Evaluation of serum KL-6 levels in summer-type hypersensitivity pneumonitis

A high level of serum KL-6 is a known feature of active pulmonary fibrosis. Some researchers have suggested that KL-6 is produced and secreted by type II pneumocytes. The present study evaluated serum KL-6 levels in patients with summer-type hypersensitivity pneumonitis (summer-type HP) (n = 6, 7 episodes), Mycoplasma pneumoniae pneumonia (n = 16), Chlamydia psittaci pneumonia (n = 3), Chlamydia pneumoniae pneumonia (n = 9), and bacterial pneumonia (n = 12). In addition, transbronchial lung biopsy (TBLB) specimens were examined pathologically in order to identify the site of production and secretion of KL-6. In patients with summer-type HP, the serum KL-6 levels exceeded 500 U/ml (2.996 +/- 2.016 U/ml), but was below 500 U/ml (302 +/- 126 U/ml, p < 0.001) in the patients with other infectious pneumonias, with the exception of two. One of these two patients with a high serum KL-6 level had adult respiratory distress syndrome due to Mycoplasma pneumoniae. The other had organizing pneumonia due to Chlamydia pneumoniae. TBLB specimens showed proliferative type II pneumocytes in all summer-type HP cases. We believe that the high serum KL-6 levels were produced by type II pneumocytes, and may provide a useful indicating serum marker for HP. Although serum LDH, serum CRP and PaO2 are known as monitoring markers in summer-type HP, our findings demonstrated no manifest correlations among these markers. However, serum KL-6 levels showed a strong positive correlation with serum LDH levels and an inverse correlation with serum CRP levels. These results suggest that serum KL-6 may be a better marker of the degree of disease activity than serum LDH, CRP, or PaO2 in summer-type HP.     

Long-term effects of delapril hydrochloride on procollagen type III amino-terminal peptide, left ventricular mass and left ventricular function in hypertensive patients

The long-term effect of delapril hydrochloride, a non-sulfhydryl angiotensin converting enzyme inhibitor, on serum concentrations of procollagen type III amino-terminal peptide (PIIIP) and left ventricular mass (LVM) and function were investigated in 15 hypertensive patients. Patients were treated with delapril hydrochloride 30 mg/day po for 12 months. Blood samples and an echocardiogram were obtained before treatment and after 6 and 12 months of treatment. Blood pressure, PIIIP, and LVM significantly decreased associated with an increase in left ventricular fractional shortening and mean systolic and diastolic posterior wall velocity at 6 and 12 months of treatment. Positive correlations between PIIIP and LVM (r=0.49, p<0.005) and negative correlations between PIIIP and left ventricular fractional shortening (r=-0.31, p<0.05) were found. Delapril hydrochloride reduced PIIIP and LVM and improved cardiac function in hypertensive patients.     

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.     

Evaluation of colchicine with or without praziquantel therapy in the control of hepatic fibrosis in murine schistosomiasis

Colchicine alone or following praziquantel was given to mice infected with Schistosoma mansoni either 6 or 10 weeks post infection. Praziquantel increased body weight gain, histologically reduced number, diameter and cellularity of granuloma and improved liver function parameters. Early praziquantel therapy decreased hepatic collagen content as detected by the colorimetric method and the serum procollagen propeptide (PIIIP), while later treatment at the 10th week of infection increased hepatic collagen content and serum PIIIP. Colchicine therapy significantly decreased body weight gain with significant weight loss after early treatment. Colchicine did not change the histologic picture of schistosomal liver fibrosis; it induced a detectable hepatocytic injury recorded ultrastructurally and histologically with excitation of the inflammatory reaction in the granuloma and in portal tracts after early treatment. Excess pigmentation in macrophages and Kupffer cells, binucleation and large sized hepatocytic nuclei were evident after colchicine therapy. Colchicine increased hepatic collagen content microgram/mg protein, raised globulin and total serum protein and normalized the raised serum PIIIP of infected mice, but had no effect on PIIIP of normal mice. Early cessation of schistosomal infection evidently minimized the adverse effects of colchicine.     

