CD14-dependent airway neutrophil response to inhaled LPS: role of atopy

BACKGROUND: Inhaled endotoxin (LPS) is associated with airway neutrophilic (PMN) inflammation in both asthmatic and control subjects, with asthmatic subjects demonstrating possibly higher sensitivity. CD14 is the principal receptor mediating LPS responses in vivo. It is unknown whether constitutive CD14 can predict the magnitude of the PMN response after LPS inhalation and whether atopy plays a role in this response. OBJECTIVE: We sought to examine associations between constitutive airway CD14 expression and LPS-induced PMNs after 5 microg of LPS inhalation and to examine associations between markers of atopy (eosinophils and eosinophil cationic protein) and CD14 expression and LPS-induced PMNs. METHODS: Ten atopic asthmatic subjects and 8 healthy control subjects inhaled 0.9% saline and LPS (Escherichia coli 026:B6, 5 microg) separated by 3 weeks. Induced sputum was collected at 24 hours before and 6 hours after inhalation. Induced sputum was analyzed for total and differential cell counts and soluble markers (soluble [s]CD14, eosinophil cationic protein, IL8, and total protein). Flow cytometry was used to analyze membrane-bound CD14 expression. RESULTS: Significant associations were found between the LPS-induced PMN response (PMNs per milligram of sputum) and both constitutive sCD14 (R = 0.7, P =.005) and membrane-bound CD14 (R = 0.9, P =.01). Asthmatic subjects demonstrated significantly higher levels of constitutive sCD14 compared with control subjects, and baseline eosinophils were significantly associated with baseline sCD14 (R = 0.7, P =.01) and LPS-induced PMNs (R = 0.6, P =.03). CONCLUSION: Constitutive airway CD14 expression can predict the magnitude of the PMN response after inhaled LPS. Atopy appears to play a role in the level of CD14 expression and may contribute to LPS sensitivity in asthmatic subjects.     

EEG effects of subcutaneous and intracerebroventricular injections of arginine vasopressin in the rat

Several studies have suggested that arginine vasopressin (AVP) may act centrally as a neurohormone or neuromodulator to produce electrophysiological and behavioral effects. However, there are few reports of EEG effects of AVP in unanesthetized, behaving animals. In the present study the EEG effects of behaviorally relevant subcutaneous (SC) doses of AVP (6 g/kg) known to raise blood pressure were compared to behaviorally relevant intracerebroventricular (ICV) doses (0.1–1.0 ng) and multiple toxic ICV doses (1.0 g) of AVP. Central injections of toxic doses of AVP produced behavioral arrest, bodily barrel rolling, and EEG slowing, but did not induce electrographic signs of seizure activity. Comparison of the spectral characteristics of the EEG revealed some similarities in the distribution of power between SC and the 1.0 ng ICV dose; whereas ICV doses of 0.1 and 0.5 ng produced power distributions that were different from those seen following saline or SC doses of AVP. The similarities in EEG activity between SC injections and the 1.0 ng ICV dose suggest a common brain state may be induced by the two routes of administration in those dose ranges.     

Sizes, laminar and topographic origins of cortical projections to the major divisions of the red nucleus in the monkey

The retrograde transport of horseradish peroxidase was used to study the topographic and laminar origins of the cortical projections to the parvocellular and the magnocellular divisions of the red nucleus in Macaca mulatta and Macaca fascicularis. Approximately 90% of the corticorubral projection is directed to the parvocellular division of the nucleus. Corticoparvocellular (CRp) neurons are pyramidally shaped, are smaller in size than corticospinal neurons, and are more numerous. They are found principally in sublamina Va of cytoarchitectonic areas 4 and 6, and in moderate quantities in sublamina Vb of posterior area 8 and area 5. In areas 4 and 6, the cells are grouped in clusters of three to 15 neurons each and are arranged in cellular bands of varying rostrocaudal thickness which course mediolaterally. With respect to functionally defined zones, CRp neurons are found throughout the supplementary motor area and the precentral motor cortex. In addition, they are found in parts of areas 5, 6, and 24 that project to these cortical motor areas, and that are thought to have "premotor" or movement-programming functions. The corticomagnocellular (CRm) projection arises principally from cells in sublamina Vb of the precentral arm and leg areas (area 4), and from adjacent parts of posterior area 6, CRm cells are pyramidally shaped, and their size distribution is bimodal, with peaks that correspond, respectively, to the modal diameters of CRp and of corticospinal neurons. These results and those of previous studies suggest that CRm neurons are involved principally in the control of hand and foot movements, with little effect on more proximal musculature. The massive CRp projection, however, is clearly part of a large cerebrocerebellar communication system, with motor and/or movement programming functions that have yet to be clearly defined.     

