Pneumocystis activates human alveolar macrophage NF-kappaB signaling through mannose receptors

Alveolar macrophages (AM) represent important effector cells in the innate immune response to the AIDS-related pathogen Pneumocystis, but the early AM host defense signaling events are poorly defined. Using AM from healthy individuals, we showed in the present study that Pneumocystis organisms stimulate AM NF-kappaB p50 and p65 nuclear translocation in a time-dependent and multiplicity-of-infection-dependent manner as determined by electrophoretic mobility shift assay and immunofluorescence microscopy and that NF-kappaB nuclear translocation is associated with I-kappaB phosphorylation. Importantly, competitive inhibition of mannose receptor and targeted short interfering RNA-mediated gene suppression of mannose receptor mRNA and protein is associated with complete elimination of NF-kappaB nuclear translocation in response to Pneumocystis. Furthermore, human immunodeficiency virus (HIV) infection of AM (as a model human disease state of reduced AM mannose receptor expression and function) inhibits Pneumocystis-mediated NF-kappaB nuclear translocation and is associated with reduced I-kappaB phosphorylation and reduced interleukin-8 (IL-8) release. In contrast, NF-kappaB nuclear translocation and IL-8 release in response to lipopolysaccharide are intact in AM from both healthy and HIV-infected individuals, indicating that the observed impairment is not a global disturbance of the NF-kappaB pathway. Thus, in addition to phagocytic and endocytic effector functions, the present study identifies mannose receptors as pattern recognition receptors capable of NF-kappaB activation in response to infectious non-self challenge. AM mannose receptor-mediated NF-kappaB activation may represent an important mechanism of the host cell response to Pneumocystis, and altered NF-kappaB activation in the context of HIV infection may impair a critical innate immune signaling response and may contribute to pathogenesis of opportunistic lung infections.     

Hyperprolactinemia does not influence hypothalamic-pituitary-adrenocortical function during hypoglycemia in women

Elevated plasma prolactin and mild hypocortisolemia have been observed in patients with rheumatic disorders. This study was designed to assess the potential inhibitory effect of hyperprolactinemia on hypothalamic-pituitary-adrenocortical function. Hypoglycemia was induced by intravenous insulin injection (0.1 IU/kg) in 10 female volunteers of fertile age during their follicular phase twice: 60 min after either domperidone (10 mg orally) or placebo administration. Blood samples were collected from an indwelling catheter inserted into the cubital vein at -60, 0, 30, 45, 60 and 90 min. The concentrations of prolactin, adrenocorticotropic hormone (ACTH), cortisol, epinephrine, norepinephrine and glucose were measured in plasma. Domperidone administration significantly increased plasma prolactin concentrations (71 +/- 11 ng/ml vs. 14 +/- 6 ng/ml; p <0.001), while basal plasma concentrations of ACTH, cortisol, norepinephrine and epinephrine were unaffected. Insulin-induced hypoglycemia resulted in a significant rise in the mean plasma ACTH levels from 10 +/- 1 pg/ml (domperidone) and 11 +/- 1 pg/ml (controls) to 148 +/- 19 pg/ml (domperidone) and 139 +/- 12 pg/ml (controls) at 45 min (p < 0.001), in plasma cortisol from 407 +/- 62 nmol/l (domperidone) and 391 +/- 42 nmol/l (controls) to 925 +/- 60 nmol/l (domperidone) and 810 +/- 52 nmol/l (controls) at 60 min (p < 0.001), and in plasma epinephrine from 40 +/- 26 pg/ml (domperidone) and 16 +/- 3 pg/ml (controls) to 274 +/- 55 pg/ml (domperidone) and 352 +/- 61 pg/ml (controls) at 30 min; (p < 0.001). The significant increase in ACTH, cortisol and epinephrine responses to hypoglycemia was similar in both groups. We observed mild norepinephrine response to hypoglycemia but this was irrespective of the medication. In conclusion, pharmacologically-induced hyperprolactinemia did not induce significant changes of hypothalamic-pituitary-adrenocortical function and did not influence sympathoadrenal activity in healthy young women.     

Repair of Lacerated Anterior Tibial Tendon with Acellular Tissue Graft Augmentation

In the present case report, we describe the surgical repair of a complete laceration of the anterior tibial tendon using acellular human dermal tissue matrix. A 17-year-old, elite league hockey player was injured in the locker room when a teammate still clad in ice skates stepped on his bare left foot. After evaluation at a local emergency department, the patient presented to our office the next day for additional evaluation. It was determined that surgery would be performed using acellular tissue graft augmentation, followed by physical therapy. Within 7 weeks of the injury, the athlete returned to his original level of activity. At 3 years of follow-up, he was playing Division 1 hockey at the university level. We believe that augmentation of the tendon repair with the grafting material enhanced the tendon tensile strength and promoted ingrowth through vascular channels. This, combined with the patient’s dedication to physical therapy, led to excellent recovery in less time than anticipated.     

