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Purposes: To describe a cohort of patients who presented with interstitial lung disease (ILD) of unknown cause, features of primary Sjögren syndrome (pSS), and a positive minor salivary gland biopsy (MSGB).Methods: Thirty-eight patients with ILD evaluated at our center underwent an MSGB to confirm a diagnosis of pSS. All of the samples were reviewed by pathologists experienced in the evaluation of salivary gland histology. We defined a positive MSGB finding as a lymphocyte focus score of >1.Results: At presentation, all patients had ILD, and symptoms of cough and dyspnea. None had a definable connective tissue disease (CTD) or known cause for their ILD. Thirteen patients (34%) had positive MSGB findings. Of these, the median age was 61 years (age range, 33 to 75 years); 7 patients (54%) were women; 8 patients (62%) had a smoking history; and 10 patients (77%) had sicca symptoms. In all patients, a thoracic high-resolution CT scan evaluation demonstrated bibasilar, peripheral-predominant, ground-glass, and reticular opacities. Four patients (31%) were negative for both antinuclear autoantibody (ANA) and rheumatoid factor (RF) autoantibody, and three patients (23%) were negative for ANA, RF, Sjögren syndrome (SS)-A, and SS-B autoantibodies. No patients experienced any complications from the MSGB. The identification of underlying pSS did not affect the management of ILD in these patients.Conclusions: Confirming a diagnosis of pSS-related ILD by performing MSGB allows for a more precise CTD classification. This study provides evidence that CTD may exist subclinically, and longitudinal studies are needed to determine whether identifying occult CTD impacts on management, longitudinal changes in lung function, or survival. [ABSTRACT FROM AUTHOR]

Purposes: To evaluate the pathologic patterns, clinical features, and survival among subjects with scleroderma (ie, systemic sclerosis [SSc]) and clinically significant interstitial lung disease (ILD) evaluated at an ILD center.Methods: Retrospective cohort study of all SSc patients who had been referred for further evaluation of ILD and had undergone surgical lung biopsy. Clinical data were abstracted by review of the medical record, and lung biopsy specimens were reviewed and classified according to current pathologic criteria.Results: All patients presented with significant respiratory symptoms. Twenty-two of 27 subjects had surgical lung biopsy-proven ILD, and 5 subjects had miscellaneous non-ILD patterns. Of those subjects with ILD, 64% (14 of 22 subjects) had a nonspecific interstitial pneumonia (NSIP) pathologic pattern (fibrotic NSIP, 13 subjects; cellular NSIP, 1 subject), and 36% (8 of 22 subjects) had the usual interstitial pneumonia (UIP) pattern. Subjects with NSIP were younger (median age, 42 vs 58 years, respectively; p = 0.003), but no differences were noted in pulmonary physiology (FVC: NSIP group, 52% predicted; UIP group, 65% predicted; p = 0.22; diffusing capacity of the lung for carbon monoxide: NSIP group, 40% predicted; UIP group, 42% predicted; p = 1.0). All patients had limited skin involvement. The Scl-70 antibody was absent among those assessed (NSIP group, 0 of 10 subjects; UIP group, 0 of 7 subjects). All patients were treated with cytotoxic therapy. The median survival time for those with NSIP was 15.3 years (5,596 days) compared with 3 years (1,084 days) for those with UIP (p = 0.07 [log-rank test]).Conclusions: In SSc patients with limited cutaneous disease and clinically significant ILD, fibrotic NSIP and UIP are the predominant pathologic patterns. Those with the UIP pattern of disease had a trend toward shorter survival time. [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence and significance of pericardial abnormalities in systemic sclerosis (SSc)-related interstitial lung disease (ILD). Methods: Retrospective study of 41 subjects with SSc-related ILD who underwent evaluation including thoracic high-resolution CT (HRCT) imaging, transthoracic echocardiography (TTE), and pulmonary function testing. HRCT review evaluated the pericardium for the presence of pericardial effusion (PEf), thickness of the anterior pericardial recess (APR) [abnormal defined as > 10 mm], and pericardial thickening as calculated by total pericardial score (TPS) [abnormal defined as > 8 mm]. Pulmonary arterial hypertension (PAH) was defined as a pulmonary artery pressure > 35 mm Hg estimated by TTE. Results: Fifty-nine percent had an abnormal pericardium, 49% had a PEf, 56% had an abnormal APR, and 49% had an abnormal TPS. An abnormal pericardium was more common in men than women. Subjects with and without pericardial abnormalities were otherwise similar with respect to age, SSc classification, autoantibodies, ILD radiographic pattern, and presence of esophageal dilation. Both groups had similar median percentage of predicted total lung capacity, percentage of predicted FVC, percentage of predicted FEV(1), and percentage of predicted diffusion capacity of the lung for carbon monoxide. Subjects with pericardial abnormalities were more likely to have coexistent PAH (35% vs 75%; p = 0.02) and a higher median right ventricular systolic pressure (31 mm Hg vs 44 mm Hg; p = 0.03). Multiple logistic regression revealed that TPS was the best individual predictor of the presence of TTE-defined PAH. Conclusions: In patients with SSc-related ILD, pericardial abnormalities are commonly seen on HRCT, and their presence is strongly associated with echocardiographically defined PAH, with abnormal TPS as the best individual predictor. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) frequently complicates connective tissue diseases (CTDs). Glucocorticoids and immunomodulatory agents are regarded as mainstays of therapy for CTD-related ILD; however, apart from those studies that have evaluated certain medications for patients with scleroderma, few studies have been performed. In this study, our objectives were to examine the safety and tolerability of mycophenolate mofetil (MMF) and to determine its impact on lung function in patients with CTD-ILD.Methods: In this retrospective observational study, we analyzed patients at our center who ever received MMF for CTD-ILD. We examined the frequency and severity of side effects associated with MMF and used longitudinal data analytic methods to determine the ability of MMF to maintain lung function over time.Results: Twenty-eight patients were treated with MMF over 35.9 patient-years. The most common underlying CTD diagnosis was scleroderma (n = 9). The most common reason for initiating MMF was an adverse effect of a prior immunomodulatory agent. Six patients had clinically significant side effects related to MMF; all resolved with dose reduction. Compared to before MMF, the mean daily prednisone dose while patients were receiving MMF was lower (10 mg/d vs 15 mg/d, p = 0.09). In addition, since starting MMF, the average percentage of predicted forced vital capacity (FVC), average percentage of predicted total lung capacity, and average percentage of predicted diffusing capacity of the lung for carbon monoxide for the cohort increased by 2.3%, 4.0%, and 2.6%, respectively.Conclusion: MMF appears to be safe and well tolerated in patients with CTD-ILD. Larger-scale studies are needed to further evaluate the efficacy of MMF in this patient population. [ABSTRACT FROM AUTHOR]

