Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.

It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.

Sociocultural factors influencing adolescent preference and use of native Hawaiian healers.

OBJECTIVE: Few studies have examined the use of alternative therapies among adolescents. This study examines the predictors of Native Hawaiian healer preference in the treatment of physical or emotional problems as well as the predictors of healer use. DESIGN: This study is a longitudinal cross-sectional design. SETTING: The survey was conducted in five high schools in Hawai'i. PARTICIPANTS: 1,322 high school students selected preference for and/or use of allopathic or alternative practitioners. MAIN OUTCOME MEASURES: Grade level, gender, ethnicity and cultural identity were used to predict healer preference. Healer preference, socioeconomic status and health status were used to predict healer use. RESULTS: Identification with the Hawaiian culture was the strongest predictor of healer preference for both Hawaiian and non-Hawaiian adolescents. Mental health was also predictive of healer preference for non-Hawaiians. Healer use by Native Hawaiian adolescents was also predicted by Hawaiian cultural identity. Gender, grade level, and socioeconomic variables were not predictive of healer preference or use. CONCLUSION: Cultural identity plays a significant role in the preference and use of alternative practitioners, especially for minority adolescent populations.

Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Collaborating Centers.

Occupational exposures were investigated in a multicenter case-control study of clinically and histologically diagnosed idiopathic pulmonary fibrosis (IPF), a chronic diffuse interstitial lung disease of unknown etiology. Results are based on 248 cases, aged 20-75 years, diagnosed at 16 referral centers between January 1989 and July 1993. There were 491 controls ascertained by random digit dialing and matched to cases on sex, age, and geographic region. Data were collected using a standard telephone questionnaire. Occupational factors were based on a detailed history of jobs lasting 6 months or more and job activity, hobby, and specific substance checklists. Several occupational factors, adjusted for age and smoking in conditional multivariate logistic regression analyses, were significantly associated with IPF: farming (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5); livestock (OR = 2.7, 95% CI: 1.3, 5.5); hairdressing (OR = 4.4, 95% CI: 1.2, 16.3); metal dust (OR = 2.0, 95% CI: 1.0, 4.0); raising birds (OR = 4.7, 95% CI: 1.6, 14.1); stone cutting/polishing (OR = 3.9, 95% CI: 1.2, 12.7); and vegetable dust/animal dust (OR = 4.7, 95% CI: 2.1, 10.4). Interaction was detected between smoking and exposure to livestock (p = 0.06) and farming (p = 0.08). Results confirm previous studies showing increased risk associated with dusty environments.

Psychometric properties of the Hawaiian Culture Scale--Adolescent Version.

This article reports on the psychometric properties of a newly constructed Hawaiian Culture Scale--Adolescent Version. A total of 2,272 Native Hawaiian and 1,170 non-Hawaiian adolescents were administered this 50-item inventory that measures the source of learning the Hawaiian way of life, how much Hawaiian beliefs are valued and important to maintain, how much non-Hawaiian beliefs are valued, Hawaiian blood quantum, and specific cultural traditions (seven subscales = Lifestyles, Customs. Activities, Folklore, Causes-Locations, Causes-Access, and Language Proficiency). The results strongly supported the internal consistency and validity of the measures for both the Hawaiian and non-Hawaiian groups. On the basis of the demographic data, partial support was offered for cross-cultural theories of ethnic identity. More consistent support was found for multiculturalism in Hawai'i's adolescents. Further research is needed to link these measures with indicators of psychological adjustment (e.g., depression, anxiety, substance use).

Depressive symptoms among Filipino American adolescents.

Minority ethnic status has been found to be related to higher levels of depressive symptoms among adolescents and adults. The present study examined the rates of depressive symptoms (as measured by the Center for Epidemiologic Studies Depression Scale: CES-D Scale) of 270 Filipino American adolescents residing in rural and small-town areas of Hawaii. CES-D scores were compared with scores of a White group, and no ethnic differences were found. Compared with Filipino males, Filipino females were found to have higher CES-D scores, with higher mean scores on the majority of the CES-D items. The few Filipino students who reported attempting suicide had moderately high to very high levels of reported depressive symptoms. Lack of ethnic differences may be due to Hawaii's unique cultural mix, where there is no single "majority group" and a high rate of cultural interaction.