Treatment of early AIDS-related Kaposi's sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial. Kaposi's Sarcoma ANRS Study Group. Agence Nationale de Recherches sur le SIDA

OBJECTIVE: To assess the efficacy and safety of all-trans-retinoic acid (ATRA), a retinoid with antitumour activity that inhibits in vitro the growth of Kaposi's sarcoma cells, in patients with low-risk AIDS-associated Kaposi's sarcoma. DESIGN: Non-randomized phase II study, using a group sequential procedure to determine whether the response rate to ATRA was above 10%. SETTING: Nine referral French centres. PATIENTS: Twenty HIV-seropositive men with CD4 cells > or = 200 x 10(6)/l, low-risk Kaposi's sarcoma [T0I0S0 according to the classification of AIDS Clinical Trials Group (ACTG)] not previously treated with systemic anti-Kaposi's sarcoma agents, and with at least four measurable lesions were included. INTERVENTIONS: ATRA was given orally 45 mg/m2 daily for 12 weeks. MAIN OUTCOME MEASURE: Tumour response evaluated according to ACTG criteria. RESULTS: Nineteen patients were evaluated for response: partial response, stabilization and progression were found in eight (42%), seven (37%), and four (21%) patients, respectively. Gradual flattening and lightening of lesions was observed in responders after at least 2 months of ATRA. All patients with partial response at week 12 pursued ATRA for another 15+/-7 weeks. Further improvement was observed in six patients. Median duration of response was 332 days. Cheilitis, transient headaches and skin dryness were the main toxicities noted. No significant changes in HIV viral burden or serum interleukin-6 pathways were observed. CONCLUSIONS: ATRA is well tolerated and effective enough in Kaposi's sarcoma patients to warrant further evaluation.     

Survey of echinococcosis in Hokkaido and measure against it

Exposure to hyperoxia results in lung injury and a decrease in lung collagen. Retinol is known to influence collagen gene expression, and retinol deficiency has been shown to potentiate hyperoxic lung injury. To investigate the combined effects of retinol deficiency and hyperoxia on lung collagen expression, retinol-deficient rats were exposed to acute hyperoxia, and expression of the alpha-1 chains of type I procollagen [pro alpha 1 (I)] and type III procollagen [pro alpha 1 (III)] were determined using Northern hybridization analyses and immunohistochemical staining. Hyperoxia alone reduced pro alpha 1 (I) mRNA by 60 +/- 4% (p < .05) and pro alpha 1 (III) mRNA by 30 +/- 5% (p < .05), and retinol deficiency alone reduced pro alpha 1 (I) mRNA abundance by 49 +/- 8.8% (p < .05) and pro alpha 1 (III) mRNA abundance by 14 +/- 7.5% (p = not significant), respectively. Retinol deficiency plus hyperoxia did not cause any further reduction in procollagen mRNA than that seen with oxygen exposure alone. Immunohistochemical staining demonstrated decreased staining for type I collagen in retinol-deficient animals. Hyperoxic exposure resulted in decreased connective tissue staining and increased alveolar wall staining for type I collagen. Retinol deficiency and hyperoxia together resulted in a marked increase in alveolar exudates staining for type I collagen. No changes in type III collagen staining were seen. These findings demonstrate that while retinol deficiency does not potentiate hyperoxia-induced reductions in procollagen mRNA, it is associated with alterations in collagen staining in distal lung and immunohistologic evidence of collagen fragments in alveolar exudates.     

