Pulmonary fibrosis induced by γ-herpesvirus in aged mice is associated with increased fibroblast responsiveness to transforming growth factor-β

Young (4 month) and aged (15-18 months) mice were given intranasal saline or γ--herpesvirus-68 infection. After 21 days, aged, but not young mice, showed significant increases in collagen content and fibrosis. There were no differences in viral clearance or inflammatory cells (including fibrocytes) between infected aged and young mice. Enzyme-linked immunosorbent assays showed increased transforming growth factor-β in whole lung homogenates of infected aged mice compared with young mice. When fibroblasts from aged and young mice were infected in vitro, aged, but not young, fibroblasts upregulate alpha-smooth muscle actin and collagen I protein. Infection with virus in vivo also demonstrates increased alpha-smooth muscle actin and collagen I protein and collagen I, collagen III, and fibronectin messenger RNA in aged fibroblasts. Furthermore, evaluation revealed that aged fibroblasts at baseline have increased transforming growth factor-β receptor 1 and 2 levels compared with young fibroblasts and are resistant to apoptosis. Increased responsiveness to transforming growth factor-β was verified by increased collagen III and fibronectin messenger RNA after treatment in vitro with transforming growth factor-β.     

The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans

Mice with a null deletion mutation in the gamma interferon (IFN-gamma) receptor gene were used to study the role of IFN-gamma responsiveness during experimental pulmonary cryptococcosis. Cryptococcus neoformans was inoculated intratracheally into mice lacking the IFN-gamma receptor gene (IFN-gammaR-/-) and into control mice (IFN-gammaR+/+). The numbers of CFU in lung, spleen, and brain were determined to assess clearance; cytokines produced by lung leukocytes were measured, and survival curves were generated. In the present study, we demonstrate the following points. (i) IFN-gammaR-/- mice are markedly more susceptible to C. neoformans infection than IFN-gammaR+/+ mice. (ii) In the absence of IFN-gamma signaling, pulmonary CFU continue to increase over the course of infection, and the infection disseminates to the brain. (iii) In the absence of IFN-gamma receptor, recruitment of inflammatory cells in response to pulmonary cryptococcal infection is not impaired. (iv) At week 5 postinfection, IFN-gammaR-/- mice have recruited greater numbers of leukocytes into their lungs, with neutrophils, eosinophils, and lymphocytes accounting for this cellular increase. (v) IFN-gamma signaling is required for the development of a T1 over a T2 immune response in the lung following cryptococcal infection. These results indicate that in the absence of IFN- gamma responsiveness, even though the recruitment of pulmonary inflammatory cells is not impaired and the secretion of IFN-gamma is not affected, IFN-gammaR-/- mice do not have the ability to resolve the cryptococcal infection. In conclusion, our data suggest that proper functional IFN-gamma signaling, possibly through a mechanism which inhibits the potentially disease-promoting T2 response, is required for mice to confine the cryptococcal infection.     

Comparison between Contrast‐Enhanced Magnetic Resonance Imaging and Selvester QRS Scoring System in Estimating Changes in Infarct Size between the Acute and Chronic Phases of Myocardial Infarction

Background: The Selvester QRS score was developed as a method to estimate infarct size (IS) using the ECG and has been validated during the prereperfusion era. Few comparisons exist with contrast‐enhanced magnetic resonance imaging (ceMRI) in reperfused patients. This study evaluates the ability of the Selvester QRS score to estimate serial changes in IS during the acute and chronic phases of the infarct evolution in patients who have received reperfusion therapy. Methods: Thirteen patients with acute myocardial infarction underwent serial ceMRI studies in the acute (<1 week) and chronic phase (>2 months) after their initial myocardial infarction. QRS scoring was performed on the corresponding ECGs. The correlation between ceMRI measurement and QRS score estimation of IS was determined at both time points and for the difference between the two phases. Results: The mean IS was 20.1 ± 11.0% of total left ventricular mass (% LV) in the acute phase and 13.3 ± 6.4% LV in the chronic phase ceMRI. The mean IS estimated by Selvester QRS score in the acute and chronic phases were 18.7 ± 8.2% and 16.4 ± 8.5% LV, respectively. A modest correlation was found for the acute (r = 0.57) and chronic phase IS (r = 0.54). However, there was no correlation for the difference in IS between the acute and chronic phases. Conclusions: In this pilot study, the Selvester QRS score correlates modestly to IS by ceMRI during both the acute and chronic phases of the infarction process. The serial changes over time in the Selvester QRS score and IS by ceMRI show no correlation.     

