Effect of endothelin inhibition on lung fibroblasts on patients with systemic sclerosis.

AIM: The aim of the study was to investigate the effect of selective ETRA Sitaxsentan on viability and differentiation into myofibroblasts of lung fibroblasts derived from SSc-ILD patients and the ability of this drug to modify the lung fibroblast synthesis of VEGF, type I collagen and fibronectin. METHODS: Primary human lung fibroblast cultures were obtained from BAL of SSc-ILD patients. Cell cultures were exposed for 48 h to crescent concentrations of Sitaxsentan (10 -6M to 10 -4M). In these experimental conditions we evaluated cell viability through crystal violet staining, the production and mRNA expression of VEGF, fibronectin and type I collagen respectively through ELISA and real-Time PCR. Further, we detected alpha-Smooth Muscle Actin (α-SMA) through immunocytochemical assay. RESULTS: The lowest concentration of sitaxsentan (10-6M) did not affect fibroblasts viability; conversely at higher concentrations, sitaxsentan induced a significant inhibition of cell viability. Synthesis and mRNA expression of VEGF, type 1 collagen and fibronectin were significantly reduced in treated lung fibroblasts compared to the untreated ones, in a dose-dependent manner. At higher concentrations, Sitaxsentan reduced the expression of α-SMA. CONCLUSION: The results of this study show that sitaxentan is able in vitro to reduce both cell viability than production of VEGF and extra-cellular matrix components in SSc lung fibroblasts, confirming the anti-fibrotic potential of ETRA in SSc. The decreased expression of α-SMA in treated cells indicate that sitaxsentan may inhibit the fibroblast differentiation toward a myo-fibroblast phenotype and further support the hypothesis that the selective ETRAs may be beneficial in patients with SSc-ILD as anti fibrotic agents.

Behavioral, neuropsychiatric and cognitive disorders in Parkinson's disease patients with and without motor complications.

BACKGROUND: Parkinson's disease (PD), commonly defined as a hypokinetic movement disorder, is hampered by the appearance of motor complications (MC), including dyskinesias and motor fluctuations, and non-motor symptoms such as behavioral, neuropsychiatric and cognitive disorders, which, in the last years, are gaining increasing attention. The factors affecting MC and these non-motor symptoms are still largely unknown and their interactions are not yet fully evaluated. OBJECTIVE: To identify the presence of behavioral, neuropsychiatric and cognitive disorders in PD patients with and without MC and to evaluate their association with MC. METHODS: Consecutive PD patients received a comprehensive structured clinical evaluation including pharmacologic treatment, MC and non-motor symptoms such as reward-seeking behaviors, neuropsychiatric symptoms (depression, anxiety, psychoses and hallucinations) and dementia. RESULTS: 349 patients were included in this analysis. Patient with MC showed enhanced frequency of dementia (p < 0.001), anxiety, depression and psychoses (p < 0.01). A higher frequency of impulse control disorders was detected in patients with dyskinesias (22.2% - p < 0.001) and motor complications (12.2% - p < 0.05). Dyskinesias were significantly more present in patients with hypersexuality (p < 0.05) and compulsive shopping (p < 0.001), while they were not significantly associated with pathological gambling and binge eating. Patients with dyskinesias also had significantly higher frequency of dopamine dysregulation syndrome, hallucinations and delusions (p < 0.001), with the exception of delusional jealousy. DISCUSSION: We found a higher frequency of behavioral, neuropsychiatric and cognitive disorders in patients with MC. The lack of detection of dyskinesias in several PD patients with pathological gambling in our study represents a very interesting issue. While binge eating mainly seems to be related to the use of dopamine agonists, the significant lack of association between dyskinesias and delusional jealousy suggests the hypothesis of a possible underlying psychopathological predisposition rather than a mere pharmacologic effect in PD patients with these behavioral complications.

Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis.