The term vasculitis encompasses a number of distinct clinicopathologic disease entities, each of which is characterized pathologically by cellular inflammation and destruction of the blood vessel wall, and clinically by the types and locations of the affected vessels. While multiple classification schemes have been proposed to categorize and simplify the approach to these diseases, ultimately their diagnosis rests on the identification of particular patterns of clinical, radiologic, laboratory, and pathologic features. While lung involvement is most commonly seen with the primary idiopathic, small-vessel or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides of Wegener granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, one should remember that medium-vessel vasculitis (ie, classic polyarteritis nodosa), large-vessel vasculitis (ie, Takayasu arteritis), primary immune complex-mediated vasculitis (ie, Goodpasture syndrome), and secondary vasculitis (ie, systemic lupus erythematosus) can all affect the lung. However, for the purpose of this review, we will focus on the ANCA-associated vasculitides. [ABSTRACT FROM AUTHOR]

Background: Prior studies have demonstrated improved efficacy when intra-articular (IA) therapeutics are injected using ultrasound (US) guidance. The aim of this study was to determine if clinical improvement in pain and function after IA hyaluronic acid injections using US is associated with changes in SF volumes and biomarker proteins at 3 months., Methods: 49 subjects with symptomatic knee OA, BMI < 40, and KL radiographic grade II or III participated. Subjects with adequate aspirated synovial fluid (SF) volumes received two US-guided IA-HA injections of HYADD4 (24 mg/3 mL) 7 days apart. Clinical evaluations at 3, 6, and 12 months included WOMAC, VAS, PCS scores, 6 MWD, and US-measured SF depth. SF and blood were collected at 3 months and analyzed for four serum OA biomarkers and fifteen SF proteins., Results: Statistical differences were observed at 3, 6, and 12 months compared to baseline values, with improvements at 12 months for WOMAC scores (50%), VAS (54%), and PCS scores (24%). MMP10 levels were lower at 3 months without changes in SF volumes, serum levels of C2C, COMP, HA, CPII, or SF levels of IL-1 ra, IL-4, 6, 7, 8, 15, 18, ILGFBP-1, 3, and MMP 1, 2, 3, 8, 9. Baseline clinical features or SF biomarker protein levels did not predict responsiveness at 3 months., Conclusions: Clinical improvements were observed at 12 months using US needle guidance for IA HA, whereas only one SF protein biomarker protein was different at 3 months. Larger studies are needed to identify which SF biomarkers will predict which individual OA patients will receive the greatest benefit from IA therapeutics.