Mentoring new faculty in a department of psychiatry.

A formalized mentoring program was developed in response to several problems experienced by new faculty in a department of psychiatry. Goals of the program were to facilitate socialization/orientation to academic psychiatry, facilitate and improve functioning of faculty, and increase retention of new faculty members. A 36-item questionnaire and a program evaluation form were developed to evaluate the effectiveness of the program. Significant differences were found for the overall mean of all pre- vs. postmeasures and the sum of the items related to facilitation of socialization/orientation to academic psychiatry. Mentors and mentees evaluated the program as worthwhile and would recommend it to other faculty members.

Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis.

We conducted a multicenter case-control study of clinically and histologically diagnosed idiopathic pulmonary fibrosis (IPF), a chronic diffuse interstitial lung disease of unknown cause. The study included 248 cases, and 491 control subjects identified through random-digit dialing, matched to cases in sex, age, and geographic region. Telephone interviews were conducted with both cases and controls to collect information on potential risk factors for IPF, including smoking and household, occupational, and environmental exposures. Pulmonary function tests, X-rays, computed tomographic (CT) scans of the chest, and lung biopsy reports were submitted by referring centers to support the diagnoses. An a priori hypothesis that smoking is associated with IPF was examined with conditional logistic regression analyses. More cases (72%) than control subjects (63%) had a history of ever smoking. The odds ratio (OR) for ever smoking was 1.6 (95% CI: 1.1 to 2.4). Risk was significantly elevated for former smokers (OR = 1.9; 95% CI: 1.3 to 2.9) and for smokers with 21 to 40 pack-yr (OR = 2.3; 95% CI: 1.3 to 3.8). A history of smoking is associated with an increased risk for the development of IPF. Although there was no clear exposure-response pattern with cumulative consumption of cigarettes, there was a trend for time since cessation of smoking, with the highest risk for those who had most recently quit.

Psychosocial risk and protective influences in Hawaiian adolescent psychopathology.

A large community sample of adolescents of a Native Hawaiian (Asian/ Pacific Islander) minority group was studied along with a small comparison group of non-Hawaiians, for the relationship between psychopathology (as measured by standard symptom scales) and (a) perceived support from family and friends, and (b) discussing problems with others. Expected gender patterns for friend support but not for family support were found. The Hawaiian boys appeared atypical, reporting nearly equal family support as Hawaiian girls. Discussing problems with another person was correlated with lower anxiety and depression scores but not aggression and substance abuse scores. It is concluded that gender and cultural factors influence symptom prevalence and severity as well as the impact of psychosocial risk factors.

Psychiatric symptoms of Hawaiian adolescents.

The purpose of this study was to examine the interrelationship of depressive symptoms with symptoms of anxiety, aggression, and substance abuse in Native Hawaiian adolescents. A total of 1,819 Native Hawaiian students were recruited from three high schools as part of the initial phase of an ongoing, 4-year, longitudinal, cross-sequential study. Psychiatric symptoms were measured with the Center for Epidemiological Studies-Depression Scale (CES-D), Spielberger's State Anxiety Inventory (SAI), Braver Aggression Dimension Scale (BADS), and Substance Abuse Subtle Screening Inventory-Abbreviated (SASSI-A). Scales were standardized for this minority population. Depressive symptoms were strongly associated with symptoms of anxiety and aggression but only weakly associated with self-reported substance abuse. Girls had substantially higher scores than boys on all scales. Ninth graders reported more aggressive symptoms than did 12th graders. The educational level of the adolescent's main caregiver was not associated with symptoms reported in any of the scales. Native Hawaiian adolescents report similar symptoms and symptom clusters as do adolescents on the mainland U.S. However, Native Hawaiian adolescent girls report a greater number of symptoms in all categories when compared to boys. This distinguishes them from most mainland adolescent populations.

Endemic work-related febrile respiratory illness among construction workers.