TRAP-1 is a mitochondrial heat shock protein (HSP), recently identified in Saos-2 osteosarcoma cells adapted to mild oxidative stress induced by diethylmaleate (DEM). TRAP-1 mRNA expression is increased in DEM-adapted cells as well as in tumor cells resistant to 5-fluorouracil and to platin derivatives. Since a strong decrease of TRAP-1 protein levels, upon cisplatin treatment, is observed only in controls but not in the DEM-adapted counterpart, a possible role for this protein in the development of resistant phenotypes could be hypothesized. To characterize the protective role of TRAP-1 against oxidative stress and apoptosis, stable transfectants were generated and characterized for their response to different stress types. These stable clones expressing constitutively high TRAP-1 levels: (i) are more resistant to H2O2-induced DNA damage and to apoptosis by cisplatin; (ii) contain higher reduced glutathione (GSH) levels than control cells; and (iii) do not release the apoptosis-inducing factor into the nucleus upon cisplatin treatment. Furthermore, high TRAP-1 levels interfere with caspase 3 activation. These results confirm the anti-apoptotic role of TRAP-1, and suggest that increased expression of this mitochondrial HSP in DEM-adapted and chemoresistant cells could be part of a pro-survival signaling pathway aimed to evade toxic effects of oxidants and anticancer drugs.

Engraftment capacity of mesenchymal cells following hematopoietic stem cell transplantation in patients receiving reduced-intensity conditioning regimen.

The engraftment ability of mesenchymal cells was investigated in 26 patients receiving allogeneic transplantation from HLA-identical siblings with reduced-intensity conditioning (RIC). The stem cell source was bone marrow (BM) in eight patients and G-CSF-mobilized peripheral blood hematopoietic cells in 18 cases. A total of 32 patients engrafted very quickly and the chimerism evaluation (both on myeloid and on lymphoid subsets) showed that they were full donor by day 60. At the time of the study they were in complete hematological remission and displayed a full donor hematopoiesis. Two patients showed early disease progression while one did not engraft. Forty-eight out-marrow samples harvested from the 26 patients generated a marrow stromal layer adequate for the chimerism evaluation. Monocyte-macrophage contamination of marrow stromal layers was always reduced below 2% by repeated trypsinizations and treatment with the leucyl-leucine (leu-leu) methyl ester. The chimerism evaluation was performed by PCR analysis of STRs microsatellites and the amelogenin locus, by using capillary electrophoresis (CE) and by FISH analysis in case of the sex mismatch. In eight patients, a partial donor origin of stromal cells was shown (7-86% cells of donor). The source of hematopoietic cells was BM in three patients and mobilized peripheral blood in the other five.

Analysis of 80 bilateral hip replacement surgeries performed in a single session. Feasibility study.

Patients affected with bilateral coxarthrosis often present with clinical and radiographic findings that are similar on both sides. The experience with 80 patients submitted to bilateral hip replacement in a single session demonstrated the usefulness and the reduction in costs in relation to hospitalization and rehabilitation. Indications and contraindications must be taken seriously.

Age and bronchial hyperresponsiveness are associated with failure to perform the single breath N2 test in a rural female population.

Because some authors have reported high rates of failure in performing the single breath N2 (SBN2) test in rural areas, the present study aimed at evaluating its acceptability in a female population, unfamiliar with lung function testing, in a rural area of northeastern France. Two hundred ninety-eight women from a rural area volunteered for a preventive medicine examination (91.6% of those invited); four of them were excluded for clinical reasons, and six (2%) were unable to perform spirometry. The protocol included completion of a questionnaire, spirometry with a bronchial reactivity test, skin prick test, and the SBN2 test utilizing a computerized assembly. Although failures caused by the apparatus were few (n = 7, 2.4%) 96 of 281 women (34.1%) were unable to produce two valid SBN2 tests in a series of six attempts. Compared with the group who succeeded in the test (n = 185), women who failed were older and had a higher prevalence of bronchial hyperresponsiveness. Logistic regression confirmed the independent association of these two variables with an inability to perform. We conclude that in a female population completely unfamiliar with lung function testing the SBN2 test has a high rate of failure associated with higher age and the presence of bronchial hyperresponsiveness.

Rehabitation of allograft with bone dehydrated with solvents in reconstruction after removal of bone tumors: MRI evaluation.

It was the purpose of this study to analyze the behavior of Tutoplast bone allograf to fill cavities produced by the removal of benigning bone tumors of those with local malignancy. X-ray and MR images obtained during follow-up demonstrated an increase in the signal in all of the sequences within the graft, indicating complete rehabitation of the grafted area.