Atrial natriuretic factor: one of the mechanisms of action of the phlebology bath at Barbotan]

The effect of thermal baths on oedema of the lower limbs might be explained by physical mechanisms of hydrostatic pressure resulting from the use of a deep bath and a centripetal underwater jet, by which the veins and lymph ducts are drained every day. The purpose of this experiment is to demonstrate the existence of hormonal mechanisms which would account for the diuretic effect of thermal baths. One of the effects observed with hydrotherapy is the physiological diuresis that follows each bath, this diuresis would appear to depend at least in part on the atrial natriuretic factor (ANF). The criteria by which assessment can be made essentially biological: ANF level and its biological effects on blood and urine; aldosterone level; plasma renin activity (PRA); creatinine clearance; hematocrit; proteinemia; and blood and urine electrolyte balance. The inclusion criteria are: subjects selected at random and willing cooperate. The criteria for exclusion are disease states which modify ANF kinesis: congestive heart failure, cardiac rhythm disorders, decompensated cirrhosis of liver, obesity, treatment antihypertensive drugs. METHODS: Thirty patients were put through the same experimental sequence, as follows: emptying of the bladder and ingestion of 200 cc of water; seated rest fort 30 mn, after which (to): blood sample; urine sample; ingestion of 200 cc of water; deep bath for 20 mn, i.e. the basic hydro treatment in phlebology at Barbotan. The deep bath is specific to Barbotan and the patient is subjected to maximum immersion in water at a mesothermal temperature of 34.5 degrees C, followed by (t1): blood and urine sample; ingestion of 200 cc of water; supine rest for 90 mn, followed by (t2): blood and urine sample. RESULTS: Data from twenty-eight patients were usable. In this protocol, we use variance analysis with repeated measurements and a 95% confidence limit. The mean value of the principal parameters studies are set out in the following table; these value are accompanied by the degree of significance of the modification at (t1) and (t2). Our experimentation with thirty patients showed that the big thermal bath at Barbotan produces a highly significant increase in ANF secretion, resulting in the diuresis observed after the use of the bath. The antagonist effect of AFN on the renin--angiotensin-aldosterone system was corroborated: we found decreased aldosterone, PRA and creatinine clearance, and increased diuresis and natriuresis. The renal and cardiovascular effects observed after extended immersion in the Barbotan bath (increased diuresis, tachycardia and hypotension, transitory venous vasoplegia and ephemeral vasodilatation of the surface capillaries) are the result of increased ANF secretion. [formula: see text] Supine rest immediately after the bath is essential. This sustains the enhanced ANF and thus reinforces its renal effects, while reducing adverse cardiovascular effects such as the orthostatic hypotension and venous vasoplegia that are normally observed after use of the bath. Moreover, by reducing venular and lymphatic pressure, clinostatism facilitate interstitial to intravascular tissue fluid exchanges and thus helps to drain oedema from the legs. It is striking to note that the hydrotherapy prescribed at Barbotan les Thermes has always included the three most potent factors for ANF release: deep immersion in the big bath, immediate supine rest, and walking. Physiological diuresis has thus been induced empirically as an essential part of the treatment of lower limb phlebopathies.     

Manganese(II) catalyzes the bicarbonate-dependent oxidation of amino acids by hydrogen peroxide and the amino acid-facilitated dismutation of hydrogen peroxide.