Background: There are currently no effective disease-modifying drugs to prevent cartilage loss in osteoarthritis and synovial fluid is a potentially valuable source of biomarkers to understand the pathogenesis of different types of arthritis and identify drug responsiveness. The aim of this study was to compare the differences between SF cytokines and other proteins in patients with OA ( n = 21) to those with RA ( n = 27) and normal knees ( n = 3)., Methods: SF was obtained using ultrasound (US) guidance and an external pneumatic compression device. RA patients were categorized as active ( n = 20) or controlled ( n = 7) based upon SF white blood cell counts (> or <300 cells/mm 3 ). Samples were cryopreserved and analyzed by multiplex fluorescent bead assays (Luminex). Between-group differences of 16 separate biomarker proteins were identified using ANOVA on log10-transformed concentrations with p values adjusted for multiple testing., Results: Only six biomarkers were significantly higher in SF from active RA compared to OA-TNF-α, IL-1-β IL-7, MMP-1, MMP-2, and MMP-3. Only MMP-8 levels in RA patients correlated with SF WBC counts ( p < 0.0001). Among OA patients, simultaneous SF IL-4, IL-6, IL-8, and IL-15 levels were higher than serum levels, whereas MMP-8, MMP-9, and IL-18 levels were higher in serum ( p < 0.05)., Conclusion: These results support the growing evidence that OA patients have a pro-inflammatory/catabolic SF environment. SF biomarker analysis using multiplex testing and US guidance may distinguish OA phenotypes and identify treatment options based upon targeted inflammatory pathways similar to patients with RA.

Despite the growing number of biologic and JAK inhibitor therapeutic agents available to treat various systemic autoimmune illnesses, the lack of a validated companion diagnostic (CDx) to accurately predict drug responsiveness for an individual results in many patients being treated for years with expensive, ineffective, or toxic drugs. This review will focus primarily on rheumatoid arthritis (RA) therapeutics where the need is greatest due to poor patient outcomes if the optimum drug is delayed. We will review current FDA-approved biologic and small molecule drugs and why RA patients switch these medications. We will discuss the sampling of various tissues for potential CDx and review early results from studies investigating drug responsiveness utilizing advanced technologies including; multiplex testing of cytokines and proteins, autoantibody profiling, genomic analysis, proteomics, miRNA analysis, and metabolomics. By using these new technologies for CDx the goal is to improve RA patient outcomes and achieve similar successes like those seen in oncology using precision medicine guided therapeutics.

Background: Fibrosis or inflammation of the bronchioles is a well-known manifestation of connective tissue disease (CTD). However, the natural history of CTD-related bronchiolitis is largely unknown., Methods: We analyzed consecutive patients evaluated at National Jewish Health (Denver, CO) from 1998 to 2008 with CTD and surgical lung biopsy-confirmed bronchiolitis. Linear mixed effects models were used to estimate the longitudinal postbronchodilator FEV1 %predicted (%pred) course and differences between subjects with or without constrictive bronchiolitis (CB)., Results: Of 28 subjects with a mean age of 53 ± 9 years, fourteen (50%) had CB. The most common CTD diagnosis was rheumatoid arthritis (n = 14; 50%). There were no significant differences in demographics, smoking status, underlying CTD diagnoses, 6-min walk distance, dyspnea score or drug therapy between subjects with CB and those with cellular bronchiolitis. Three subjects with CB (11%) and four with cellular bronchiolitis (14%) died. Compared with subjects with CB, those with cellular bronchiolitis had higher mean FEV1 %pred at all times. There were no significant differences in FEV1 %pred slope within- or between-groups (CB vs. cellular bronchiolitis) preceding surgical lung biopsy or afterward., Conclusion: Subjects with CTD-related CB had lower FEV1 %pred values than those with CTD-related cellular bronchiolitis at all time points, but FEV1 %pred remained stable over time in both groups regardless of therapy received., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Small series suggest mycophenolate mofetil (MMF) is well tolerated and may be an effective therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). We examined the tolerability and longitudinal changes in pulmonary physiology in a large and diverse cohort of patients with CTD-ILD treated with MMF., Methods: We identified consecutive patients evaluated at our center between January 2008 and January 2011 and prescribed MMF for CTD-ILD. We assessed safety and tolerability of MMF and used longitudinal data analyses to examine changes in pulmonary physiology over time, before and after initiation of MMF., Results: We identified 125 subjects treated with MMF for a median 897 days. MMF was discontinued in 13 subjects. MMF was associated with significant improvements in estimated percentage of predicted forced vital capacity (FVC%) from MMF initiation to 52, 104, and 156 weeks (4.9% ± 1.9%, p = 0.01; 6.1% ± 1.8%, p = 0.0008; and 7.3% ± 2.6%, p = 0.004, respectively); and in estimated percentage predicted diffusing capacity (DLCO%) from MMF initiation to 52 and 104 weeks (6.3% ± 2.8%, p = 0.02; 7.1% ± 2.8%, p = 0.01). In the subgroup without usual interstitial pneumonia (UIP)-pattern injury, MMF significantly improved FVC% and DLCO%, and in the subgroup with UIP-pattern injury, MMF was associated with stability in FVC% and DLCO%., Conclusion: In a large diverse cohort of CTD-ILD, MMF was well tolerated and had a low rate of discontinuation. Treatment with MMF was associated with either stable or improved pulmonary physiology over a median 2.5 years of followup. MMF appears to be a promising therapy for the spectrum of CTD-ILD.

Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin α(X) chain (CD11c). This unexpected population also appears in young lupus-prone mice. On stimulation, CD11c(+) B cells, both from autoimmune-prone and healthy strains of mice, secrete autoantibodies, and depletion of these cells in vivo leads to reduction of autoreactive antibodies, suggesting that the cells might have a direct role in the development of autoimmunity. We have explored factors that contribute to appearance of ABCs and demonstrated that signaling through Toll-like receptor 7 is crucial for development of this B cell population. We were able to detect a similar population of B cells in the peripheral blood of some elderly women with autoimmune disease, suggesting that there may be parallels between the creation of ABC-like cells between mice and humans.

The purpose of this study was to identify rheumatoid arthritis (RA)-related autoantibodies in subjects with interstitial lung disease (ILD) and no articular findings of RA, supporting the hypothesis that RA-related autoimmunity may be generated in non-articular sites, such as the lung. This was a retrospective chart review utilizing clinic databases of patients with ILD to identify cases with lung disease, RA-related autoantibody positivity, and no clinical evidence of articular RA. Four patients with ILD, RF, and anti-CCP positivity and no articular findings of RA were identified. All four patients were male with a mean age at time of diagnosis of ILD of 70 years old. All had a history of smoking. Three patients died within 2 years of diagnosis of ILD and never developed articular symptoms consistent with RA; the final case met full criteria for articular RA several months after stopping immunosuppressive treatment for ILD. RF and anti-CCP can be present in smokers with ILD without clinical evidence of articular RA and in one case symptomatic ILD and autoantibody positivity preceded the development of articular RA. These findings suggest that RA-specific autoimmunity may be generated due to immunologic interactions in the lung and may be related to environmental factors such as smoking.

Systemic lupus erythematosus (SLE) is considered the archetypal systemic autoimmune disease. Clinically characterized by multisystem involvement and varied serologic abnormalities, no two patients present or have disease that evolves in exactly the same way. Viewed histologically, SLE is characterized by some combination of inflammation and fibrosis, and the clinical phenotype is dictated by the relative contributions of each and the organs affected. Tissue injury appears to be mediated by characteristic autoantibody production, immune complex formation, and their organ-specific deposition. As expected in a multisystem disease, the entire pulmonary system is vulnerable to injury. Any of its compartments-airways, lung parenchyma, vasculature, pleura, or the respiratory musculature-may be independently or simultaneously affected. This article offers the reader a comprehensive review of the numerous pulmonary and thrombotic manifestations of SLE and suggests approaches to their management.

Study Objectives: To describe the characteristics of systemic sclerosis sine scleroderma (ssSSc)-associated interstitial lung disease (ILD) presenting as idiopathic interstitial pneumonia (IIP)., Design: Retrospective review of six patients with ssSSc-associated ILD diagnosed after referral for evaluation of IIP., Measurement and Results: All patients were white, their mean age was 56 years (range, 37 to 86), and gender was evenly divided. Sclerodactyly, skin thickening, and digital edema were absent in all patients. All patients had scattered telangiectasia, and four patients had Raynaud phenomenon with abnormal nailfold capillaroscopy findings. All described gastroesophageal reflux, and three patients had esophageal dysmotility by esophagography. All had restrictive pulmonary physiology and a reduced diffusion capacity. High-resolution CT revealed nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) radiographic patterns. Of the three patients who underwent surgical lung biopsy, two patients had NSIP and one patient had UIP pathologic patterns. Five patients had asymptomatic pericardial effusions and elevated pulmonary artery pressures by echocardiography. All patients had nucleolar-staining anti-nuclear antibodies (ANAs), and one patient was anti-Scl-70 positive. All five anti-Scl-70-negative patients were anti-Th/To positive, and the anti-Scl-70-positive patient was anti-Th/To negative., Conclusions: In the presentation of an IIP, the presence of a nucleolar-staining ANA, telangiectasia, Raynaud phenomenon with abnormal capillaroscopy findings, gastroesophageal reflux, or pericardial disease suggests underlying systemic sclerosis. These findings should aid clinicians in the evaluation and treatment of patients with otherwise undefined ILD.