Pathological and High Resolution CT Findings in Churg-Strauss Syndrome

Objective To investigate the Churg-Strauss syndrome (CSS) associated lung involvement,concentrating on clinical characteristics,pathological findings of lung involvements,response to treatment,and prognosis.Methods We retrospectively analyzed the characters of the clinical manifestations,thin-section CT and pathological findings of CSS.The study involved 16 patients.Clinical data were obtained by chart review.All patients underwent transbronchial lung biopsy (TBLB).Six of them underwent surgical lung biopsy as well.Results The patients included 7 men and 9 women,aged from 14 to 61 years (median,47.5 years).Extrathoracic organs involved included nervous system (7/16) and skin (5/16).Respiratory symptoms included cough (12/16),exertional dyspnea (11/16),hemoptysis (4/16),and chest pain (3/16).CT findings included bilateral ground-glass opacities (12/16),bilateral patchy opacities (12/16),and centrilobular nodules (6/16).The pathological findings of TBLB demonstrated increased eosinophils (3/16),vasculitis (3/16),and interstitial pneumonia (16/16).The pathological findings of surgical lung biopsy of 6 cases showed ne-crotizing vasculitis in 4 cases,capillaries in S,eosinophilic pneumonia in 3,granulomas in 2,and airway abnormalities in 3.All patients improved in symptoms after therapy during the study period (range,3 to 51 months; median,15 months).Conclusions Asthma may be present in CSS patient when there is bronchial involvement.Ground-glass opacities and consolidation seen on high-resolution CT reflect the presence of eosinophilic pneumonia,vasculitis,and pulmonary alveolar hemorrhage.TBLB has significant limitations for the diagnosis of CSS.Early diagnosis and therapy can result in satisfactory prognosis.     

A case report of pneumonia due to Chlamydia trachomatis with pleural effusion

A 64-year-old male consulted our hospital with a 6-day history of malaise, body temperature to 38 degrees C, anorexia, and light headedness. The chest radiograph showed consolidation in the left lower lung area. Chest CT and ultrasonography revealed left pleural fluid. The pleural fluid was exudative (yellowish in color, protein 3.0 g/dl, Rivalta reaction positive, adenosine deaminase 19.4 U/L), and had a total cell count of 4.7 x 10(6)/ml with 45% lymphocytes, 40% histiocytes, and 15% polymorphonuclear leukocytes. He had kept a budgerigar, but we could not isolate Chlamydia from the pleural fluid or the pet bird. Transbronchial lung biopsy from left S10 revealed an increase of mononuclear leukocytes within the interstitial spaces, and the alveolar spaces contained polymorphonuclear leukocytes, fibrin, and organized alveolar exudate. Bronchoalveolar lavage cellular constituents were 50% lymphocytes, 27% neutrophils, and 23% macrophages. Serologic studies demonstrated C. trachomatis specific IgM antibody titers at 1:20 in a serum sample and at 1:10 in pleural fluid. We report a case of community-acquired pneumonia caused by C. trachomatis diagnosed by serologic studies.     

Prospective randomized comparison of imipenem-cilastatin and piperacillin-tazobactam in nosocomial pneumonia or peritonitis