Familial membranous nephropathy.

Numerous HLA studies suggest that genetic factors play an important role in the development of membranous nephropathy (MN). We studied seven patients with idiopathic MN, from three unrelated families of Italian ancestry. Complement phenotype analysis and restriction fragment length polymorphism (RFLP) typing of HLA class II and of the switch region genes were done in family members. In the first family, the father, one son, and one daughter had MN; another daughter had clinical glomerulonephritis. The three members with MN shared one HLA haplotype carrying DR beta 11; in the two siblings with the disease, the second HLA haplotype carried the DR beta 3.2 allele. In families 2 and 3, two brothers had MN: in family 2, they differed in at least one haplotype; in family 3, they differed in both haplotypes. Only family 3 was informative with regard to the RFLP of the switch region genes: the two siblings were identical for both Ig heavy chain haplotypes. No clinical, laboratory or morphologic features consistent with a secondary form of the disease were found. Familial clustering of MN suggests a genetically transmitted mechanism.

The single-breath nitrogen test in coal miners: factors associated with failure to perform.

The single-breath nitrogen washout (SBN2) test was used, along with spirometry, in the baseline examination of a longitudinal study in a cohort of active coal miners from North-eastern France. The procedure was computerized, allowing the technician to coach and encourage the subject, and excluding computation errors. While all miners performed satisfactory spirometry, a significant number were unable to meet the National Heart and Lung Institute recommendation concerning a 10% agreement of vital capacities. When the limits were set at +/-12%, 57 miners (24.2%) were still classified as failing to perform. When compared to those who succeeded, those failing proved to be significantly older, had more cumulated dust exposure, a higher prevalence of chronic cough and sputum, and a trend for more micronodulation on the chest radiographs. The ventilatory function did not differ between the two groups. These results confirm previous data on spirometric test failure concerning older age and respiratory symptoms, extending them to the SBN2 test. The present study further indicates that dust exposure and roentgenologic pneumoconiosis nodulation are associated with failure to perform the SBN2 test.

Cholesterol atheromatous embolism: an increasingly recognized cause of acute renal failure.

BACKGROUND: Cholesterol atheromatous embolism is a systemic disease resulting from cholesterol crystal embolization to many organs, including the kidney. Vascular surgery, vascular radiology investigations and anticoagulation have been identified as inciting factors. METHODS: Fifteen patients with extensive atherosclerosis, presenting with simultaneous occurrence of acute renal failure and peripheral ischaemic changes were diagnosed as having acute renal failure due to cholesterol atheromatous embolism. RESULTS: The patients, 12 men and three women, had an average age of 65 years. In one patient, spontaneous occurrence of the disease was observed. An inciting factor was identified in 14 patients: aortography in 10, aortic surgery in two, and thrombolysis in two. Clinical course of acute renal failure was quite variable. Four patients required dialysis; 11 were conservatively managed. All patients had concomitant skin lesions, including digital mottling, cyanosis and gangrene of the toes, and livedo reticularis of the lower limb and abdomen. Eosinophilia was the most common laboratory abnormality. The diagnosis of cholesterol atheromatous embolism was confirmed by tissue examination in eight; in three it was based on the finding of retinal cholesterol emboli; in four patients it was made on clinical grounds. Seven patients died within 36 months. Death was most commonly from cardiac causes. CONCLUSIONS: Since the population at risk for cholesterol embolism is growing and the disease is iatrogenic in origin, we should expect to detect cholesterol embolism with greater frequency as cause of acute renal failure in the future.

Computerized single-breath nitrogen washout: predicted values in a rural French community.

Comparative manual and computer measurements of the alveolar N2 slope and closing volumes have indicated systematic differences. When a computerized system is used in field surveys, predicted values are to be obtained under the same conditions. Therefore, we measured the alveolar nitrogen slope (phase III, PIII), closing volume (CV), and closing capacity (CC) from single-breath N2 washout maneuvers in 158 healthy subjects (68 females), ages 21 to 64 years, from a rural community living in a nonpolluted area of northeast France. PIII, the CV to vital capacity ratio (CV:VC, %), and the CC to the total lung capacity ratio (CC:TLC, %) were regressed against age, height, weight, and the body mass index (BMI, kg/m2) and prediction equations with 95% confidence intervals were computed. PIII increased with age in both sexes and tended to decrease with height in males (r = -0.19, p = .08). The CV:VC and CC:TLC ratios depended on age and, in males, increased with the BMI. Despite accepting a 15% difference between the test VC and the spirometric VC, only 46.3% of asymptomatic nonsmokers produced a valid single-breath nitrogen washout (SBN2) test. This high failure rate limits the usefulness of the test for epidemiologic purposes when older populations "naive" to pulmonary function testing are studied under field-survey conditions.