Construction workers building Denver International Airport (DIA) reported work-related respiratory and flulike symptoms of several months duration. We performed a cross-sectional interview study of 495 randomly selected DIA workers from six contractors in comparison with preplacement workers. We defined cases as workers with two work-attributed lower respiratory symptoms and one work-attributed systemic symptom. Case rates were significantly higher among DIA workers (34%) compared with those who had never worked at DIA (2%). Risk factors for illness included exposure to fireproofing (OR, 4.21; 95% CI, 1.95-9.08), work in tunnels and adjoining areas (OR, 3.07; 95% CI, 1.84-5.12), length of DIA employment (OR, 0.65; 95% CI, 0.46-0.92), and preexisting bronchitis (OR, 2.43; 95% CI, 1.17-5.05). Our industrial hygiene investigation revealed alkaline dust (pH 11) present at a worksite associated with elevated risk of illness, and we identified airborne Penicillium mold widely distributed indoors at DIA. Clinical evaluation of 26 self-identified symptomatic DIA employees, including bronchoalveolar lavage and biopsy in 10, revealed work-related asthma in three workers and histologic evidence of chronic bronchitis in four who had never smoked. We concluded that future investigations of endemic work-related febrile respiratory illness among construction workers should evaluate its association with indoor exposure to dusts from alkaline fireproofing, Penicillium mold, mycotoxins, and bacterial bioaerosols.

Cytogenetic findings in 200 patients with multiple myeloma.

Cytogenetic studies were performed in 200 consecutive patients with multiple myeloma and related disorders. Structurally or numerically abnormal clones were found in 63 patients (32%), including 8 of 45 untreated patients (18%), and 55 of 155 treated patients (35%). The abnormal karyotypes generally showed numerous numerical and structural aberrations and in some patients multiple abnormal clones. The most striking feature of patients with hyperdiploid karyotypes was the finding of consistent recurring trisomies for chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, cosegregating together in many cases. Monosomy for chromosome 13 was the most common chromosome loss, occurring in 18 abnormal patients (29%), while interstitial deletions involving band 13q14 occurred in an additional 9 patients, indicating a loss of all or part of chromosome 13 in a high percentage of patients with abnormal karyotypes (43%). Structural aberrations of chromosome 1 were most frequent, occurring in 30 of 63 patients (48%), and involved almost equally the short and long arms. The single most frequent chromosome breakpoint involved band 14q32 and was found in 21 patients (33%), including 11 patients with a 14q+ chromosome, 8 with t(11;14)(q13;q32), and 2 with t(8;14)(q24;132).

Morphological characterization of stromal cell types in hematopoietically active long-term murine bone marrow cultures.

Accurate histological evaluation of stromal morphology is very difficult in cultures incubated in plastic flasks. Employing glass flasketts, we were able to characterize the morphology and immunocytochemistry of four marrow stromal cell types in a functionally intact microenvironment of murine long-term bone marrow cultures (LTBMCs). Fibroblastoid cells stained positively for collagen Type I and III, negatively for von Willebrand factor (vWf), the mouse macrophage F4/80 antigen, and the Bandeiraea simplicifolia lectin I isolectin B4 (BSL I-B4). Endothelial cells stained positively for vWf antigen and lectin BSL I-B4 but negatively for collagen Types I and III and for F4/80 antigen. Fat-containing cells had a dense, ovaloid, indented nucleus and fat-containing vacuoles. Macrophages were strongly positive for the F4/80 antigen and stained weakly with BSL I-B4. Between the fourth and ninth weeks after culture initiation, fibroblastoid and endothelial cells remained constant, between 21 +/- 2% and 24 +/- 2% and between 3 +/- 0.3% and 4 +/- 0.4%, respectively, of the total stromal cell population. By contrast, the percentage of fat-containing cells decreased significantly from 26 +/- 3% at Week 4 to 17 +/- 2% at Week 9, and macrophages increased significantly from 49 +/- 1% at Week 4 to 57 +/- 1% at Week 9. This characterization of the stromal cell types in functionally intact LTBMCs should assist in the study of the complex interactions among the marrow stroma, cytokine production, and hematopoiesis.

