Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disorder with poor prognosis. Response to treatment is infrequent and the use of immunosuppressive agents other than corticosteroids is the subject of ongoing discussion because of uncertain efficacy and side-effects. To determine the efficacy and safety of cyclophosphamide pulse therapy in IPF, this study retrospectively analysed 18 patients with progressive IPF who were treated with intermittent i.v. cyclophosphamide (1-13 g x month(-1)) and additional oral prednisolone for 1 yr. Static lung volumes, arterial oxygen tension (Pa,O2) at rest, clinical symptoms and potential treatment-related side-effects were recorded. Cyclophosphamide had to be stopped in one patient, owing to repeated pulmonary infection; 11 patients were responders (five improving, six stabilizing) and six patients deteriorated. The change in vital capacity (VC) of responders was +6.7+/-18.0% (mean +/-SD), compared with -20.6+/-18.2% in nonresponders (p=0.008). Pa,O2 remained constant in responders (+0.13+/-0.88 kPa (+1.0+/-6.6 mmHg)), while it decreased in nonresponders (-2.08+/-1.92 kPa (-15.6+/-14.4 mmHg, p=0.008)). Additional prednisolone was reduced by 19.1+/-13.4 mg in responders, compared with 6.7+/-16.3 mg in nonresponders (p=0.02). VC at initiation of therapy was higher in responders (60.2+/-10.2 versus 40.3+/-12.9% predicted; p=0.004). No side-effects occurred, other than respiratory tract infection. These data demonstrate that intravenous cyclophosphamide pulse therapy may be a favourable regimen for certain patients with progressive idiopathic pulmonary fibrosis. Patients with a vital capacity of more than 50% predicted and a shorter duration of disease may benefit most.     

Distribution of HLA antigens in idiopathic pulmonary fibrosis

Divergent observations suggest that genetic factors contribute to the susceptibility to or clinical course of idiopathic pulmonary fibrosis. To determine whether there is an association between the major histocompatibility (HLA) system and idiopathic pulmonary fibrosis, the distribution of 35 antigens of HLA loci A and B was determined among 33 white patients with idiopathic pulmonary fibrosis and 329 healthy white control subjects. Although certain antigens tended to be more prevalent among patients with idiopathic pulmonary fibrosis compared with control subjects, there were no significant differences in the phenotype frequencies of the HLA-A and HLA-B antigens between these 2 groups. Thus, although subtle associations may exist between the HLA loci and idiopathic pulmonary fibrosis, these results indicate that antigens of the HLA-A and HLA-B loci are not linked with major risk factors in this disease.     

Two patients with idiopathic pulmonary fibrosis and monoclonal gammopathy

A 67-year-old man and a 70-year-old man were admitted to our hospital because of dyspnea and dry coughing. Chest X-ray films showed bilateral reticulonodular shadows in the middle and lower lung fields. Specimens were obtained by open lung biopsies and the findings were compatible with those of usual interstitial pneumonia. Immunoelectrophoresis revealed monoclonal gammopathy in both patients. The levels of interleukin 6 in bronchoalveolar lavage fluid were high. In these two patients, idiopathic pulmonary fibrosis was associated with multiple myeloma and monoclonal gammopathy, and the levels of interleukin-6 in bronchoalveolar lavage fluid were high. These findings may help to elucidate the pathogenesis and development of idiopathic pulmonary fibrosis.     

Oligo-2',5'-adenylate synthetase in pulmonary sarcoidosis and idiopathic pulmonary fibrosis

Oligo-2',5'-adenylate synthetase (2,5AS) is an enzyme induced by all types of interferon (IFN). We measured the levels of 2,5AS activity in peripheral blood mononuclear leukocytes (PBML) and bronchoalveolar lavage fluid (BALF) cells of patients with pulmonary sarcoidosis (SAR), idiopathic pulmonary fibrosis (IPF), and normal controls (NC). In NC, the levels of BALF cell 2,5AS activity were approximately seven times as high as the levels of PBML 2,5AS activity. The measurement 2,5AS activity from isolated cells showed that the levels of 2,5AS activity are independent of cell differential from PBML and BALF cells. The levels of PBML and BALF cell 2,5AS activity in SAR were both significantly high in comparison with those in NC. In patients with IPF, the levels of PBML 2,5AS activity were significantly increased as compared with those in NC, whereas there was no significant difference regarding the levels of BALF cell 2,5AS activity between patients with IPF and NC. These results suggest the following: (1) in patients with SAR, IFN production is enhanced both in the alveolar space and peripheral circulation; (2) in patients with IPF, IFN production is greatly enhanced in the circulation, whereas IFN production is not enhanced in the alveolar space; and (3) IFN may contribute to the pathogenesis of SAR and IPF.     

Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP

Based on past difficulties in clinically differentiating patients with idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans-organizing pneumonia (BOOP), and nonspecific interstitial pneumonia/fibrosis (NSIP), which all manifest clinically as interstitial lung disease, experience with pathologically confirmed examples of the three diseases was reviewed to compare clinical profiles and prognosis and to define NSIP more clearly. Thirty-one patients (15 males and 16 females) were pathologically identified as NSIP and subclassified into either the cellular (n=16) or fibrotic group (n=15). All 31 patients were clinically considered to be idiopathic NSIP cases. Patients with idiopathic BOOP (n=16) and IPF (n=64) were compared with the NSIP patients. Subacute presentation of interstitial lung disease characterized both idiopathic NSIP and idiopathic BOOP. NSIP patients showed volume loss on a chest radiograph (29.0%) and honeycombing on a computed tomography scan (25.8%); these features were not found in BOOP patients. Bronchoalveolar lavage lymphocytosis was characteristic of both BOOP and NSIP. Two subgroups of NSIP can be recognized histologically: patients in the fibrotic group had a less favourable outcome than those in the cellular group. BOOP and NSIP had a more favourable outcome than IPF. In conclusion, idiopathic nonspecific interstitial pneumonia can be differentiated from other types of idiopathic interstitial pneumonia, both pathologically and clinically.     

Clinical evaluation of serum type IV collagen 7S in idiopathic pulmonary fibrosis

Type IV collagen is one of the major components of the basement membrane (BM). 7S domain (7S collagen) of type IV collagen is an N-terminal peptide which is stable against protease and heat. We investigated serum concentration of 7S collagen in patients with idiopathic pulmonary fibrosis (IPF) and other pulmonary diseases. The aim of this study was to evaluate whether changes in the serum concentration of 7S collagen reflect the fibrotic process of IPF. We measured the concentration of serum 7S collagen with radioimmunoassay in patients with IPF, chronic pulmonary emphysema (CPE), sarcoidosis, infectious pulmonary diseases (IPD) and normal healthy controls. We also monitored 7S collagen during the clinical course in some patients with IPF and investigated the correlation between the serum 7S collagen, and lactate dehydrogenase (LDH) and erthrocyte sedimentation rate (ESR) in patients with IPF. Patients with IPF showed significantly higher serum concentration of 7S collagen than other pulmonary diseases and healthy controls. The serum concentration of 7S collagen significantly decreased in IPF patients who showed roentgenographic improvement after corticosteroid treatment. There was a correlation between the serum 7S collagen and LDH, and ESR. In conclusion, serum concentrations of 7S collagen increase in patients with IPF. The measurement of 7S collagen is useful for the evaluation of fibrotic change in the lung.     

Gastrin-releasing peptide-like immunoreactive substance in bronchoalveolar lavage of idiopathic pulmonary fibrosis and sarcoidosis

The neuropeptide gastrin releasing peptide (GRP) is present in the lung, and functions as a modulator of tissue growth and repair in fibrotic processes, or as a modulator of cell movement and differentiation in various inflammatory processes, including granulomatous ones. In idiopathic pulmonary fibrosis (IPF), changes in the bronchoalveolar lavage (BAL) content of GRP can be expected. We measured GRP-like immunoreactive substances (GRP-IS) and another neuropeptide, vasoactive intestinal peptide (VIP)-IS in BAL by enzyme immunoassay. Our results showed a decrease in BAL GRP-IS in patients with IPF (26.5 +/- 5.5 pg.mg-1 protein) and sarcoidosis (35.9 +/- 9.2 pg.mg-1), compared to healthy nonsmokers (63.4 +/- 9.0 pg.mg-1). When data were expressed as pg.ml-1 BAL fluid recovered, a decrease was only seen in IPF, not in sarcoidosis. The levels of VIP-IS in BAL were not different between the groups studied. Increased protein levels in BAL had no correlation with the levels of GRP-IS or VIP-IS in BAL. Furthermore, BAL neutrophil percentages had no correlation with the levels of GRP-IS in BAL of patients with IPF. Using reversed phase high performance liquid chromatography (HPLC), several kinds of GRP-IS were detected in BAL. These findings suggest that the decreased level of GRP-IS in BAL may reflect a loss of GRP-producing cells due to chronic lung injury and fibrosis in patients with IPF.     

