The relationship between social anxiety disorder and alcohol use disorders: a critical review

Epidemiological studies have demonstrated a significant co-morbidity between social anxiety disorder (SAD) and alcohol use disorders (AUDs). Despite the fact that many studies have demonstrated strong relationships between SAD and AUD diagnoses, there has been much inconsistency in demonstrating causality or even directionality of the relationship between social anxiety and alcohol-related variables. For example, some studies have showed a positive relationship between social anxiety and alcohol-related variables, while others have shown a negative relationship or no relationship whatsoever. In an attempt to better understand the relationship between social anxiety and alcohol, some researchers have explored potential moderating variables such as gender or alcohol expectancies. The present review reports on what has been found with regard to explaining the high co-morbidity between social anxiety and alcohol problems, in both clinical and non-clinical socially anxious individuals. With a better understanding of this complex relationship, treatment programs will be able to better target specific individuals for treatment and potentially improve the efficacy of the treatments currently available for individuals with co-morbid SAD and AUD.     

Coxsackievirus B3-Induced Myocarditis : Perforin Exacerbates Disease, But Plays No Detectable Role in Virus Clearance

Viral myocarditis is remarkably common, being detected in approximately 1% of unselected asymptomatic individuals. Many cases are attributable to enteroviral infection, and in particular to coxsackievirus B3. The underlying pathogenesis is controversial, but most studies admit the important immunopathological role of infiltrating CD8⁺ (cytotoxic) T lymphocytes (CTLs). We have previously shown that CTLs play conflicting roles in coxsackievirus B (CVB) myocarditis; they assist in controlling virus replication, but also are instrumental in causing the extensive inflammatory disease, which often results in severe myocardial scarring. A role for perforin, the major CTL cytolytic protein, in CVB myocarditis has been suggested, but never proven. In the present study we use perforin knockout (PKO) mice to show that perforin plays a major role in CVB infection; in broad terms, perforin is important in immunopathology, but not in CVB clearance. For example, PKO mice are better able to withstand a normally lethal dose of CVB (100% survival of PKO mice compared with 90% death in +/+ littermates). In addition, PKO mice given a nonlethal dose of CVB develop only a mild myocarditis, whereas their perforin⁺ littermates have extensive myocardial lesions. The myocarditis in PKO mice resolves more quickly, and these mice show minimal histological sequelae; in contrast, late in disease the perforin⁺ mice develop severe myocardial fibrosis. PKO mice, despite lacking this major CTL effector function, can control the infection and eradicate the virus; growth kinetics and peak CVB titers are indistinguishable in PKO and perforin⁺ mice. Therefore, the immunopathological and antiviral effects of CTLs can be uncoupled by ablation of perforin; this offers a promising target for therapy of myocarditis. Furthermore, we evaluate the possible roles of apoptosis, and of chemokine expression, in CVB infection. In perforin⁺ mice, apoptotic cells are detected within the inflammatory infiltrate, whereas in their PKO counterparts, apoptotic myocyte nuclei are seen. Chemokine expression in both PKO and perforin⁺ mice precedes and parallels the course of myocarditis. Several chemokines are detectable earlier in PKO mice than in perforin⁺ mice, but PKO mice show reduced peak levels, and chemokine expression decays sooner. In particular, MIP-1α expression is barely detectable at any time point in PKO mice, but it is readily identified in perforin⁺ animals, peaking just before the time of maximal myocarditis; this is particularly interesting, given that MIP-1α knockout mice are resistant to CVB myocarditis, but remain able to control viral infection. Thus, the chemokine pathway offers a second route of intervention to diminish myocarditis and its sequelae, while permitting the host to eradicate the virus.     

Identification of a fibronectin-binding protein from Staphylococcus epidermidis

Staphylococcus epidermidis has been reported to bind to a number of host cell extracellular matrix proteins, including fibronectin. Here we report the identification of a fibronectin-binding protein from S. epidermidis. A phage display library of S. epidermidis genomic DNA was constructed and panned against immobilized fibronectin. A number of phagemid clones containing overlapping inserts were identified, and one of these clones, pSE109FN, contained a 1.4-kb insert. Phage pSE109FN was found to bind to fibronectin but not to collagen, fibrinogen, laminin, or vitronectin. However, pSE109FN also bound to heparin, hyaluronate, and plasminogen, although to a lesser extent than it bound to fibronectin. Analysis of The Institute for Genomic Research S. epidermidis genome sequence database revealed a 1.85-kb region within a putative 30.5-kb open reading frame, to which the overlapping DNA inserts contained within the fibronectin-binding phagemids mapped. We have designated the gene encoding the fibronectin-binding domain embp. A recombinant protein, Embp32, which encompassed the fibronectin-binding domain of Embp, blocked the binding of S. epidermidis, but not the binding of Staphylococcus aureus, to fibronectin. In contrast, a recombinant protein, FnBPB[D1-D4], spanning the fibronectin-binding domain of the S. aureus fibronectin-binding protein FnBPB, blocked binding of S. aureus to fibronectin but had a negligible effect on the binding of S. epidermidis.     

Regulation of inflammation-primed activation of macrophages by two serum factors, vitamin D3-binding protein and albumin.

A very small amount (0.0005 to 0.001%) of an ammonium sulfate [50% saturated (NH4)2SO4]-precipitable protein fraction of alpha 2-globulin efficiently supported inflammation-primed activation of macrophages. This fraction contains vitamin D3-binding protein essential for macrophage activation. Comparative macrophage activation studies with fetal calf serum, alpha 2-globulin fraction, 50% (NH4)2SO4 precipitate, and purified bovine vitamin D3-binding protein revealed that fetal calf serum and alpha 2-globulin fraction appear to contain an inhibitor for macrophage activation while ammonium sulfate precipitate contains no inhibitor. This inhibitor was found to be serum albumin. When bovine serum albumin (25 micrograms/ml) was added to a medium supplemented with 0.0005 to 0.05% (NH4)2SO4 precipitate or 1 to 10 ng of vitamin D3-binding protein per ml, activation of macrophages was inhibited.     