Nosocomial pneumonia and acute peritonitis may be caused by a wide array of pathogens, and combination therapy is often recommended. We have previously shown that imipenem-cilastatin monotherapy was as efficacious as the combination of imipenem-cilastatin plus netilmicin in these two settings. The efficacy of imipenem-cilastatin is now compared to that of piperacillin-tazobactam as monotherapy in patients with nosocomial pneumonia or acute peritonitis. Three hundred seventy one patients with nosocomial pneumonia or peritonitis were randomly assigned to receive either imipenem-cilastatin (0.5 g four times a day) or piperacillin-tazobactam (4.5 g three times a day). Three hundred thirteen were assessable (154 with nosocomial pneumonia and 159 with peritonitis). For nosocomial pneumonia, clinical-failure rates in the piperacillin-tazobactam group (13 of 75 [17%]) and in the imipenem-cilastatin group (23 of 79 [29%]) were similar (P = 0.09), as were the numbers of deaths due to infection (6 in the imipenem-cilastatin group [8%], 7 in the piperacillin-tazobactam group [9%]) (P = 0.78). For acute peritonitis, clinical success rates were comparable (piperacillin-tazobactam, 72 of 76 [95%]; imipenem-cilastatin, 77 of 83 [93%]). For infections due to Pseudomonas aeruginosa, 45 patients had nosocomial pneumonia (21 in the piperacillin-tazobactam group and 24 in the imipenem-cilastatin group) and 10 had peritonitis (5 in each group). In the patients with nosocomial pneumonia, clinical failure was less frequent in the piperacillin-tazobactam group (2 of 21 [10%]) than in the imipenem-cilastatin [corrected] group (12 of 24 [50%]) (P = 0.004). Bacterial resistance to allocated regimen was the main cause of clinical failure (1 in the piperacillin-tazobactam group and 12 in the imipenem-cilastatin group). For the patients with peritonitis, no difference in clinical outcome was observed (five of five cured in each group). The overall frequencies of adverse events related to treatment in the two groups were similar (24 in the piperacillin-tazobactam group, 22 in the imipenem-cilastatin group). Diarrhea was significantly more frequent in the piperacillin-tazobactam group (10 of 24) than in the imipenem-cilastatin group (2 of 22). This study suggests that piperacillin-tazobactam monotherapy is at least as effective and safe as imipenem-cilastatin monotherapy in the treatment of nosocomial pneumonia or peritonitis. In P. aeruginosa pneumonia, piperacillin-tazobactam achieved a better clinical efficacy than imipenem-cilastatin, due to reduced development of microbiological resistance. Tolerance was comparable, with the exception of diarrhea, which was more frequent with piperacillin-tazobactam.     

Trafficking of newly synthesized surfactant protein A in isolated rat alveolar type II cells

We examined the synthesis, transport, and localization of surfactant protein A (SP-A) in primary cultures of alveolar type II cells. In type II cells maintained in culture for 6 h, 39% of the SP-A pool detected with an enzyme-linked immunosorbent assay (ELISA) was found in lamellar bodies (LBs). After 24 h in culture, 53% of the cellular SP-A pool was found in LBs. The absolute amount of SP-A in the LB compartment was almost identical at 6 and 24 h of culture. In contrast to the results obtained with ELISA, 35S labeling of newly synthesized SP-A revealed that less than 7% of the cellular SP-A pool was in LBs at either 6 or 24 h of culture. In the 6-h cultures, 17% of the total (i.e., cells and media) [35S]SP-A pool was extracellular. In the 24-h cultures, 70% of the [35S]SP-A pool was extracellular. The secretion of [35S]SP-A was blocked by brefeldin A at all times. When medium containing newly secreted [35S]SP-A was incubated with alveolar type II cells maintained in culture for 24 h, the protein was taken up and incorporated into the LB fraction. More than 80% of the internalized SP-A was associated with the LB compartment after a 6 h incubation. The uptake of [35S]SP-A was blocked at 4 degrees C and was promoted by addition of unlabeled SP-A at 37 degrees C. These findings support a pathway of extracellular routing of SP-A prior to its accumulation in LBs in cultured type II cells.     

Intra-macrophage lipid particles collected by bronchoalveolar lavage: incidence and diagnostic value

This study aimed to determine the incidence and diagnostic value of fat-laden alveolar macrophages obtained by bronchoalveolar lavage (BAL). In 128 patients, including 66 patients admitted for multiple trauma, 158 BAL were carried out. However, 41 BAL from 32 patients were excluded because of poor quality of samples (not enough macrophages, too many ciliated cells, or haemorrhage). All the patients were intubated and mechanically ventilated, having pulmonary infiltrates on the chest film. BAL samples were examined after staining with oil-red-O. They were considered to be positive when more than 5% of alveolar macrophages contained fat droplets. Among them 14 out of 47 patients (30%) without multiple trauma were positive; 7/14 had never been given any intravenous lipid infusion, and 5/14 had aspiration pneumonia (as opposed to 3/32 patients with negative BAL). Further 27 patients out of the 49 (55%) with multiple trauma were positive. Among them 10/49 had clinical evidence of fat embolism, however, only 7/10 had positive samples. All these last ten patients had been given intravenous lipid infusions. The rate of positive alveolar macrophages was correlated neither with the plasma triglyceride concentration, nor the Fracture Index Score, nor the delay between the end of the lipid infusion and the BAL. There was no significant difference in PaO2/FIO2 ratio between the patients with positive and negative BAL. Positive BAL was significantly associated with lipid infusions. The data therefore suggest that the presence of fat-laden alveolar macrophages are associated with various pathological pulmonary conditions, particularly aspiration pneumonia and lipid infusions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Susceptibility of heterozygous MnSOD gene-knockout mice to oxygen toxicity

