Interleukin-1 beta and beta-endorphin circadian rhythms are inversely related in normal and stress-altered sleep.

Normal sleep is associated to physiological nocturnal rises in Interleukin 1 beta (IL 1 beta) secretion. The 24 h pattern of IL 1 beta, beta-Endorphin (beta-EPH), ACTH and cortisol (F) production was evaluated in four male healthy volunteers. Two subjects were unable to sleep, due to the stress of the experiment; in these cases, no detectable plasma IL 1 beta secretion, both diurnal and nocturnal, was present, beta-EPH plasma levels were significantly higher (p < 0.01) than in the subjects who slept regularly and, in one case, increased F plasma levels were also reported. A strong negative correlation between IL 1 beta and beta-EPH plasma levels was present in all the cases. In conclusion, stress-induced sleep alterations might deeply affect both diurnal and nocturnal IL 1 beta plasma secretion, probably due to the hypothalamus-pituitary-adrenal axis (HPAA) activation, and beta-EPH might be the reliable marker of the stress-induced HPAA activation level.     

Lack of Polarized Type 1 or Type 2 Cytokine Profile in Asymptomatic HIV-1-Infected Patients During a Two-Year Bimonthly Follow-Up

The production of type 1 (interferon or IFN-γ) and type 2 (interleukin or IL-4 and IL-10) cytokines by mitogen-stimulated peripheral blood mononuclear cells (PBMCs) obtained from asymptomatic human immunodeficiency virus-seropositive (HIV⁺) patients untreated with any antiviral, antibacterial or antimycotic drugs, and from healthy individuals, was evaluated by quantitative ELISA. Patients who were HIV⁺ were characterized by the absence of abnormal cytokine production. The level of each cytokine differed among individuals in the same group with intersubject variations greater for HIV⁺ patients than for healthy individuals. The longitudinal evaluation of IFN-γ, IL-4 and IL-10 production showed intrasubject variations which were particularly marked in HIV⁺ patients. Accordingly, HIV⁺ patients and, to a lesser extent, healthy individuals were characterized by a wide spectrum of possible profiles, which were confined to type 0 phenotype. In HIV⁺ patients no correlation was found between each cytokine level and the number of CD4⁺ T cells, not even in those with a falling CD4⁺ T-cell count and clinical symptoms.     

Toxic effects of dietary methylmercury on immune function and hematology in American kestrels (Falco sparverius)

Fifty-nine adult male American kestrels (Falco sparverius) were assigned to one of three diet formulations including 0 (control), 0.6, and 3.9?μg/g (dry wt) methylmercury (MeHg). Kestrels received their diets daily for 13 weeks to assess the effects of dietary MeHg on immunocompetence. Immunotoxic endpoints included assessment of cell-mediated immunity (CMI) using the phytohemagglutinin (PHA) skin-swelling assay and primary and secondary antibody-mediated immune responses (IR) via the sheep red blood cell (SRBC) hemagglutination assay. Select hematology and histology parameters were evaluated to corroborate the results of functional assays and to assess immunosuppression of T and B cell-dependent components in spleen tissue. Kestrels in the 0.6 and 3.9?μg/g MeHg groups exhibited suppression of CMI, including lower PHA stimulation indexes (p?=?0.019) and a 42 to 45% depletion of T cell-dependent splenic lymphoid tissue (p?=?0.006). Kestrels in the 0.6?μg/g group exhibited suppression of the primary IR to SRBCs (p?=?0.014). MeHg did not have a noticeable effect on the secondary IR (p?=?0.166). Elevation of absolute heterophil counts (p?相似文献   

Air and bone conduction change after stapedotomy and partial stapedectomy for otosclerosis.

OBJECTIVE: The aim of this study was to analyze and compare the results obtained in otosclerosis patient undergoing stapedotomy and partial stapedectomy. STUDY DESIGN AND SETTINGS: Retrospective review of surgical series. The guidelines of the American Academy of Otolaryngology-Head and Neck Surgery for the evaluation of results of treatment of conductive hearing loss were used. RESULTS: Pure tone average (0.5 to 3 kHz) air-bone gap was 6.1 dB in the partial stapedectomy and 6 dB in the stapedotomy group. The air-bone gap (ABG) closure rate did not differ between the 2 groups, except at 4 kHz, where stapedotomy group showed greater closure (P 0.003). Mean postoperative ABG gain was significantly (P < 0.05) higher in the stapedotomy group at 2, 3, and 4 kHz. Mean postoperative air-conduction gain did not differ significantly. Mean postoperative bone conduction (BC) change (1, 2, and 4 kHz) was 3.68 dB in partial stapedectomy and -0.02 dB in stapedotomy group, the difference being significant (P 0.007). Differences in BC change between the 2 groups were significant at each frequency. CONCLUSIONS: Similar good results can be obtained in experienced hands using either partial stapedectomy or stapedotomy technique. ABG closure rates were analogous in the 2 techniques as well as the complication rate. Although stapedotomy obtain better results at high frequencies, partial stapedectomy is associated with increased BC threshold at all frequencies.     