Safety and Efficacy of a Steroid Avoidance Immunosuppression Regimen in Renal Transplant Patients With De Novo or Preformed Donor-Specific Antibodies: A Single-Center Study

Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing. Cohorts included kidney transplant recipients with de novo DSAs (dnDSAs; n = 27), preformed DSAs (pfDSAs; n = 15), and no DSAs (nDSAs; n = 146). Median time to dnDSA development (classes I and II) was shorter (102 days) than in previous studies. Rejection of any type was associated with DSAs to class I HLA (P < .05) and class II HLA (P < .01) but not with graft loss. Although mean fluorescence intensity (MFI) independently showed no association with rejection, an MFI >5000 showed a trend toward more antibody-mediated rejection (P < .06), though graft loss was not independently associated. Banff chronic allograft nephropathy scores and a modified chronic injury score were increased in the dnDSA cohort at 6 months, but not at 2 years (P < .001 and P < .08, respectively). Our data suggest that dnDSAs and pfDSAs impact short-term rejection rates but do not negatively impact graft survival or histopathological outcomes at 2 years. Periodic protocol post-transplant DSA monitoring may preemptively identify patients who develop dnDSAs who are at a higher risk for rejection.     

Chromogranin A: osmotically active fragments and their susceptibility to proteolysis during lysis of the bovine chromaffin granules

Osmotically active fragments of chromogranin A (Chr A) were studied in lysates from bovine chromaffin granules (CG) disrupted in the presence or absence of inhibitors of endogenous proteolytic activities. The effects of various methods of lysis were examined by micro-osmometry, PAGE-SDS electrophoretic techniques and immunoblots with polyclonal anti-Chr A sera. Osmotically active 'small' Chr A fragments (below 30 kDa) were conspicuous in lysates containing cocktails of leupeptin, pepstatin A, pHMB, PMSF and aprotinin. The osmotically inactive native Chr A in the 68-100 kDa range and the osmotically active fragments below 47 kDa were degraded in lysates at neutral or acid pH in the absence of inhibitors. However, degradation of the native Chr A and intermediates below 47 kDa could be prevented by extraction directly from intact CG, notably in cold or boiling distilled water. On the other hand, the main product after large-scale extraction of CG in 1 M acetic acid (pH 1.9, 100 degrees C) was a novel, osmotically active fragment (22 kDa), immunostaining only for the N-terminal sequence (Chr A1-40). The heat-stable fraction (Mr,n 23 kDa) exhibited concentration-independent colloid osmotic pressures even in the absence of phosphate, a property which may distinguish this N-terminal-containing fragment from the larger intermediates, probably containing the pancreastatin sequence, and other regions at the C-terminal side of the prohormone molecule. The functional roles of these osmotically active intermediates in the processing of Chr A are not yet known.     

Duration of improved muscle glucose uptake after acute exercise in obese Zucker rats

Skeletal muscle is insulin resistant in the obese Zucker rat. Endurance training reduces muscle insulin resistance, but the effects of a single acute exercise session on muscle insulin resistance in the obese Zucker rat are unknown. Therefore, insulin responsiveness of muscle glucose uptake was measured in 15-week-old obese rats either 1, 48, or 72 hours after two hours of intermittent exercise (30:30 min; work:rest). Hindlimbs of sedentary lean (LS) and obese (OS) rats and exercised obese (OE) rats were perfused after a 10-hour fast under both basal (0 mU x ml(-1)) and maximal (20 mU x ml(-1)) insulin concentrations to measure net glucose uptake. Insulin responsiveness of net glucose uptake was significantly reduced in OS compared to LS (8.5 +/- 1.6 vs 15.3 +/- 2.0 micromol x g(-1) x h(-1), respectively). Compared to OS, insulin responsiveness of net glucose uptake was significantly increased by 56% and 80% at 1 hour and 48 hours after acute exercise. However, 72 hours after acute exercise, the increased insulin responsiveness of net glucose uptake was no longer evident. These results indicate that improved responsiveness of muscle glucose uptake persists for at least 48 hours after two hours of acute intermittent exercise in 15-week-old obese Zucker rats.     

The impact of participation in health promotion on medical costs: a reconsideration of the Blue Cross and Blue Shield of Indiana study

PURPOSE. The purpose of this study was to investigate whether participation in a comprehensive worksite health promotion program was associated with reduced employee health care costs. DESIGN. Four independent study groups, two treatment and two comparison, were identified based on type and date of first participation in the intervention. Two years of pre-program health cost data and five years of post-program data were collected for each subject. The Jonckheere-Terpstra statistical test was used to analyze the data. SETTING. The health promotion program was offered at Blue Cross and Blue Shield of Indiana corporate headquarters. The study period began on January 1, 1976, and continued through December 31, 1982. SUBJECTS. Seven hundred and forty-three men and women employed continuously by Blue Cross and Blue Shield of Indiana throughout a seven-year period were studied. INTERVENTION. The health promotion program consisted of four progressive phases which involved 1) health risk reduction mass education, 2) completion of a health risk appraisal and risk reduction counseling, 3) health promotion classes such as smoking cessation and nutrition education, and 4) follow-up and maintenance. MEASURES. The principal dependent variable was pre-program to post-program changes in health costs as measured by employee health care expense claims paid for by the company's health insurance plan. RESULTS. This study found that program participation was not associated with reduced health care costs. CONCLUSIONS. It would be prudent to remain guarded about the health cost savings effects of worksite health promotion programs.