/- 0.73 micrograms/g in nonsmokers, P = .011). The ratio of urinary 2-hydroxyestrone to estriol was higher on average among smokers (1.46 +/- 0.19 v 0.81 +/- 0.11, P = .006), and individual values correlated well with the radiometric test (r = .71, P less than .002). These data indicate that smoking is associated with significantly increased estrogen 2-hydroxylation in men. Preliminary evidence suggests that the smoking effect on C-2 hydroxylation may be opposed by ethanol. Elevated 2-hydroxylation in smokers, in the setting of modestly increased peripheral estrogens and a net decrease in HDLC, may be explained by the fact that lipoprotein synthesis and estrogen 2-hydroxylation both occur predominantly in the liver. Thus, greater metabolic inactivation of hepatic estrogens in male smokers could reduce HDLC, despite a modest rise in circulating hormone levels.     

Proliferation of myeloid progenitor cells in human long-term bone marrow cultures is stimulated by interleukin-1 beta

To study the effect of interleukin-1 (IL-1) beta on the proliferation of hematopoietic progenitor cells (HPC) in long-term bone marrow cultures (LTBMC), stromal cell layers were established from normal human bone marrow. Autologous cryopreserved mononuclear phagocyte- and T-lymphocyte-depleted bone marrow cells were reinoculated on the stromal layers in fresh culture medium, with or without the addition of human IL-1 beta (30 U/mL). Once a week, half of the culture supernatant was replaced with fresh culture medium with or without IL-1, and all nonadherent cells were returned to the flasks. At weekly intervals during a period of 5 weeks, one culture was sacrificed to determine the total number of cells and hematopoietic progenitor cells, present in the adherent and the nonadherent cell fractions. In IL-1-stimulated cultures, the number of cells recovered during a period of 5 weeks exceeded the number of cells in unstimulated control cultures by 1.5 times. This difference was attributed to a twofold increase in the number of adherent cells. The number of HPC recovered from IL-1- stimulated cultures was not different from that recovered from controls. The levels of colony-stimulating activity (CSA) in supernatants from IL-1-stimulated cultures were significantly higher than those in supernatants from control cultures. These results indicate that IL-1 enhances the recovery of cells in LTBMC by stimulating the proliferation of HPC with the concurrent release of CSA from stromal cells, without diminishing the number of HPC.