This study examined psychosocial correlates of immune function and illness in 89 male first-year US Air Force Academy cadets. A psychosocial questionnaire was administered to cadets prior to their arrival at the academy and was readministered during cadet orientation and during the stressful environment of Basic Cadet Training (BCT). Immune responsiveness was analyzed by PHA-, PMA-, or anti-CD3-stimulated thymidine uptake in mononuclear leucocytes. Illness episodes were assessed via medical chart review and self-reported symptoms. There were significant increases in distress levels as cadets entered BCT. No psychosocial measure assessed prior to arrival at the academy predicted level of PHA-, PMA-, and anti-CD3-stimulated thymidine uptake or risk of illness. However, hostility levels reported during BCT predicted risk of illness in the four weeks following psychosocial assessment (odds ratio = 7.1; 95% confidence interval: 1.4-36.1). Elevated response to environmental stressors and lower well-being levels also predicted impending illness, but only in the cohort of cadets who had not contracted food poisoning prior to assessment during BCT (OR = 9.3, CI = 1.9-46.7; OR = 0.09, CI = 0.02-0.53). These results suggest that self-report measures of hostility, response to environmental stressors and well-being may be useful predictors of impending illness episodes in males encountering high stress environments.

We measured intraocular pressures and retinal vascular diameters from 11 subjects during 20 seconds of microgravity produced by parabolic flight on board a KC-135 aircraft. Intraocular pressures increased 58% during parabolic flight compared to baseline values (19 +/- 1 mm Hg vs 12 +/- 1 mm Hg, respectively; P < .001). A 4% reduction in the caliber of retinal arteries was also noted during microgravity, but this change did not achieve statistical significance (7.8 +/- 0.3 pixels at zerogravity vs 8.1 +/- 0.3 pixels at 1g; P = .07). The increase in intraocular pressure and trend of arteries to constrict are thought to result from cephalad shifts in intravascular and extravascular body fluids as a result of the absence of the 1g hydrostatic gradient. The results of our study confirm that this fluid shift and its effects on the eye occur rapidly, within 20 seconds of exposure to microgravity.

Spaceflight induces a cephalad redistribution of fluid volume and blood flow within the human body, and space motion sickness, which is a problem during the first few days of spaceflight, could be related to these changes in fluid status and in blood flow of the cerebrum and vestibular system. To evaluate possible changes in cerebral blood flow during simulated weightlessness, we measured blood velocity in the middle cerebral artery (MCA) along with retinal vascular diameters, intraocular pressure, impedance cardiography, and sphygmomanometry on nine men (26.2 +/- 6.6 yr) morning and evening for 2 days during continuous 10 degrees head-down tilt (HDT). When subjects went from seated to head-down bed rest, their heart rate and retinal diameters decreased, and intraocular pressures increased. After 48 h of HDT, blood flow velocity in the MCA was decreased and thoracic impedance was increased, indicating less fluid in the thorax. Percent changes in blood flow velocities in the MCA after 48 h of HDT were inversely correlated with percent changes in retinal vascular diameters. Blood flow velocities in the MCA were inversely correlated (intersubject) with arterial pressures and retinal vascular diameters. Heart rate, stroke volume, cardiac output, systolic arterial pressure, and at times pulse pressure and blood flow velocities in the MCA were greater in the evening. Total peripheral resistance was higher in the morning. Although cerebral blood velocity is reduced after subjects are head down for 2 days, the inverse relationship with retinal vessel diameters, which have control analogous to that of cerebral vessels, indicates cerebral blood flow is not reduced.