OBJECTIVE: To study type IV collagen of skin and serum in patients with ALS. BACKGROUND: Collagen abnormalities of skin have been reported in ALS patients. However, little is known concerning type IV collagen in ALS. METHODS: We studied type IV collagen immunoreactivity of skin and measured serum levels of the 7S fragment of the N-terminal domain of type IV collagen (7S collagen) in patients with ALS and control subjects. RESULTS: The basement membrane as well as blood vessels of skin in ALS patients was weakly positive for type IV collagen as compared with those of diseased control subjects. This weak immunostaining became more pronounced as ALS progressed. The optical density for type IV collagen immunoreactivity in ALS patients was significantly lower (p < 0.001) than in diseased control subjects and was significantly decreased with duration of illness (r = -0.85, p < 0.01). Serum 7S collagen levels in patients with ALS were significantly decreased (p < 0.01) as compared with those in diseased and healthy control subjects and were negatively and significantly associated with duration of illness (r = -0.81, p < 0.001). There was an appreciable positive correlation between concentrations of serum 7S collagen and the density for type IV collagen immunoreactivity in ALS patients (r = 0.81, p < 0.02). CONCLUSIONS: These data suggest that a metabolic alteration of type IV collagen may take place in the skin of ALS patients and that the decreased levels of serum 7S collagen may reflect a decreased type IV collagen immunoreactivity of skin in patients with ALS.     

Hemodynamic effects of the somatostatin analog lanreotide in humans: placebo-controlled, cross-over dose-ranging Echo-Doppler study

Fas is expressed in various cells and transduces the cell death signal. p21 is a mediator of p53-dependent G1 arrest associated with deoxyribonucleic acid (DNA) damage. The upregulation of p53 and p21 associated with DNA damage in idiopathic pulmonary fibrosis has been described previously. In this study, p53, p21, and Fas expression and DNA damage were examined in interstitial pneumonia associated with collagen vascular diseases (CVD-IP). DNA damage was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labelling (TUNEL) and p53, p21 and Fas proteins were detected by immunohistochemistry in 13 cases of CVD-IP, 13 of sarcoidosis, seven of hypersensitivity pneumonitis (HP) and eight control patients with normal lung parenchyma. TUNEL-positive signals were found in bronchiolar or alveolar epithelial cells in 11 of 13 (85%) specimens of CVD-IP, but not in sarcoidosis, HP or controls, except for a case of chronic HP with pulmonary fibrosis. p53, p21 and Fas were detected in bronchiolar or alveolar epithelial cells in nine (69%), 10 (77%) and 12 (92%) of 13 specimens of CVD-IP, respectively, but not in sarcoidosis, HP or controls, except for a case of chronic HP. These results suggest that the upregulation of p53, p21 and Fas in bronchiolar and alveolar epithelial cells associated with deoxyribonucleic acid damage may participate in the process of pulmonary fibrosis in interstitial pneumonia associated with collagen vascular diseases and chronic hypersensitivity pneumonitis.     