Short-term effects of continuous positive airway pressure on oxidative stress in severe sleep apnea

Sleep and Breathing - Obstructive sleep apnea (OSA) is associated with oxidative stress that is involved in the pathogenesis of cardiovascular and metabolic complications. The concentrations of...     

The role of neuroendocrine system in the pathogenesis of rheumatic diseases (minireview)

Interactions between the neuroendocrine and immune system play an important role in maintaining and restoring homeostasis. In susceptible individuals a dysfunction of the neuroendocrine system may be one of the risk factors involved in the pathogenesis of rheumatic diseases. Specific causes of altered neuroendocrine function are still not fully elucidated. Accumulation of genetical, environmental, behavioral and other risk factors during long preclinical period may result in chronic imbalances in homeostatic mechanisms maintained by neuroendocrine, microvascular and immune systems. Chronic inflammatory stress mediated by humoral and neural signals during active stages of the disease and autoantibodies against the structures of the neuroendocrine system may further participate in the neuroendocrine dysfunction. In a subset of patients with rheumatoid arthritis (RA), an assumed defect of the hypothalamic-pituitary-adrenocortical axis may be implicated in the pathogenesis. Results of some studies support the concept of adrenal dysfunction in women with premenopausal onset of the RA. Significantly lower levels of dehydroepiandrosterone sulfate (DHEAS) plasma levels of women who subsequently developed RA indicate that neuroendocrine dysfunction may be present already in preclinical period and thus are not only secondary due to ongoing inflammatory process. These findings are sketching the new prospects of possible primary prevention of RA in the future. The role of some other hormones including prolactin, growth hormone, sex hormones and involvement of autonomic nervous system in relation with the rheumatic diseases is also reviewed in the paper. Further research concerning their role in the pathogenesis of other rheumatic diseases will possibly provide new prospects in optimizing their therapy.     

Combined air pollution particle and ozone exposure increases airway responsiveness in mice

We investigated whether coexposure to inhaled ambient particles and ozone affects airway responsiveness (AR, measured as enhanced pause, Penh) and allergic inflammation (AI) in a murine model of asthma. Ovalbumin-sensitized mice were challenged with either ovalbumin ("asthmatic") or phosphate-buffered saline (PBS) aerosols for 3 successive days. Immediately after daily challenge, mice were exposed for 5 h to concentrated ambient particles (CAPs), or 0.3 ppm ozone, or both, or neither (n > or = 61/group, 12 experiments). Exposure to CAPs alone or coexposure to CAPs + O(3) caused an increase in Penh in both normal and "asthmatic" mice. These responses were transient and small, increasing approximately 0.9% per 100-microg/m(3) increase in CAPs. Analysis of the effects of particle composition on AR revealed an association between the AlSi particle fraction and increased AR in "asthmatic" mice exposed to ozone and particles. No effects of pollutants on AI were noted. We conclude that (1) particle exposure causes an immediate, short-lived (<24 h) increase in AR in mice; (2) these responses are small; and (3) changes in AR may be correlated with specific elements within the particle mixture.     

Pharmacological hyperprolactinemia attenuates hydrocortisone-induced expression of CD11b on human CD8+ cells in vivo

OBJECTIVE: To study the short-term influences of pharmacologic hyperprolactinemia on hydrocortisone (HC)-induced effects on selected immune parameters. METHODS: A single dose of HC (40 mg per os) was administered to eleven healthy female volunteers 1 h after domperidone (10 mg per os) or placebo administration. Immune cell subsets and expression of adhesion molecules was assessed by flow cytometry at baseline and 4 and 6 h after HC administration. Intracellular staining of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) production in CD4+ lymphocytes after phorbol myristate acetate and ionomycin stimulation was performed at the same time points. RESULTS: HC administration was followed by a significant increase in cortisol levels, numbers of leukocytes and granulocytes and the percentage of CD16+, CD19+, CD11a+, CD11a+CD8+, CD11b+ and CD11b+CD8+ cells. The number of lymphocytes and monocytes and the percentage of CD3+, CD4+, CD4+/CD8+ ratio, CD62L+, CD54+ and CD54+CD16+ cells decreased, while the percentage of CD8+ cells was unaffected. Domperidone administration resulted in a significant increase in prolactin (PRL) concentrations. During hyperprolactinemia, the HC-induced increase in CD11b+CD8+ cells was significantly (p < 0.05) attenuated at 4 h. HC-induced changes in other immune parameters remained unaffected. No significant changes in the intracellular production of IL-4 and IFN-gamma in CD4+ lymphocytes were observed after a single dose of HC alone or during hyperprolactinemia. CONCLUSIONS: This study shows an attenuated HC-induced increase in CD11b+CD8+ cells in the peripheral blood of healthy females during hyperprolactinemia. Our in vivo observations suggest that short-term interactions occur between PRL and glucocorticoids, affecting selected immune functions. Further studies are needed for confirmation of these results.