Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.     

The effect of HIPing on the fatigue and tensile strength of a case, porous-coated Co-Cr-Mo alloy

The process required to sinter porous Co-Cr-Mo alloys results in the formation of substrate porosity through carbide dissolution. Since hot isostatic pressing (HIPing) has been shown to eliminate casting porosity in the Co-Cr-Mo alloy, it is possible that it may be equally effective on pores that are generated from the sintering operation. The effect that HIPing a porous-coated Co-Cr-Mo material has on the fatigue and tensile properties was investigated. Fatigue testing was performed on sintered materials as well as sintered and HIPed materials, both with and without a porous coating. Further, the effect of varying coating thickness on the resulting fatigue strength of sintered and HIPed materials was studied. Light microscopy was performed in order to define the microstructural changes brought about by the various thermal cycles. Scanning electron microscopy was utilized to define the crack initiation process. The fatigue strength of uncoated "as sintered" materials was found to be reduced by 34% relative to the "as cast" condition. The same material that was HIPed revealed a fatigue strength slightly lower than the "as cast" condition. It was found that porous coatings created preferential sites for fatigue crack initiation. However, the presence of the coating did not further reduce the fatigue strength of "as sintered" materials because of the already low strength created by the sintering operation. Materials that were sintered exhibited a lowering in both tensile strength and elongation to failure relative to the "as cast" condition. The HIPing of sintered materials improved both fatigue and tensile properties relative to the "as sintered" condition.     

Six new DPB1 alleles identified in a study of 1,302 unrelated bone marrow donor-recipient pairs

Six new DPB1 alleles were identified by PCR-SSOP methodologies in the course of a retrospective study of the role of HLA matching in the outcome of unrelated donor bone marrow transplantation. Sequencing confirmed that five of these alleles (DPB1*5901, *6801, *7101, *7201, and *7301) represent novel combinations of previously described sequence motifs in the variable regions of DPB1; the sixth (DPB1*7001) appears to result from a novel point mutation. These data support previous observations which suggest that multiple mechanisms, including segmental exchange and mutation, appear to be responsible for generating sequence diversity at the DPB1 locus. The extremely low discrepancy rate of 0.1% between the two laboratories which typed the samples, and the ability to predict the new sequences from probe hybridization patterns, indicate that SSOP is an accurate and efficient method for studying polymorphism at DPB1.     

Classification of depression by grade of membership: a confirmation study

One hundred and thirty out-patients with depression were studied by grade of membership multivariate (GOM) analysis. Five depressive types were generated. Pure Type I represented a mild form of melancholia in older, stable males, who showed a modest drug response. Pure Type II included obsessive-anxious symptoms in older patients who responded well to an MAOI drug, but poorly to placebo. Pure Type III was a mildly symptomatic form of depression which responded well to placebo. Pure Type IV included features of agitation, mood worsening later in the day, anorexia and depersonalization; it was commonly precipitated by external stress and MAOI treatment was more effective than placebo. In Pure Type V depression, patients were mostly younger females with high levels of symptomatology, atypical vegetative symptoms, unstable life-styles, disadvantaged backgrounds and a poor response to MAOI and placebo. These results resemble in many ways our earlier GOM study of depression, as well as other multivariate studies of depression in the literature.     

Antibodies to maize in patients with Crohn''s disease, ulcerative colitis and coeliac disease.

The incidence of antibodies to maize using an immunofluorescent technique has been found to be 14% in controls, 33% in Crohn's disease, 50% in ulcerative colitis and 44% in coeliac disease. This result indicates that humoral immunity to maize is probably unimportant in the pathogenesis of Crohn's disease. The similar incidence of antibodies in the inflammatory bowel disease and coeliac groups suggests absorption of dietary antigen secondary to an increased mucosal permeability.     

Comparison of the immediate effects of five beta-adrenoreceptor-blocking drugs with different ancillary properties in angina pectoris

We compared the immediate effects of five beta-adrenoreceptor-blocking agents in 16 patients with stable angina pectoris. Acute dose-response studies showed that all five drugs improved exercise tolerance and reduced ST-segment depression, heart rate and blood pressure by a similar degree in comparison with a placebo (P less than 0.01). Near maximum improvement in exercise tolerance occurred when the acute cumulative oral dose had reached 160 mg for propranolol and oxprenolol, 200 mg for metoprolol and tolamolol and 400 mg for practolol. When these drugs were administered as a single doses, increase in walking time before the development of angina and reduction in ST-segment depression, heart rate and systolic blood pressure all occurred within one hour and persisted for eight hours--effects markedly different from the response to a placebo (P less than 0.01). These data show that non-cardioselective agents (propranolol and oxprenolol), cardioselective agents (practolol, metoprolol and tolamolol), as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective in the treatment of angina pectoris.     

Bacterial clearance and cytokine profiles in a murine model of postsurgical nosocomial pneumonia

The development of a nosocomial pneumonia is facilitated by alterations in host innate pulmonary antibacterial defenses following surgical trauma, which can result in decreased pulmonary bacterial clearance and increased morbidity and mortality. In a murine model of postoperative nosocomial infection, surgical stress (laparotomy) decreased Escherichia coli clearance from the lungs of animals that underwent surgery. Consistent with previous studies, (i) pulmonary levels of tumor necrosis factor alpha at 6 h and of interleukin-1beta (IL-1beta), IL-6, and gamma interferon (IFN-gamma) at 24 h post-bacterial infection (PBI) were decreased in animals that underwent laparotomy 24 h prior to E. coli infection (LAP/E. coli) compared to animals that received E. coli only; (ii) KC and macrophage inhibitory protein 2 were elevated at 6 h PBI in LAP/E. coli animals compared to E. coli-only animals; however, at 24 h PBI, levels were higher in the E. coli-only group; (iii) at 24 h PBI, monocyte chemoattractant protein 1 was lower in the LAP/E. coli group compared to the E. coli-only group; (iv) IL-10 levels were unaffected at all time points evaluated; and (v) the total number of neutrophils present in the lungs of LAP/E. coli animals at 6 h PBI was decreased in comparison to that in E. coli-only animals, resulting in decreased bacterial clearance and increased mortality in LAP/E. coli animals by 24 h PBI. Similar changes in cytokine profiles, pulmonary bacterial clearance, and mortality were consistent with reported findings in patients following surgical trauma. This model, therefore, provides a clinically relevant system in which the molecular and cellular mechanisms that lead to the development of nosocomial pneumonia can be further explored.