Coralyne binds tightly to both T.A.T- and C.G.C(+)-containing DNA triplexes

Coralyne is a DNA-binding antitumor antibiotic whose structure contains four fused aromatic rings. The interaction of coralyne with the DNA triplexes poly(dT).poly(dA).poly(dT) and poly[d(TC)].poly[d(GA)].poly[d(C+T)] was investigated by using three techniques. First, Tm values were measured by thermal denaturation analysis. Upon binding coralyne, both triplexes showed Tm values that were increased more than those of the corresponding duplexes. A related drug, berberinium, in which one of the aromatic rings is partially saturated, gave much smaller changes in Tm. Second, the fluorescence of coralyne is quenched in the presence of DNA, allowing the measurement of binding parameters by Scatchard analysis. The binding isotherms were biphasic, which was interpreted in terms of strong intercalative binding and much weaker stacking interactions. In the presence of 2 mM Mg2+, the binding constants to poly(dT).poly-(dA).poly(dT) and poly[d(TC)].poly[d(GA)].poly[(C+T)] were 3.5 x 10(6) M-1 and 1.5 x 10(6) M-1, respectively, while the affinity to the parent duplexes was at least 2 orders of magnitude lower. In the absence of 2 mM Mg2+, the binding constants to poly[d(TC)].poly[d(GA)].poly[d(C+T)] and poly-[d(TC)].poly[d(GA)] were 40 x 10(6) M-1 and 15 x 10(6) M-1, respectively. Thus coralyne shows considerable preference for the triplex structure but little sequence specificity, unlike ethidium, which will only bind to poly(dT).poly(dA).poly(dT). Further evidence for intercalation of coralyne was provided by an increase in the relative fluorescence quantum yield at 260 nm upon binding of coralyne to triplexes as well as an absence of quenching of fluorescence in the presence of Fe[(CN)6]4-.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic and clinical features of sensorineural hearing loss associated with the 1555 mitochondrial mutation

This article describes the modulation, by extracellular collagen, of DNA and proteoglycan synthesis in articular chondrocytes stimulated with transforming growth factor-beta 1. Type-I and type-II collagen, heat-denatured type-II collagen, and bovine serum albumin were each incorporated into alginate in increasing concentrations. Bovine articular chondrocytes were isolated and were resuspended in the alginate, yielding alginate beads with final extracellular protein concentrations of 0-1.5% (wt/vol) for the collagens and 0-2.5% (wt/vol) for bovine serum albumin. Cultures of beads were maintained for 7 days in basal Dulbecco's modified Eagle medium or in medium supplemented with 10 ng/ml transforming growth factor-beta 1. Subsequently, the synthesis of DNA and proteoglycan was measured by radiolabel-incorporation methods with [35S]sulfate and [3H]thymidine, and the values were normalized to the DNA content. Transforming growth factor-beta 1 stimulated the synthesis of both DNA and proteoglycan in a bimodal fashion. The presence of extracellular type-II collagen increased the rate of DNA and proteoglycan synthesis in a dose-dependent fashion in cultures stimulated by transforming growth factor-beta 1, whereas heat-inactivated type-II collagen abrogated the effects observed with type-II collagen for synthesis of both DNA and proteoglycan. In contrast, the presence of extracellular type-I collagen caused a dose-dependent inhibition of synthesis of both DNA and proteoglycan in cultures stimulated with transforming growth factor-beta 1. Extracellular bovine serum albumin brought about a limited increase in synthesis rates, presumably by blocking nonspecific cytokine binding. These results suggest that type-II collagen has a specific role in chondrocyte regulation and serves to mediate the response of chondrocytes to transforming growth factor-beta 1.     