In bicarbonate/CO2 buffer, Mn(II) and Fe(II) catalyze the oxidation of amino acids by H2O2 and the dismutation of H2O2. As the Mn(II)/Fe(II) ratio is increased, the yield of carbonyl compounds per mole of leucine oxidized is essentially constant, but the ratio of alpha-ketoisocaproate to isovaleraldehyde formed increases, and the fraction of H2O2 converted to O2 increases. In the absence of Fe(II), the rate of Mn(II)-catalyzed leucine oxidation is directly proportional to the H2O2, Mn(II), and amino acid concentrations and is proportional to the square of the HCO3- concentration. The rate of Mn(II)-catalyzed O2 production in the presence of 50 mM alanine or leucine is about 4-fold the rate observed in the absence of amino acids and accounts for about half of the H2O2 consumed; the other half of the H2O2 is consumed in the oxidation of the amino acids. In contrast, O2 production is increased nearly 18-fold by the presence of alpha-methylalanine and accounts for about 90% of the H2O2 consumed. The data are consistent with the view that H2O2 decomposition is an inner sphere (cage-like) process catalyzed by a Mn coordination complex of the composition Mn(II), amino acid, (HCO3-)2. Oxidation of the amino acid in this complex most likely proceeds by a free radical mechanism involving hydrogen abstraction from the alpha-carbon as a critical step. The results demonstrate that at physiological concentrations of HCO3- and CO2, Mn(II) is able to facilitate Fenton-type reactions.     

A new injection portal for brachially inserted central venous catheter. A multicenter study

Totally implantable portal systems are widely used for long-term central venous access. A new venous portal system inserted via the brachial veins (P.A.S. Port system, Pharmacia Deltec Inc, U.S.A.) was studied in five centres. From January 1988 through May 1989 61 systems were implanted. Fifty-two patients had malignant diseases. Nine cases had non-malignant disorders. The portals were implanted subcutaneously in the fore-arm and catheterization was done percutaneously (46) or by cutdown-technique (15) under local anesthesia. Catheter tip position was controlled by fluoroscopy or x-ray. The basilic vein (49) and the cephalic vein (12) were used. The total follow-up time for all systems was 323 months. Forty-five systems were still in use at the end of the observation period, six were explanted electively at the end of infusion therapy and six systems were still functioning at the time of the patient's death (at a maximum of 14 months after implantation). Temporary armphlebitis was noticed on the first postoperative week in five patients. Two P.A.S. Port systems were explanted due to infection and one because of skin rupture at the wound. One intact system was removed as it was thought to be leaking because of needle displacement. The P.A.S. Port system is easy and safe to implant with a high success rate and a low complication rate. It is well accepted by patients and nurses. The device should be advantageous in patients unsuitable for standard venous portal systems and offers an excellent alternative system for venous access.     

Application of the EXPERT consultation system to accelerated laboratory testing and interpretation

The EXPERT consultation system-building tool, a knowledge-based artificial intelligence program developed at Rutgers University, has been applied to the development of a laboratory consultation system facilitating sequential laboratory testing and interpretation. Depending on the results of a basic panel of laboratory tests, the system requests that specific secondary tests be performed. Input of these secondary findings can result in requests for tertiary testing, to complete the database necessary for interpretation. Interpretation of all results is based upon final inferences from the collected findings through a series of rules, a hierarchical network that yields an efficient production system not easily obtained through conventional programming. The rules included in this model are based upon initial results for total protein, calcium, glucose, total bilirubin, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, thyroxin, hemoglobin, mean corpuscular volume, and the concentrations of four drugs. Pertinent clinical history items included are jaundice, diabetes, thyroid disease, medications, and ethanol. Implementing this system in a laboratory-based accelerated testing program involving outpatients maximized the effective use of laboratory resources, eliminated useless testing, and provided the patient with low-cost laboratory information.