Interleukin-8 expression in bronchoalveolar lavage cells in the evaluation of alveolitis in idiopathic pulmonary fibrosis

OBJECTIVES: We evaluated the relationship between alterations in coronary flow velocity during the acute phase of acute myocardial infarction (AMI) and the recovery of left ventricular wall motion in patients who underwent successful primary angioplasty. BACKGROUND: The status of the coronary microcirculation is the major determinant of the prognosis of patients who have had successful reperfusion after AMI. Animal studies have shown that dynamic changes in regional flow are associated with the extent of infarction. Evaluation of alterations in coronary flow velocity in infarcted arteries may provide information about microcirculatory damage. METHODS: Flow velocity of the distal anterior descending artery was continuously monitored with the use of a Doppler guide wire immediately after recanalization for 18 +/- 4 h in 19 patients who underwent successful primary angioplasty after anterior AMI. Subjects were divided into two groups on the basis of the time course of alterations in average peak velocity (APV). Group D consisted of patients who had progressive decreases in APV through the next day (n = 9), and Group I comprised patients with an increase in APV after a transient decline (n = 10). Ejection fraction (EF) and regional wall motion (RWM) were assessed by left ventriculography performed on admission and at discharge. RESULTS: The APV at the end of monitoring was greater in group I than in group D. In group I, EF and RWM were significantly improved at discharge. The change in EF was greater in group I than in group D (17 +/- 9% vs. 4 +/- 9%, p = 0.007), as was the change in RWM (0.96 +/- 0.23 vs. 0.13 +/- 0.36 SD/chord, p < 0.0001). CONCLUSIONS: The alteration in flow velocity in recanalized infarcted arteries is related to left ventricular recovery. A progressive decrease in velocity after angioplasty implies no reflow, which is associated with a poor recovery of left ventricular function. Reperfusion injury may account in part for this phenomenon.     

替米沙坦联合糖皮质激素治疗特发性肺纤维化30例临床观察

目的:探讨替米沙坦联合泼尼松治疗特发性肺纤维化的临床疗效.方法:选取我院2008年1月～2010年1月收治的60例特发性肺纤维化病人的临床资料,随机分为治疗组(30例)和对照组(30例),对照组病人应用泼尼松治疗,治疗组病人在对照组治疗的基础上加用替米沙坦,连续治疗6个月,比较两组病人的临床疗效.结果:治疗组病人临床症状和肺功能改善优于对照组,两组病人比较差异有统计学意义(p＜0.05).结论:替米沙坦联合泼尼松治疗肺纤维化,能明显减轻病人的临床症状,改善肺功能,疗效满意值得在临床推广.     

The role of neutrophils in peritoneal adhesion formation

The most common cause of intraperitoneal adhesions is previous abdominal surgery. Postoperative adhesion formation results from a fibroproliferative inflammatory reaction that begins with an influx of polymorphonuclear leukocytes (PMNs) into the peritoneal cavity. Adherence of the PMNs to the endothelial cells (EC) is necessary for PMN migration into the tissue in response to a stimulus. Several receptor-counterreceptor pairs of ligands such as CD11/CD18 on the PMN and ICAM-1 (CD54) on EC have been identified. Monoclonal antibody against CD11/CD18 (R15.7) inhibits PMN adherence and migration and consequently protects against PMN-induced tissue injuries. We therefore studied the effect of preventing PMN-EC adherence, using anti-CD18 monoclonal antibody, on postoperative adhesion formation in rabbits. Group 1 was a control receiving physiologic saline, and group 2 received anti-CD18 antibody (R15.7, 2 mg/kg). The treatment was administered iv at the end of surgery and repeated on the first and second postoperative days. Peritoneal adhesions were induced at laparotomy by repairing two peritoneal defects, by oversewing the defect (model 1), and by resuturing the removed parietal peritoneum in its place as an ischemic graft (model 2). Adhesions were evaluated blindly at 10 days after operation by measuring the percentage of the suture line covered with adhesions (model 1) or by a scoring system (model 2). All control animals developed intraperitoneal adhesions and the percentage of the suture line covered with adhesions was 25 +/- 5.9% (mean +/- SEM) and the mean score in model 2 was 0.9 +/- 0.2. Anti-CD18 antibody, R15.7, increased the degree of postoperative adhesion formation in both models, but the results were significant only in model 2. Also, anti-CD18 antibody significantly decreased peritoneal neutrophils from 11.1 x 10(7) +/- 1.8 x 10(7) to 2.2 x 10(7) +/- 0.4 x 10(7) (P < 0.001) on the first postoperative day. It is concluded that inhibition of PMN-EC adherence does influence the postoperative adhesion formation. These results might suggest that PMNs have a role in modulating postoperative adhesion formation.     

Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis

An enzyme-linked immunosorbent assay using monoclonal antibodies to human lung surfactant protein A (SP-A) was applied to sera from patients with lung diseases. We examined whether SP-A appears in the sera of patients with diseases that are known to cause alterations in surfactant composition in bronchoalveolar lavage fluids, and we characterized the SP-A that was found. The level of SP-A in sera from 57 healthy volunteers was 45 +/- 3 ng/ml (mean +/- SEM). The levels in patients with idiopathic pulmonary fibrosis (IPF) (205 +/- 23 ng/ml, n = 32) and pulmonary alveolar proteinosis (PAP) (285 +/- 23 ng/ml, n = 6) were significantly higher than those in healthy control subjects (p < 0.01), whereas those of sarcoidosis (n = 16), pneumonia (n = 14), and tuberculosis (n = 14) were 52 +/- 27 ng/ml, 65 +/- 11 ng/ml, and 49 +/- 23 ng/ml, respectively. Electrophoresis and immunoblotting analysis demonstrated that the fraction isolated from serum of a patient with PAP or IPF by anti-SP-A immunoaffinity column chromatography consisted chiefly of human IgG and IgM, and that it also contained SP-A. Furthermore, IgG was found in preparation of purified human SP-A. SP-A was demonstrated to bind to nonimmune IgG coated onto microtiter wells. Gel filtration analysis revealed that serum SP-A was eluted at fractions of larger molecular size than was the purified SP-A. These findings suggest that SP-A appears in the bloodstream as a complex with immunoglobulin in IPF and in PAP.     

The role of eosinophils and neutrophils in helminth-induced keratitis

PURPOSE: Intrastromal injection of mice with antigens from the parasitic helminth that causes river blindness (Onchocerca volvulus) induces eosinophil recruitment to the corneal stroma at the time of maximum corneal opacification and neovascularization. The present study was conducted to examine the role of eosinophils and neutrophils in onchocercal keratitis in control C57Bl/6 mice and in interleukin-5 gene knockout (IL-5(-/-)) mice. METHODS: C57Bl/6 and IL-5(-/-) mice were immunized subcutaneously and injected intrastromally with soluble O. volvulus antigens. Mice were killed at various times thereafter. Development of keratitis was assessed by slit lamp examination, and inflammatory cells in the cornea were identified by immunohistochemistry. RESULTS: A biphasic recruitment of inflammatory cells was observed in C57Bl/6 mice; neutrophils predominated during the first 72 hours after intrastromal injection and subsequently declined, whereas eosinophil recruitment increased as time elapsed and comprised the majority (90%) of cells in the cornea by day 7. In contrast, neutrophils were the predominant inflammatory cells in IL-5(-/-) mice at early and late time points and were associated with extensive stromal damage and corneal opacification and neovascularization. Eosinophils were not detected in these mice at any time. CONCLUSIONS: In the absence of eosinophils, neutrophils can mediate keratitis induced by helminth antigens. Together with the early neutrophilic infiltrate in control animals, these observations indicate that neutrophils have an important role in onchocercal keratitis.     

The role of infection in the pathogenesis of autoimmune disease

BACKGROUND AND PURPOSE: Several strategies now exist for the use of gene transfer methodologies to sensitize tumour cells to radiation. These include the transfection of genes synthesizing cytokines, p53 gene replacement and methods based on the use of HSV-tk and gancyclovir. Very recently, the sequencing of radioprotector or repair genes, such as ATM, Ku80 and XRCC2, has made it possible to consider the design of gene transfer strategies resulting in protector gene knock-out. Selectivity of transfected gene expression might be achieved by use of tissue-specific promoters or by the trophism of viral vectors. The purpose of this study was to evaluate the probable efficacy of such strategies. METHODS: We have modelled gene transfer-mediated radiosensitization of tumour cells during radiotherapy, focusing on anti-protector gene strategies, to explore the role of transfection frequency, sensitizing efficacy, transfection stability, untransfectable subpopulations, the timing of gene therapy and the treatment schedule structure. RESULTS: We predict a substantial therapeutic benefit of gene transfer treatment (with at least weekly transfection) which modifies cellular radiosensitivity by a factor of 1.5 or more, despite modest efficiency of cellular transfection (e.g. 50%), transient retention of the transfected gene (e.g. 2-day half-life) and the existence of a small minority (e.g. 1%) of untransfectable cells. CONCLUSIONS: The analysis shows repeated administration of gene transfer treatment to be obligatory and implies that the existence of untransfectable minority subpopulations (i.e. cells inaccessible to the vector) will be the major limiting factor in therapy. Experimental work is needed to confirm these predictions before clinical studies begin.     