Assessment of the fibrogenetic activity in chronic pancreatitis. The role of circulating levels of extracellular matrix components

Determination of circulating levels of extracellular matrix components has been proposed as a reliable method to assess the activity of fibrogenetic processes. Therefore, we aimed to analyze circulating levels of laminin, fibronectin, and procollagen III peptide (PIIIP) in patients with chronic pancreatitis (CP) and to correlate them with the morphological and functional stage, and duration of the disease. Thirty patients with CP and 18 healthy controls were studied. Serum PIIIP concentrations (RIA), but not fibronectin (RID) and laminin (RIA), were abnormally high in 8 patients with CP. No correlation was found between circulating levels of extracellular matrix components and both functional and morphological stage and duration of CP. Nevertheless, patients with elevated serum PIIIP levels tend to have a more advanced CP (morphological and functional changes) than those with normal levels after a similar duration of the disease. We hypothesize that whereas functional and morphological findings reflect the cumulative effect of chronic inflammation on the pancreas, serum PIIIP concentrations would reflect the activity of the fibrogenetic process within the gland at the time of sampling. The results shown in the present study may be considered a starting point for longitudinal studies that examine the relationship between serum PIIIP or other markers for fibrogenetic activity and evolution of CP.     

Bacteremic pneumococcal pneumonia: bone marrow release and pulmonary sequestration of neutrophils

OBJECTIVES: Neutrophils have been implicated in the pathogenesis of acute lung injury in bacteremic pneumococcal pneumonia. The characteristics of the population of neutrophils that injure the lung are still not known. This study was designed to compare the bone marrow release and lung sequestration of neutrophils during bacteremic pneumococcal pneumonia with nonbacteremic pneumonia and isolated bacteremia. DESIGN: Prospective, controlled, experimental study. SETTING: University research laboratory. SUBJECTS: Female New Zealand white rabbits (n = 17; weight 2.3 to 2.7 kg). INTERVENTIONS: The rabbits were pretreated with intravenous 5'-bromo-2-deoxyuridine (BrdU 100 mg/kg i.v.) to pulse label dividing neutrophils in the bone marrow. Twenty hours after the treatment with BrdU, the rabbits were anesthetized and pneumonia was induced by instilling Streptococcus pneumoniae (1.5 x 10(9) organisms) into the lower lobe of the lung. Four hours after pneumonia, bacteremia was induced by infusing S. pneumoniae (3.0 x 10(9) organisms) into the circulation (pneumonia + bacteremia: n = 6). These animals were compared with those with just pneumonia (n = 5) or bacteremia (n = 6). MEASUREMENTS AND MAIN RESULTS: White blood cell, neutrophil, and differential count. BrdU-labeled neutrophils (neutrophilBrdU) were identified using immunohistochemistry. Cells in tissues were examined microscopically, using sequential level stereologic analysis. The pneumonia + bacteremia group developed a leukopenia (7.3 +/- 0.7 to 2.4 +/- 0.2 x 10(9)/L) following the bacteremia that was associated with an increase in circulating band cells and neutrophilBrdU (2.3 +/- 0.8% to 33.5 +/- 2.8%) which were both higher than those in the other groups (p < .005). Bone marrow smears showed accelerated maturation of neutrophils in the pneumonia + bacteremia group (neutrophilBrdU increased from 11.6 +/- 1.0 to 45.3 +/- 2.1%). Morphometric studies of the lung showed increased neutrophil sequestration in the untreated lung tissue of the pneumonia + bacteremia group (16 +/- 0.8 x 10(8)/mL tissue) compared with the pneumonia (6.6 +/- 0.3 x 10(8)/mL tissue) and bacteremia (12 +/- 0.6 x 10(8)/mL tissue) groups (p < .0001). NeutrophilBrdU preferentially sequester in the lungs of all groups but were slow to migrate into the alveolar air spaces (p < .05). CONCLUSIONS: During bacteremic pneumococcal pneumonia there is an accelerated maturation of neutrophils in the bone marrow with an enhanced release of neutrophils into the circulation. These newly released neutrophils preferentially sequester in lung microvessels but are slow to migrate into the alveolar air space.     