Influence of protein catabolic rate on nutritional status, morbidity and mortality in elderly uraemic patients on chronic haemodialysis: a prospective 3-year follow-up study.

It has been recently reported that elderly chronic haemodialysis (CHD) patients have a reduced protein catabolic rate (PCRn) in spite of an adequate Kt/V. However until now the long-term consequences of this fact on the nutritional status, morbidity, and mortality were not known. This prospective study evaluates, over a period of 3 years, the effect of the reduced PCRn on some nutritional parameters, morbidity mortality in CHD patients older than 65 years with adequate and stable Kt/V. Over the period 1990-1993 we evaluated 42 CHD patients over 65 years (mean +/- SD 72 +/- 5 years). PCRn, total serum proteins, serum albumin concentration, body weight, body mass index (BMI) and serum transferrin were determined at the start of the study and followed yearly until the end of observation. The incidence of hospitalization/patient-year, the mortality rate and the causes of death were also recorded. All the patients were managed to maintain a Kt/V > 0.9 throughout the study. Twenty-two patients (Group A), mean age 70 +/- 4 years, completed the entire period of observation. Their Kt/V was 1.10 +/- 0.12, PCRn was 0.95 +/- 0.12 g/kg/day, and serum albumin concentration was 40.2 +/- 1.5 g/l, and these did not change significantly. The other parameters also remained stable over time. Twenty patients (Group B) died. Their mean age was 74 +/- 6 years. This group's Kt/V was 1.11 +/- 0.15, PCRn was 0.94 +/- 0.18 g/kg/day, and serum albumin concentration was 39 +/- 3.1 g/l, and there were no significant variations between the start and the end of observation for all the parameters studied.(ABSTRACT TRUNCATED AT 250 WORDS)

[Estimation of static lung volumes by nitrogen washout method. Single breath of oxygen]. / Estimation des volumes pulmonaires (statiques) par la méthode du rinçage d'azote. Inspiration unique d'oxygène.

Total lung capacity (TLC) and residual volume (RV) estimations were obtained from single-breath nitrogen washouts in 96 male and 77 female healthy never-smokers with normal spirometry from a non-polluted rural area in north-east France. TLC depended on height (both sexes) and diminished slightly with age in males, with the body-mass index (kg/m2) in females. RV increased with age in both sexes and with weight in males. The RV/TLC ratio was related only to age. When compared with values obtained using multiple-breath helium dilution, our results yielded lower predicted values. The test depends heavily on the subject's co-operation, and errors are frequent if a standard procedure is not observed. This method cannot thus be recommended for routine use in patients with respiratory diseases.

Variability of the computerized single-breath nitrogen washout test in healthy adults. Results from a field survey in a French rural area.

Within-subject (difference between paired tests, or coefficient of variation [c. var.] of three consecutive measurements) and between-subjects (standard deviation of the mean group) variability were assessed for the variables derived from the single-breath nitrogen (SBN2) test in a group of healthy, asymptomatic subjects (n = 289) aged 20-64 years, from a rural area in North-East France. Duplicate measurements in 99 subjects showed excellent agreement between the two attempts (correlation coefficients between 0.94 and 0.98) for static lung volumes and the alveolar N2 slope (PIII); closing volumes (CV) were more variable (r = 0.77 for absolute value, 0.79 for % VC) while closing capacities (CC) were in intermediate position (r = 0.86 for absolute value, and 0.88 for % TLC). The variability of three consecutive measures in 190 subjects showed the coefficients of variation to be low for static volumes and closing capacity (2.4-7.4%) and higher for PIII (15.1%) and CV or CV/VC (18.2 and 17.8%). The analysis of variance did not detect significant differences between the three sets of measurements, with the exception of a progressive increase of vital capacity (VC), and decrease in residual volume (RV) from test 1 to test 3, the total lung capacity being the same. Variability was uninfluenced by age or sex, except a higher c. var. for female VC as compared to males (2.8 vs. 2.2%, P = 0.02) and a higher variability of TLC (2.9 vs. 2.3%, P = 0.03) and VC (2.8 vs. 1.9%, P = 0.003) in people older than 40 years as opposed to those younger than 40 years.