The role of autoantibodies in the pathogenesis of lupus nephritis

The purpose of this study was to determine if 60 Hz magnetic fields can alter the clinical progression of leukemia in an animal model. Large granular lymphocytic (LGL) leukemia cells from spleens of leukemic rats were transplanted into young male Fischer 344 rats, producing signs of leukemia in approximately 2-3 months. The animals were randomly assigned to 4 treatment groups (108/group) as follows: 1) 10 G (1.0 mT) linearly polarized 60 Hz magnetic fields, 2) sham exposed [null energized unit with residual 20 mG (2 microT) fields], 3) ambient controls [<1 mG (0.1 [microT)], and 4) positive controls (a single 5 Gy whole body exposure to 60Co 4 days prior to initiation of exposure). All rats were injected intraperitoneally (ip) with 2.2 x 10(7) LGL leukemic cells at the initiation of exposure or sham exposure. The magnetic fields were activated for 20 h/day, 7 days/week, allowing time for animal care. The experimental fields were in addition to natural ambient magnetic fields. Eighteen rats from each treatment group were bled, killed, and evaluated at 5, 6, 7, 8, 9, and 11 weeks of exposure. Peripheral blood hematological endpoints, changes in spleen growth, and LGL cell infiltration into the spleen and liver were measured to evaluate the leukemia progression. No significant or consistent differences were detected between the magnetic field exposed groups and the ambient control group, although the clinical progress of leukemia was enhanced in the positive control animals. These data indicate that exposure to sinusoidal, linearly polarized 60 Hz, 10 G magnetic fields did not significantly alter the clinical progression of LGL leukemia. Furthermore, the data are in general agreement with previous results of a companion repeated-bleeding study in which animals were exposed for 18 weeks.     

The role of genetics in the pathogenesis of alcoholism.

This article reviews behavior genetic methods and critiques some of the major studies that converge on a genetic basis for alcohol abuse. In particular, it critically examines the adoption studies from Scandinavia and the United States. Serious flaws with respect to a number of important methodological considerations, such as problematic diagnostic criteria and high rates of foster parent psychopathology, suggest that the conclusions drawn by the authors of these studies should be tempered. An evaluation of high-risk research underscores the contradictory findings from different studies and the lack of a coherent conceptual framework to assess results. More sophisticated assessments of environmental factors are suggested to take into account Gene?×?Environment interactions and gene–environment correlation effects that may lead to more precise specifications of the etiology of alcohol disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of hypergastrinemia in the pathogenesis of intussusception in infants

From 1988 to 1992 the serum gastrin levels of 124 patients with intussusception and 20 normal infants and 15 patients with intestinal obstruction under 3 years of age were measured. Serum cAMP levels of 10 normal infants and 10 patients with intussusception were determined. In animal experiment study, the pressures of ileum cavity and ileoceal valve were determined before and after injectting pentagastrin into the veins of 8 young dogs. The levels of gastrin (219.9 +/- 100.6 pg/ml) and cAMP (32.4 +/- 7.6 pmol/ml) were higher in patient group than in the control group. (89 +/- 3 pg/ml, P < 0.05 and 22.2 +/- 7.5 pmol/ml P < 0.05). The result of animal experiment showed that the effect of gastrin and etiology of intussusception are identical. The main physiological funcitons of gastrin is to increase the intestinal peristalsis and relax the ileocecal sphincter. Our study showed that hypergastrinemia may be the basis etiologic factor of intussusception. Main clinical feactures were explained by this new theory.     

The role of genetic factors in the pathogenesis of thyroid neoplasms

This paper summarizes the current knowledge on the role of genetic factors in the development of thyroid neoplasms. The introduction of the methods and concepts of molecular genetics (as, e.g. recombinant DNA technology) have elucidated etiopathogenesis of the majority of thyroid tumours and, in the future, can make the diagnosis easier. Mutations of genes involved in the control of cellular growth and/or differentiation (ras, c-myc, RET, met) affect the development of thyroid neoplasms. Loss of heterozygosity (LOH) may suggest the presence of tumor suppressor genes and has been reported in thyroid follicular carcinomas. Activation of tyrosine kinase, whether by specific oncogene amplification or by rearrangement, appears to be highly specific for the transformation of thyroid follicular cells into papillary tumours. Cytogenetic studies have shown frequent clonal abnormalities in thyroid follicular adenomas and carcinomas.