Perceptions of family values and roles among Japanese Americans: clinical considerations.

A follow-up study of intact families in Hawaii found that Japanese Americans' perceptions of family values and roles were more likely than those of European Americans to reflect a hierarchical family status with greater role differentiation and the male role as central. Additionally, Japanese Americans emphasized collective harmony, cooperation, interpersonal acceptance, and positive mutual social interactions. Clinical implications of the findings are discussed.

Structural and functional characterization of potent antithrombotic oligonucleotides possessing both quadruplex and duplex motifs.

We report the results of a selection for single-stranded DNA oligonucleotide ligands to the serine protease thrombin using recently developed methods. This selection yielded a family of DNA sequences that conform to a consensus structure comprised of a unimolecular quadruplex motif and complementary flanking sequences capable of forming an additional Watson-Crick duplex motif. This novel quadruplex/duplex structure was not reported in a previous selection for DNA molecules which bind to thrombin [Bock et al. (1992) Nature 355, 564-566]. All quadruplex/duplex molecules tested bound to thrombin with higher affinity than quadruplex structures lacking the duplex structure. However, binding affinities did not always correlate with inhibitory potency since some molecules with high affinity were not potent inhibitors in vitro. 1H NMR spectroscopy studies demonstrated that the complementarity of bases in the duplex portion of a selected sequence allows it to form multimolecular structures. Constraining these molecules to the unimolecular quadruplex/duplex structure by bridging the 5' and 3' ends of the duplex motif with either triethylene glycol or disulfide bonds improved their thrombin inhibitory activity. All bridged quadruplex/duplex molecules were more potent inhibitors than molecules with only a quadruplex motif. Bridging the ends of these structures not only increased thrombin inhibition but also improved resistance to nucleases in serum more than 40-fold over the unbridged quadruplex. In addition, we have found that both the length and sequence of the duplex motif are important for inhibition.

Correlation of structure and function in idiopathic pulmonary fibrosis.

The early stage of idiopathic pulmonary fibrosis (IPF) is thought to involve a smaller number of alveoli and to be characterized predominantly by cellularity and minimal fibrosis, whereas advanced disease involves a large number of alveoli and is characterized predominantly by fibrosis with minimal cellularity. In addition, correlative studies have indicated that prognosis and response to therapy is determined in part by the extent of fibrosis and cellularity. This study was undertaken to determine whether pulmonary function assessment would help distinguish between the cellular and fibrotic phases of this disorder, as determined by a semiquantitative pathology scoring system that comprised four factor scores: fibrosis, cellularity, granulation/connective tissue, and desquamation. Ninety-six untreated patients with biopsy-confirmed IPF (27 never smokers, 32 current smokers, and 37 ex-smokers) were evaluated. In the group as a whole, there was no significant relationship between the fibrosis or the connective/granulation tissue factor scores and any of the physiologic parameters. The DLCO correlated with the "desquamation" and the total pathology scores, whereas the TLC and FVC correlated with the cellularity factor score. In the current smokers, the coefficient of elastic retraction, DLCO/VA, and FEV1/FVC ratio were significantly lower than in never smokers and ex-smokers, and TLC and FVC were higher than in never smokers. Also, the mean cellularity and granulation/connective tissue factor scores were significantly lower, and the desquamation factor score was significantly higher than those in never smokers and ex-smokers. Both age and smoking status were significant for the cellularity factor score, whereas for the connective/granulation tissue factor score, age was not significant but smoking status was.(ABSTRACT TRUNCATED AT 250 WORDS)

Significance of overall treatment time for the development of radiation-induced intestinal complications. An experimental study in the rat.

