SHIP represses mast cell activation and reveals that IgE alone triggers signaling pathways which enhance normal mast cell survival

The hemopoietic specific, Src homology 2-containing inositol 5' phosphatase (SHIP) hydrolyzes the phosphatidylinositol (PI)-3-kinase generated second messenger, PI-3,4,5-trisphosphate (PIP(3)), to PI-3,4-bisphosphate (PI-3,4-P(2)) in normal bone marrow derived mast cells (BMMCs). As a consequence, SHIP negatively regulates IgE+antigen (Ag)-induced degranulation as well as leukotriene and inflammatory cytokine production. Interestingly, in the absence of SHIP, BMMCs degranulate extensively with IgE alone, i.e. without Ag, suggesting that IgE alone is capable of stimulating signaling in normal BMMCs and that SHIP prevents this signaling from progressing to degranulation. To test this, we compared signaling events triggered by monomeric IgE versus IgE+Ag in normal BMMCs and found that multiple pathways are triggered by monomeric IgE alone and, while they are in general weaker than those stimulated by IgE+Ag, they are more prolonged. Moreover, while SHIP prevents this IgE-induced signalling from progressing to degranulation or leukotriene production it allows sufficient production of autocrine acting cytokines, in part by activation of NFkappaB, to enhance BMMC survival. Interestingly, the activation of NFkappaB and the level of cytokines produced are far higher with IgE than with IgE+Ag. Moreover, IgE alone maintains Bcl-X(L) levels and enhances the adhesion of BMMCs to fibronectin and this likely enhances their survival still further.     

Differential association of phosphatases with hematopoietic co-receptors bearing immunoreceptor tyrosine-based inhibition motifs

A novel family of inhibitory co-receptors has been recently defined according to the presence in their intracytoplasmic domain of immunoreceptor tyrosine-based inhibition motifs (ITIM). In particular, this family includes a low-affinity receptor for IgG, FcγRIIB, which is widely expressed on hematopoietic cells, as well as killer cell inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I proteins, expressed on both T and natural killer (NK) lymphocytes. FcγRIIB and KIR inhibitory function depends upon the tyrosine phosphorylation of their respective ITIM. Phosphorylated FcγRIIB and KIR ITIM bind the tandem SH2 tyrosine phosphatases, SHP-1 and SHP-2. Recently, FcγRIIB has been shown to associate with a polyphosphate inositol 5-phosphatase, SHIP, which appears to be involved in its inhibitory function. Using cell lysate adsorption to phosphorylated ITIM peptides and surface plasmon resonance, we demonstrate here that, in contrast to FcγRIIB, KIR (CD158b: p58.2) do not bind to SHIP, and only recruit SHP-1 and SHP-2. In addition, we show that point mutation of the amino acid residue in position tyrosine-2 of FcγRIIB and KIR ITIM abolihes their binding to SHP-1 and SHP-2, but leaves intact the association of SHIP with FcγRIIB ITIM. These data contribute to the structural definition of ITIM and document a differential recruitment of phosphatases by distinct ITIM. These findings also reveal that diverse strategies of inhibition are used by distinct members of the ITIM-bearing co-receptor family.     

Infectious influenza A and B virus variants with long carboxyl terminal deletions in the NS1 polypeptides

An influenza A virus, A/turkey/Oregon/71, was shown by protein gel analysis to code for an NS1 protein approximately half the size of those of other influenza A viruses. Sequence analysis of the NS gene of this virus revealed a 10 nucleotide deletion resulting in an NS1 protein of only 124 amino acids. This truncated NS1 polypeptide retained its karyophilic pattern as detected by indirect immunofluorescence analysis of virus infected cells. Also, A/turkey/Oregon/71 virus grew to high titer in embryonated chicken eggs comparable to other influenza A viruses. We also identified a laboratory variant of an influenza B virus, clone 201, which codes for a truncated NS1 protein. Sequence analysis revealed a 13 nucleotide deletion resulting in a shortened NS1 protein of only 127 amino acids as compared to other influenza B virus NS1 proteins possessing a length of 281 amino acids. Again as shown for the NS1 proteins of other influenza B viruses the NS1 polypeptide of B virus clone 201 was found to localize in the nucleus of infected cells. It appears that large deletions in the carboxyl terminus of the NS1 proteins of influenza A and B viruses can be tolerated without affecting the functional integrity of the NS1 polypeptide.     

EEG correlates of the response to ECT: a possible antidepressant role of brain-derived neurotrophic factor

Studies on the relationship of electroencephalographic (EEG) data to the therapeutic response to electroconvulsive therapy (ECT) have been carried out since the 1940s, but for many years they did not yield any consistent correlates. Recent studies, however, are providing a growing body of evidence of relationships between the antidepressant response to ECT and both the ictal (recorded during ECT seizures) and interictal (recorded during waking) EEG. These studies appear to be consistent in pointing to the importance of electrophysiologic changes in the prefrontal cortex as a potential mediator of the antidepressant response to ECT. The available findings are reviewed and discussed in light of recent neurophysiologic and neuropsychiatric research, including that related to neurotrophic factors.     

Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine

The effects of oral administration of the ₂ adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful ₂ antagonist in humans.     

Invited commentary: complexities in evaluating neurobiological models for stress resistance

Professors Salmon and Stanford are to be commended for their efforts in drawing attention to noradrenergic contributions to stress resistance and the potential importance of within-subject patterns of stress response. In commenting on their paper, I would like to develop the following points: (1) self-control over stress exposure strongly influences the noradrenergic response to stress; (2) β-receptor regulation may reflect a lower sensitivity to stress under a carefully specified range of conditions; and (3) genetic and environmental factors may interact in a complex fashion that may not fit simple linear models based on β-receptor function.     

Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients.

Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.     

Ranolazine for the treatment of refractory angina in a veterans population

BackgroundPivotal ranolazine trials did not require optimization of conventional medical therapy including coronary revascularization and antianginal drug therapy prior to ranolazine use. This case series describes the use of ranolazine for the treatment of chronic stable angina refractory to maximal medical treatment in a veterans population.ResultsA total of 18 patients with a median age of 66 years were identified. All patients had prior percutaneous coronary intervention and/or coronary artery bypass graft surgery; 83% had three-vessel coronary artery disease, with left main disease present in 39% of patients. Prior to initiating ranolazine, antianginal use consisted of beta blockers (94%), long-acting nitrates (83%) and calcium channel blockers (61%). Median blood pressure (116.2/61.8 mmHg) and pulse (65 beats per min) were controlled. Median preranolazine angina episodes and sublingual nitroglycerin (SLNTG) doses per week were 14 and 10, respectively, with a Canadian Cardiovascular Society (CCS) angina grade of III–IV in 67% of patients. After initiation of ranolazine, median angina episodes per week and SLNTG doses used per week decreased to 0.7 and 0, respectively, with CCS grade of III–IV declining to 17%. Of the 18 subjects enrolled, 44% had complete resolution of angina episodes.ConclusionThe addition of ranolazine to maximally tolerated conventional antianginal drug therapy post coronary revascularization was associated with decreases in angina episodes and SLNTG utilization and improvement in CCS angina grades. Ranolazine may provide an effective treatment option for revascularized patients with refractory angina.