Does a Reduction of Adhesion Molecules by LDL‐Apheresis Have a Role in the Treatment of Sudden Hearing Loss?

Sudden hearing loss (SHL) is a highly disabling affliction that can severely affect the subject's social and relational life. Although the etiology of the complaint is still debated, it is thought that microcirculation disturbances conditioned by an endothelial dysfunction might be the main pathogenetic mechanism. Adhesion molecules favoring interaction between leukocytes and endothelial cells are early markers of endothelial damage. In the present report, we describe a case of SHL that derived evident benefit from a single session of LDL/fibrinogen apheresis, with complete hearing recovery. In this patient, in addition to reducing LDL cholesterol and fibrinogen, the circulating adhesion molecules (sE-selectin, sVCAM-1 and sICAM-1), previously present in higher than normal concentrations, were reduced by the treatment.     

Co-Spray-Dried Urea Cross-Linked Hyaluronic Acid and Sodium Ascorbyl Phosphate as Novel Inhalable Dry Powder Formulation

The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL–SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA–SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 ± 4.8% and 75.5 ± 7.2% for SD HA–SAP, 70.0 ± 1.5% and 66.5 ± 5.7% for SD HA-CL–SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter ～ 3.4 μm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 ± 0.7% for SD HA–SAP and 35.3 ± 0.3% for SD HA-CL–SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (>90% of SAP transported within 4 h). The innovative SD HA-CL–SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders.     

Toxic effects of dietary methylmercury on immune system development in nestling American kestrels (Falco sparverius)

This study evaluated the effects of dietary methylmercury (MeHg) on immune system development in captive-reared nestling American kestrels (Falco sparverius) to determine whether T cell-mediated and antibody-mediated adaptive immunity are targets for MeHg toxicity at environmentally relevant concentrations. Nestlings received various diets, including 0 (control), 0.6, and 3.9?μg/g (dry wt) MeHg for up to 18 d posthatch. Immunotoxicity endpoints included cell-mediated immunity (CMI) using the phytohemagglutinin (PHA) skin-swelling assay and antibody-mediated immune response via the sheep red blood cell (SRBC) hemagglutination assay. T cell- and B cell-dependent histological parameters in the spleen, thymus, and bursa of Fabricius were correlated with the functional assays. For nestlings in the 0.6 and 3.9?μg/g MeHg groups, CMI was suppressed by 73 and 62%, respectively, at 11 d of age. Results of this functional assay were correlated with T cell-dependent components of the spleen and thymus. Dose-dependent lymphoid depletion in spleen tissue directly affected the proliferation of T-lymphocyte populations, insofar as lower stimulation indexes from the PHA assay occurred in nestlings with lower proportions of splenic white pulp and higher THg concentrations. Nestlings in the 3.9?μg/g group also exhibited lymphoid depletion and a lack of macrophage activity in the thymus. Methylmercury did not have a noticeable effect on antibody-mediated immune function or B cell-dependent histological correlates. We conclude that T cell-mediated immunosuppression is the primary target of MeHg toward adaptive immunity in developing kestrels. This study provides evidence that environmentally relevant concentrations of MeHg may compromise immunocompetence in a developing terrestrial predator and raises concern regarding the long-term health effects of kestrels that were exposed to dietary MeHg during early avian development.     

Probing the Binding Site of Abl Tyrosine Kinase Using in Situ Click Chemistry

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Pyrrolo[2,3-d]pyrimidines active as Btk inhibitors

Introduction: Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases, and this has given rise to a search for Btk inhibitors. Nevertheless, only one Btk inhibitor, ibrutinib, has been approved to date, although other compounds are currently being evaluated in clinical trials or in preclinal stages.

Area covered: This review, after a brief introduction on Btk and its inhibitors already in clinical trials, focusses on pyrrolo[2,3-d]pyrimidine derivatives patented in the last five years as Btk inhibitors. Indeed, the pyrrolo[2,3-d]pyrimidine scaffold, being a deaza-isostere of adenine, the nitrogenous base of ATP, is an actively pursued target for Btk inhibitors. The patent literature since 2012 have been extensively investigated, pointing out the general features of the patented compounds and, when it is possible, their mechanism of action.

Expert opinion: The recently patented pyrrolo[2,3-d]pyrimidines, acting as reversible or irreversible inhibitors, showed a very interesting in vitro activity. For this reason, the development of compounds endowed with this scaffold could afford a significant impact in the search for drug candidates for the treatment of immune diseases or B-cell malignancies.