Structures of Toxoplasma gondii Tachyzoites, Bradyzoites, and Sporozoites and Biology and Development of Tissue Cysts

Infections by the protozoan parasite Toxoplasma gondii are widely prevalent worldwide in animals and humans. This paper reviews the life cycle; the structure of tachyzoites, bradyzoites, oocysts, sporocysts, sporozoites and enteroepithelial stages of T. gondii; and the mode of penetration of T. gondii. The review provides a detailed account of the biology of tissue cysts and bradyzoites including in vivo and in vitro development, methods of separation from host tissue, tissue cyst rupture, and relapse. The mechanism of in vivo and in vitro stage conversion from sporozoites to tachyzoites to bradyzoites and from bradyzoites to tachyzoites to bradyzoites is also discussed.     

Regulation of synaptic inputs to paraventricular-spinal output neurons by alpha2 adrenergic receptors

Neurons in the paraventricular nucleus (PVN) that project to the brain stem and spinal cord are important for autonomic regulation. The excitability of preautonomic PVN neurons is controlled by the noradrenergic input from the brain stem. In this study, we determined the role of alpha(2) adrenergic receptors in the regulation of excitatory and inhibitory synaptic inputs to spinally projecting PVN neurons. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were recorded using whole cell voltage-clamp techniques on PVN neurons labeled by a retrograde fluorescence tracer injected into the thoracic spinal cord of rats. Bath application of 5-20 muM clonidine, an alpha(2) receptor agonist, significantly reduced the amplitude of evoked GABAergic IPSCs in a dose-dependent manner. Also, 10 microM clonidine significantly decreased the frequency (from 2.68 +/- 0.41 to 1.22 +/- 0.40 Hz) but not the amplitude of miniature IPSCs (mIPSCs), and this effect was blocked by the alpha(2) receptor antagonist yohimbine. Furthermore, clonidine increased the paired-pulse ratio of evoked IPSCs from 1.25 +/- 0.05 to 1.61 +/- 0.08 (P < 0.05). On the other hand, clonidine had little effect on evoked glutamatergic EPSCs, mEPSCs, and the paired-pulse ratio of evoked EPSCs in most labeled cells examined. Additionally, immunofluorescence labeling revealed that the alpha(2A) receptor and GABA immunoreactivities were co-localized in close apposition to labeled PVN neurons. Collectively, these data suggest that stimulation of alpha(2) adrenergic receptors primarily attenuates GABAergic inputs to PVN output neurons to the spinal cord. The presynaptic alpha(2) receptors function as heteroreceptors to modulate synaptic GABA release and contribute to the hypothalamic regulation of sympathetic outflow.     

The oxidation of glucose, ketone bodies and acetate by the brain of normal and ketonaemic sheep.

1. The utilization and oxidation of glucose, acetate and ketone bodies by the brain of sheep has been determined from measurements of arteriovenous (A-V) differences and cerebral blood flow, as well as by infusing 14C-labelled metabolites. 2. The A-V difference for glucose was generally more than one sixth, on a molar basis, that of oxygen. 3. The mean rate of glucose utilization by the brain of conscious sheep (0-508 +/- 0-063 mumole/g per minute) was maintained even when the capillary glucose concentration was below 1-4 mM. 4. The amount of 14CO2 produced from [U-14C]glucose by the brain was consistent with glucose being the only energy source for the brain, even during hypoglycaemia and hyperketonaemia. 5. There was no appreciable production of lactate or pyruvate by the brain. 6. There was no significant A-V difference for acetate across the brain in normal or undernourished pregnant sheep. The small A-V differences that were measured show that less than 5% of the CO2 produced could be derived from acetate, a conclusion that is supported by experiments using [U-14C]acetate. 7. No significant A-V difference was detectable across the brain for 3-hydroxybutyrate or acetoacetate in normal fed, pregnant ketonaemic or even anaesthetized sheep infused with acetoacetate. Experiments in which [U-14C]-D(-)-3-hydroxybutyrate was infused also showed that less than 5% of CO2 was derived from ketone bodies. 8. In anaesthetized sheep infused with acetoacetate, measurements were made simultaneously across brain, heart and skeletal muscle. In contrast to the non-significant uptake of ketone bodies by the brain, uptake by heart and skeletal muscle was sufficient to account for nearly 60% of their oxygen consumption. 9. Experiments using [14C]hydroxybutyrate confirmed that during infusion of acetoacetate most of the CO2 produced by the heart, but not by the brain, was derived from ketone bodies. 10. In anaesthetized sheep ketone bodies penetrate only slowly into cerebrospinal fluid. 11. It is proposed that mechanisms for the utilization of ketones by the sheep brain have not evolved because glucose utilization by the brain is a smaller fraction of whole body glucose utilization than in man and rats.     

Identification of a novel mycoplasma species from an Oriental white-backed vulture (Gyps bengalensis)

An intracellular organism was isolated from the tissues of an Oriental white-backed vulture (Gyps bengalensis) in chicken embryo fibroblast cell cultures. Biochemical and physical properties, ultrastructural features, and 16S ribosomal DNA sequencing classified this organism as a new taxon of mycoplasma, for which the name "Mycoplasma vulturii" is proposed.