Relation between lipoprotein(a) concentrations in patients with acute-phase response and risk analysis for coronary heart disease

This study investigated whether lipoprotein(a) [Lp(a)] is an acute-phase reactant that can cause important bias in risk factor analysis for coronary heart disease among patients with an acute-phase response (APR patients). To determine whether serum Lp(a) concentrations increase among APR patients, we compared the Lp(a) concentrations and apolipoprotein(a) [apo(a)] phenotypes of 100 controls with those of a random sampling of 100 APR patients. Serum Lp(a) concentration was measured by ELISA; Lp(a) phenotyping was performed by electrophoresis on sodium dodecyl sulfate-polyacrylamide gel. Lp(a) was significantly (P <0.0001) higher among APR patients (mean +/- SD 0.300 +/- 0.284 g/L) than among controls (0.118 +/- 0.193 g/L) even though the distribution of apo(a) phenotypes did not differ significantly. The 100 APR patients were grouped into 4 categories: 48 patients with infections, 25 postoperative patients, 17 patients with tumors, and 10 patients with other diseases, all of whom showed substantially higher Lp(a) values than did the controls. For the S5, S4S5, S5S5, and S4 phenotypes, the mean concentrations of serum Lp(a) were substantially higher among the APR patients.     

Effects of PTH-rP(107-111) and PTH-rP(7-34) on adult cardiomyocytes

We investigated whether parathyroid hormone-related peptide (PTH-rP), recently found expressed in the heart, exerts growth and contractile effects on adult cardiomyocytes from rat hearts. Synthetic PTH-rP peptides were used covering either a protein kinase C (PKC)-activating domain [PTH-rP(107-111)], or an adenylate cyclase activating domain [PTH-rP(1-34) and PTH-rP(7-34)]. PTH-rP(107-111) (1 micro M) increased creatine kinase BB activity (CK-BB), a CK isoform re-expressed during cardiac hypertrophy, within 24 h by 62+/-12%. This induction was abolished in the presence of the mitogen-activated-protein (MAP)-kinase-kinase inhibitor PD 98059. PTH-rP(107-111) activated p42-MAP-kinase within 15 min, increased protein synthesis (19+/- 4%), total protein mass (19+/-5%), cell volume (45+/-7%), and cross-sectional area (38+/-9%) of cardiomyocytes. Activation of p42-MAP-kinase and increase in protein synthesis were abolished in presence of bisindolylmaleimide, a PKC inhibitor. PTH- rP(107-111) did not directly influence contractile activity but reduced the contractile response to isoprenaline. In contrast, PTH-rP(1-34) and PTH-rP(7-34) induced spontaneous contractile activity in 3-day-old cultures. This induction was abolished in presence of Rp-cAMPS, a protein kinase A inhibitor, indicating an involvement of cAMP in this response. PTH-rP(1-34) also increased the cellular accumulation of cAMP. It is concluded that PTH-rP exert direct effects on adult cardiomyocytes by activating either PKC via a functional domain covered by amino acids 107-111 or by activation of cAMP-dependent protein kinase via a functional domain covered by amino acids 7-34. Since these parts of PTH-rP have either no homology [PTH-rP(107-111)] or only a limited structural similarity [PTH-rP(7-34)] to parathyroid hormone, these activities of PTH-rP have to be clearly distinguished from those described for parathyroid hormone.     

Second-line treatment with ifosfamide and carboplatin in patients with ovarian carcinoma relapsing after treatment with carboplatin

20 patients with ovarian carcinoma whose disease had relapsed (1-42 months, median 4 months) after showing either response or stable disease to carboplatin, were treated with ifosfamide (5 g/m2 intravenously over 24 h, day 1) and carboplatin (200 mg/m2 intravenously day 2) as second-line treatment. The mean number of treatment cycles was 3.5 (range 1-6). The major toxicities were thrombocytopenia (WHO grade 3/4, 25%), neutropenia (WHO grade 3/4, 40%) and encephalopathy (WHO grade 3/4, 15%). Overall response rate was 15% [complete response, 0; partial response, 3 (15%); no change, 5 (25%) and progressive disease, 12 (60%)]. The median survival from the date of second-line treatment was 7 months. This combination offers no advantage over either agent used alone.