Reduced in vitro mitogen-stimulated proliferative responses have routinely been observed from astronauts' mononuclear leucocytes following space flight. This study investigated the effect of space flight on subpopulations of peripheral blood mononuclear cells from 30 shuttle astronauts prior to launch, upon landing and 3 days after flight. The total number of peripheral blood leucocytes, granulocytes and monocytes were increased after space flight (5.7 +/- 0.2 versus 7.0 +/- 0.2; 3.1 +/- 0.1 versus 5.0 +/- 0.1; and 0.16 +/- 0.02 versus 0.25 +/- 0.28 x 10(3) cells/mm3, respectively) whereas lymphocytes were decreased (2.2 +/- 0.1 versus 1.7 +/- 0.1 x 10(3) cells/mm3). Flow cytometry analysis on Ficoll-Hypaque isolated mononuclear cells upon landing revealed significant decreases in T-inducer (CD4+, Leu-8+; 32 +/- 2 versus 23 +/- 2%) and T-cytotoxic lymphocytes (CD8+, CD11b-; 17 +/- 1 versus 12 +/- 1%), and increases in monocytes (CD14+; 13 +/- 1 versus 21 +/- 1%) compared to pre-flight and post-flight samples whereas B cells (CD19+), T-helper (CD4+, Leu-8-) and T-suppressor (CD8+, CD11b+) populations did not change. Additional phenotypic analysis of these mononuclear leucocytes from 10 crew members upon landing revealed a reduction in natural killer (NK) cells (CD16+ or CD56+; 9 +/- 1 versus 3 +/- 1%) and an increase in monocytes that were negative for insulin and insulin-like growth factor-1 (IGF-1) receptor expression. Flow cytometric analysis indicated these hormone receptor negative monocytes were smaller and less granular than receptor positive monocytes. Therefore, a novel population of monocytes may be released into the peripheral blood during the stress of space flight or upon landing. These findings may explain some of the diverse in vitro immunological and endocrine changes observed in crew members following space flight.

It has been proposed, but not confirmed, that environmental stressors alter immune function and increase the risk of viral infection among healthy individuals. We evaluated this hypothesis, examining the relationship among stress, immune function, and illness in 96 first-year U.S. Air Force Academy cadets during orientation and 4 weeks later during the stressful environment of Basic Cadet Training (BCT). Perceived stress and well-being levels of cadets were assessed via questionnaire. Immune responsiveness was analyzed by PHA-stimulated thymidine uptake in mononuclear leucocytes and by serologic evidence of reactivation of the Epstein-Barr virus (EBV). We documented significant declines in in vitro PHA-induced lymphocyte transformation (-35%; p less than 0.05) and subjective well-being (-19%; p less than 0.05) from orientation to BCT with corresponding, significant increases in perceived stress (+32%; p less than 0.05). Despite significantly altered in vitro immune responsiveness, there was no serologic evidence of EBV reactivation nor was there an association between these measures and risk of illness as determined by medical chart review and self-reported symptoms. These results suggest that reduced in vitro immune responsiveness during a moderate stressor may not necessarily lead to an increased risk of infection and/or reactivation of EBV in normal individuals.

Insulin-like growth factor-I (IGF-I) is a potential modulator of responses to a variety of immunological challenges. Previous studies have suggested that specific IGF-I receptors are present on peripheral blood leukocytes, including polymorphonuclear leukocytes, lymphocytes, and monocytes. We sought to determine what type of IGF receptor was present on peripheral blood mononuclear cells and which types of cells possessed these receptors. Binding of [125I]IGF-I to mononuclear cells was inhibited by both unlabeled IGF-I and insulin, insulin being 200-fold less potent than IGF-I. Covalent affinity labeling with [125I]IGF-I, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography, revealed a specific binding species with an apparent mol wt of 130 kDa. Two color flow cytometric analysis of mononuclear cells stained with mouse monoclonal antibodies specific for the human IGF-I receptor, the human insulin receptor, and monoclonal antibodies directed against specific monocyte and lymphocyte subset cell surface antigens revealed that both IGF-I receptors and insulin receptors were present on nearly all monocytes and B-lymphocytes, but were present on only 2% of T-lymphocytes. We conclude from these data that among human peripheral blood nonactivated mononuclear cells, IGF-I binds to specific type I IGF receptors found predominantly on monocytes and B-lymphocytes.

Intraocular pressures, retinal vascular diameters, and visual acuities of nine men (ages 19-29), were repeatedly measured while the subjects were tilted 10 degrees head-down for 48 h and while they were seated before (baseline), and after the tilt. An immediate increase in intraocular pressure, measured by pneumatonometer (4.7 +/- 0.6 mm Hg, p less than 0.001) was recorded when subjects assumed the head-down position, and diurnal variations in intraocular pressures were observed for the 48 h. The initial and final head-down intraocular pressures were not significantly different (18.9 +/- 1.2 mm Hg vs. 17.9 +/- 1.4 mm Hg, respectively). However, when subjects resumed the sitting position, intraocular pressures fell below the initial sitting values (14.2 +/- 0.9 pre vs. 11.2 +/- 0.5 post, p less than 0.04). Computer image analysis of the retinal vasculature detected a 6% and 2% reduction in the caliber of arteries and veins, respectively, as compared with sitting baseline values. No changes in visual acuity were documented during the 48 h of head-down tilt. Our data suggest that the choroidal blood reservoir increases in volume over 48 h at continuous head-down position with a compensatory decrease in aqueous volume. These findings may explain intraocular pressure changes noted in astronauts during previous space missions and in studies associated with change in body position.