BACKGROUND: Late normal tissue reactions generally are believed to be independent of treatment time. However, previous studies suggest a relationship between acute mucosal injury and development of intestinal obstruction and enterocutaneous fistula formation. Thus, the pathogenesis of late intestinal complications may be complex, and mucosal cell proliferation during treatment may be important. This study assessed the influence of overall radiation treatment time on development of intestinal injury and complications after localized fractionated irradiation of rat ilium. METHODS: Ninety-four male rats underwent orchiectomy, and a loop of small intestine was transposed to the scrotum. Orthovoltage irradiation was administered to the transposed, but functionally intact, intestine using 9 fractions of 5.6 Gy with interfraction intervals of 24, 48, or 72 hours. The animals were observed for complications and killed in groups 2 and 26 weeks after irradiation for assessment of injury. Incidence of intestinal complications and quantitative and semiquantitative histopathologic assessment of injury were used as endpoints. RESULTS: Increasing total treatment time by extending interfraction intervals from 24 to 48 hours significantly reduced radiation injury and the incidence of intestinal complications. Differences in mucosal and fibrotic changes were most prominent. No significant differences were found between groups with interfraction intervals of 48 and 72 hours. CONCLUSIONS: Overall treatment time significantly influenced development of chronic radiation enteropathy. Thus, rapidly proliferating cells, as found in the intestinal mucosa, appear to be involved in the pathogenesis of intestinal complications. This probably represents consequential damage secondary to disruption of mucosal integrity.

Cryptogenic constrictive bronchiolitis. A clinicopathologic study.

Four women with a chronic respiratory illness characterized by chronic cough, dyspnea, mild to severe physiologic abnormalities, relatively normal chest radiographs, and lack of response to bronchodilators or prednisone were identified and prospectively evaluated. Constrictive bronchiolitis, defined as concentric narrowing of the bronchiolar lumen, mural scarring, smooth muscle hyperplasia, and mucus stasis, was the major histologic finding on open lung biopsy in all cases. Each presented with an illness clinically distinct from asthma, connective tissue disorders, occupational or environmental lung disease, bronchiectasis, diffuse panbronchiolitis, cystic fibrosis, and emphysema. None of the patients smoked cigarettes. None had clinical evidence of a recent viral lower respiratory tract infection. The physical examinations were normal except for rales heard on chest examination in two patients. Chest radiographs showed increased bronchovascular markings in three patients. Lung function was normal in one patient, two of the patients had a reduced diffusing capacity associated with moderate hypoxemia and an obstructive ventilatory defect, and one patient exhibited a mixture of restrictive and obstructive defects. None have experienced significant progression of their disease over 1 to 5 yr of follow-up. However, complete return to normal function did not occur. We hypothesize that patients with the constellation of findings described represent a distinct and definable clinicopathologic entity and further clarifies the spectrum of "small airways disease." Establishing the diagnosis appears important for prognostic and possibly therapeutic reasons.

Pulmonary capillaritis. The association with progressive irreversible airflow limitation and hyperinflation.

We report two patients with systemic necrotizing vasculitis (microscopic polyarteritis) and associated recurrent pulmonary capillaritis, in whom progressive irreversible airway dysfunction began approximately 10 yr after disease onset. Their course was characterized by repeated episodes of diffuse alveolar hemorrhage, glomerulonephritis, palpable purpura, and splinter hemorrhages. The lung revealed intraalveolar hemorrhage, neutrophilic infiltration and cellular fragmentation, fibrinoid necrosis of the alveolar interstitium, and parenchymal hemosiderin deposits. No medium-sized vessel involvement, granulomatous inflammation, or bronchiolar obliteration were seen. Renal biopsies revealed focal segmental necrotizing glomerulonephritis, and a cutaneous biopsy in one case showed a leukocytoclastic vasculitis. Immunofluorescent studies of lung and kidney showed minimal or no immunoreactivity. The clinical course and serologic tests did not support another systemic vasculitis, connective tissue disease, or antiglomerular basement membrane antibody disease. The acute episodes responded to antiinflammatory and immunosuppressive therapy. Symptoms, serial pulmonary function tests, and chest imaging documented the development of a progressive irreversible obstructive airway disease. No other predisposing factors were identified. These cases demonstrate the unexpected appearance of an irreversible obstructive airway disease with lung parenchymal hyperinflation after systemic necrotizing vasculitis associated with recurrent pulmonary capillaritis and diffuse alveolar hemorrhage.