Nutritional status in long-term CAPD patients.

We studied normalized urea nitrogen appearance (NUNA), normalized protein catabolic rate (NPCR), and normalized daily creatinine excretion (NDCE) in twenty-one patients (15 men, 6 women; mean age 63 +/- 9 years) on CAPD for more than 4 years (80 +/- 27 months). In the same patients we evaluated the changes in serum albumin and transferrin with time. After 74 +/- 26 months on CAPD, NUNA was 0.12 +/- 0.03 g/Kg IBW/day, NPCR = 1.09 +/- 0.19 g/Kg IBW/day; NDCE = 15.1 +/- 3.1 mg/Kg IBW/day; serum albumin = 3.8 +/- 0.2 g/dl. NUNA was correlated with NPCR (p < 0.001) and both were correlated with NDCE (p = 0.007 and p = 0.008). NPCR significantly decreased as patient age increased (p = 0.007) but was not correlated with time on CAPD, sex or serum albumin. Serum albumin did not change as age increased. Serum albumin and serum transferrin had not significantly changed after 4 years (after 8 years in a subgroup of eight patients). Finally, we compared these data to the initial data recorded for the same patients (mean interval: 64 +/- 21 months). NUNA, NPCR and NDCE did not change significantly. Changes in NPCR were directly related to changes in NDCE (p = 0.019). This study supports that long-term CAPD does not necessarily impair nutritional status and suggests that the oldest patients can maintain stable serum albumin concentrations on lower protein intake than younger ones.

Thymomodulin increases the depressed production of superoxide anion by alveolar macrophages in patients with chronic bronchitis.

Thymomodulin is an immunomodulating agent which is derived from calf thymus by partial acid lysis. It promotes T-cell maturation, enhances antibody synthesis and improves the phagocytic response of neutrophils. Clinical trials have revealed the effectiveness of this thymic derivative in the prevention of recurrent respiratory infections (RRI) in children and in adults; 11 patients (8 males and 3 females; age range 18-76 years) with chronic bronchitis dominated by recurrent respiratory infections were studied. They were treated orally for 6 months during the winter season with 120 mg/day of thymomodulin. All the subjects were asked to keep a diary recording the intensity of their symptoms, the number of working days lost (days of illness) and the use of antibiotic and/or mucolytic drugs. At the beginning and at the end of the trial each patient was subjected to a control with a flexible fibreoptic bronchoscope with bronchoalveolar lavage to evaluate the phagocytic response of alveolar macrophages. At the end of therapy a significant improvement of the clinical status, evaluated by the above-mentioned parameters, of the bronchial mucosa aspect and an increase in alveolar macrophage superoxide production was noticed (from 0.1 +/- 0.09 and 0.8 +/- 0.5 nmol to 1.6 +/- 0.8 and 4.1 +/- 2.2 nmol with PMA or zymosan particles respectively; p less than 0.001). During thymomodulin treatment no side-effects were recorded.

[Pramiverine/metamizole - a spasmoanalgesic for routine therapy of symptoms in emergency/a clinical trial in patients with biliary colics (author's transl)]. / Pramiverine/Metamizol - ein Spasmoanalgetikum für die symptomatische Routinebehandlung im Notdienst. Klinische Prüfung des Präparates bei Patienten mit Gallenkoliken

The authors refer to a previous trial with the combination 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine Sistalgin) and N-methyl-N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-aminomethanesulfonate (metamizole) (Sistalgin comp.) in patients with renoureteral lithiasis and report results obtained with the same spasmoanalgesic and a comparative preparation in patients with biliary colics. On the basis of parameters selected for the trial, the success of pramiverine/metamizole therapy in subjective and objective complaints induced by biliary stone diseases is considered positive.