The width of retinal arteries and veins was measured by digital image analysis using an automated vessel-tracking software program. Mean coefficients of variations in vessel width of less than 3% were easily achieved from digitized 35-mm retinal photographs taken with a table-top or hand-held fundus camera. Retinal images were analyzed from seven subjects exposed to sea level or altitudes equivalent to 10,000 (3048 m), 17,500 (5334 m), and 25,000 (7620 m) ft and nine subjects exposed to sea level and 14,110 ft (4300 m). At each altitude, retinal veins dilated more than did arteries (5 +/- 1 versus 0 +/- 1% at 10,000 ft and 28 +/- 9% versus 9 +/- 2% at 25,000 ft; veins versus arteries, respectively). However, widths of retinal arteries and veins were reduced in nine subjects tested after 15 minutes, 24 hours, and 48 hours of 10 degrees head-down tilt; and values varied inversely with intraocular pressures (IOP). Hand-held retinal fundus photography and digital image analysis were found to provide a sensitive and objective method for detecting and quantifying retinal vascular responses in humans exposed to novel environments.

This paper is a review and interpretation of prior studies that have investigated the effects of hypoxia on immune function. A summary of current methods used to assess immune effector cell function in human beings is presented using in vitro models of mononuclear cell activation. Animal studies indicate that impaired host defenses against bacterial pathogens may be compromised, but that resistance to virus infections may remain intact. Data from human studies and animal models indicate that active immunization and B cell function are unimpaired, whereas T cell function is blunted following exposure to hypoxia. Mechanisms that may be responsible for alterations in normal immunoregulation are presented. The implications of altered immune function in subjects exposed to high altitude are discussed.

The effect of hypoxia (H) on plasma renin (PRA), aldosterone (PA), and arginine vasopressin levels (AVP) was evaluated during 6 h of mild exercise (treadmill: 0 grade, 1 mph). A crossover study was performed on seven male volunteers during steady state conditions of H2O, Na+ and K+ balance while breathing 12.5% O2 (PaO2 42 +/- 3 mm Hg) and room air (N, 21% O2). After exercise there were no significant differences in body weight, hematocrit, calculated plasma volumes, serum or urine osmolality, urine Na+ or K+ excretion or AVP. Mean arterial pressure (MAP) while exercising was reduced during hypoxia (86 +/- 2 vs. 92 +/- 4 mm Hg), p less than 0.05. Normal diurnal variation in serum cortisol was lost during exercise (N and H). Plasma renin and aldosterone levels fell with exercise in both groups: PRA N 3.3 to 2.4 vs. H 4.9 to 2.3 ng X ml-1 X h-1; PA N 6.5 to 2.8 vs. H 9.3 to 2.3 ng X dl-1 (p less than 0.05). Hypoxia per se did not exert influence beyond mild exercise regarding serum osmolality, urine osmolality or Na+ or K+ excretion. Sustained hypoxia during 6 h of mild exercise despite a lower MAP failed to elevate PRA, aldosterone, or AVP levels when normal hydration is maintained.

We wished to determine in a field study the effectiveness of dexamethasone for prevention and treatment of acute mountain sickness (AMS). Prevention Trial: We transported 15 subjects from sea level to 4,400 m (PB = 400 mm Hg) on Denali (Mt. McKinley) by means of a 1-h helicopter flight. In a randomized, double-blind fashion we gave eight subjects a placebo and seven subjects 2 mg dexamethasone orally every 6 h, starting 1 h before take-off. The entire placebo group and five of the dexamethasone group developed AMS within 5 h, and became progressively more ill until 12 h when the trial was terminated. We concluded that 2 mg of dexamethasone every 6 h did not prevent AMS in active soldiers rapidly transported to high altitude. Treatment Trial: We treated 11 of those with moderate to severe AMS (symptom score 4.5 +/- 0.7, range 3 to 11) with 4 mg of dexamethasone every 6 h orally or intramuscularly for 24 h. All were markedly improved at 12 h (symptom score 1.0 +/- 0.3, p less than 0.001, range 0 to 3), but symptoms increased after the drug was discontinued at 24 h (symptom score = 2.4 +/- 0.5). We conclude that dexamethasone in a dosage of 4 mg PO or IM every 6 h is an effective treatment for AMS, but that illness may recur with abrupt discontinuation of the drug.

We evaluated retrospectively the effect of superimposed pregnancy upon the course of systemic lupus erythematosus (SLE) in patients receiving glucocorticoids or azathioprine at conception. About equal numbers of flares (10 vs 12) occurred among 22 pregnant patients with lupus and 22 nonpregnant control patients with lupus matched by disease duration and prior organ system involvement. Pregnancy per se did not appear to accelerate SLE in patients receiving immunosuppressive therapy.

Complex physiologic responses occur as nonacclimatized lowland dwellers ascend above 10,000 feet, with a resulting partial pressure of arterial oxygen of less than 60 mm Hg. There are marked hemodynamic changes and shifts in body fluids that may result in organ dysfunction. The suspected pathogenesis of these acute hypobaric hypoxic-induced illnesses is discussed. Cerebral dysfunction may present as acute mountain sickness or high-altitude cerebral edema. Usually asymptomatic high-altitude retinal hemorrhage and noncardiogenic high-altitude pulmonary edema also are described. All of these illnesses apparently represent a spectrum of pathologic states initiated by an exaggerated vascular response to hypoxia. With the exception of retinopathy, high-altitude illness can be prevented by slow ascent. Early recognition of cerebral or pulmonary edema and immediate descent will prevent serious consequences of nonacclimatized persons who are acutely exposed to hypobaric environments.

Though B-cell division and Ig synthesis in response to pokeweed mitogen (PWM) require interaction with T-cells and monocytes, it is not clear which earlier events in B-cell activation share this requirement, and which are the result of direct interaction of mitogen with the B-cell. Having previously shown that the acceleration of lecithin synthesis in human B-cells at 16-20 hr requires both T-cells and monocytes, we now examine whether B-cells require similar interactions to increase their protein synthetic rate, another important activation event. At 21-24 hr of PWM stimulation, the stimulation index (SI) for incorporation of [35S]methionine into protein was 2.1 +/- 0.4 for unfractionated cells, 1.7 +/- 0.1 for B-cells, 2.5 +/- 0.1 for T-cells, and 3.4 +/- 0.5 for monocytes. Thus monocytes contributed substantially to early mitogen-induced protein synthesis by human peripheral blood mononuclear cells. When the monocyte/B-cell fraction (MB) and T-cell fraction (T) were mixed at various ratios in PWM-stimulated cultures, synergy was apparent at MB:T ratios of 1:1 and 1:2, indicating cell interactions augmented early mitogen-driven protein synthesis in at least one of these cell types. However, much or all of this synergy could be attributed to T-cells, whose protein synthetic response was augmented by B-cells and monocytes. In contrast, the early increase in B-cell protein synthesis appeared to be independent of cell interactions, since their SI of 1.7 was not influenced by varying the proportion of M- or T-cells over a 50-fold range. These contrasting results between two contemporary events fits the hypothesis that one (accelerated phospholipid synthesis) requires a first signal plus one or more cell interaction signals, whereas the other (accelerated protein synthesis) requires only the first signal.

This retrospective study of 31 patients with systemic lupus erythematosus during 38 pregnancies shows a spontaneous or missed abortion rate of 7.9%, elective abortion rate of 10.5%, and a perinatal mortality rate of 12.9%. There was one maternal death 5 weeks post partum. If the onset of systemic lupus erythematosus during pregnancy included nephritis or significant thrombocytopenia, the mothers were acutely ill. All of the perinatal mortality occurred in these patients. Management of systemic lupus erythematosus during pregnancy need not differ from that in the nonpregnant state. However, immunosuppressive therapy should not be diminished or discontinued during pregnancy. Clinical parameters, renal function studies, and hematologic information were far more useful than immunologic laboratory data in assessing the course of systemic lupus erythematosus during pregnancy and indicating alterations in treatment. Antepartum fetal surveillance is advised. The timing of and route of delivery must be individualized, and systemic lupus erythematosus in and of itself is not an indication for delivery by cesarean section.

Cultured T lymphocytes from pig blood can be activated by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Activation is additive with that induced by the mitogenic lectin phytohaemagglutinin (PHA). Activation by TPA differs from that induced by PHA or other mitogenic lectins in that it is not inhibited even by high concentrations of the immunosuppressive drug cyclosporin A (CS-A). Neither co-culture of lymphocytes with PHA and TPA nor addition of culture supernatants from TPA-stimulated cultures affected the sensitivity to CS-A of the response to PHA.