[Prognosis of myocardial infarction in women. Effect of the therapeutic effort and the socioeconomic status].

The causes of the high mortality of acute myocardial infarction in women as compared with men are controversial. The objective of this study is to assess the role of the therapeutic effort and socioeconomic factors on the genesis of this excess of mortality. We studied, using a retrospective cohort design, 491 men and 124 women admitted with the diagnosis of acute myocardial infarction. As a group, women were older (69 versus 61 years of age, p < 0.00001), showed a higher prevalence of cardiac failure on admission (44% versus 26%; p = 0.00008) and a higher mortality in the coronary care unit (29.3% versus 12.9%; p = 0.00002). In addition, the women showed an unfavorable socioeconomic profile and received a lower relative therapeutic effort, as assessed by the Therapeutic Intervention Scoring System. There was statistical interaction between gender and marital status, with a higher mortality in the unmarried male, comparable to that of women. Within the married group, the excess of mortality in women persisted after adjusting for age and Killip group (adjusted odds ratio = 2.48, 95% confidence interval between 1.26 and 4.89). None of the studied socioeconomic variables was independently associated to mortality, once age, Killip group and marital status were taken into account. After adjusting for therapeutic effort, the differences between men and women increased. Women admitted with acute myocardial infarction show a poor short-term prognosis that is not explained by their socioeconomic profile nor by the differences in therapeutic effort.


[Clinical and angiographic course after coronary angioplasty. Analysis of predictor factors of restenosis].

In order to know the restenosis rate and its predictive factors and the short-term clinical outcome (6-12 months) after coronary angioplasty (PTCA), we prospectively followed 200 consecutive patients with 231 coronary stenoses successfully dilated (residual stenosis < 50%). Patients have been clinically and angiographically followed 6-9 months after the procedure. Forty-nine clinical, hemodynamic, angiographic and technical variables were analyzed. Restenosis (stenosis > or = 50% in late angiographic control) rate was 51.5%, and 61% of the study population was symptomless. Variables associated with restenosis in the univariate analysis were: pre-PTCA positive exercise test (p = 0.004); stenosis severity pre-PTCA (p = 0.04); eccentricity (p < 0.0001) and irregularity (p < 0.0001) of the pre-PTCA stenosis; total dilation time (p = 0.02) and post-PTCA dissection (p = 0.002). The multivariate analysis revealed the following variables as independent predictors of restenosis: presence of dissection after PTCA, eccentricity and irregularity of pre-PTCA stenosis, positive pre-PTCA stress test and duration of symptoms before the procedure. These data suggest that the probability of restenosis after PTCA is predominantly determined by the characteristics of the lesion being dilated and the degree of intimal injury produced during the procedure. These variables could define high and low risk populations and may modify PTCA indications and follow up strategies.


[Antifoaming agent microembolism in patients undergoing extracorporeal circulation. Its frequency in post mortem material and its pathogenic potential in vitro].

Antifoam microembolisms in patients that undergo open heart surgery, represent a risk for postoperative complications. We decided to study its frequency in an autopsy population of patients who died after heart surgery. Forty-five patients were selected and histological sections from the kidneys were studied under light microscopy, scanning electron microscopy and X-ray microanalysis. Thirty-six cases (80%) showed microemboli in the glomerular capillaries lumens. There was a positive correlation between the number of particles found and the length of the surgery. Microemboli were composed of an amorphous fraction and a particulated one composed of silicon. In vitro experimentation demonstrated that the particles are capable to induce cell lysis in a dose related manner. They also are susceptible of been phagocitated by macrophages. We conclude that bubble oxygenator are capable to induce microembolisms in a high percentage of the cases studied. Components of the microemboli are cytotoxic. Therefore microembolisms could be participating in the morbidity of patients subjects to cardiopulmonary bypass.


[Peripheral vascular reflexes in obstructions of the left ventricular outflow tract. Experimental study].

The aim of this work is to analyze the vascular tone behaviour of the muscular arteries in relation to the reflexes generated during aortic root obstruction when spontaneous heart rate is permitted and also with induced tachycardia. An experimental model used involved anaesthetized and intubated dogs in which a resistance vessel (gracilis muscle artery) was isolated, while innervation and venous backflow remained intact. Moderate (54.4 +/- 23.2 mmHg of mean increase in left ventricular pressure) and severe (240.1 +/- 92.5 mmHg) aortic obstructions for 30 s were provoked during spontaneous heart rate (n = 15) and during ventricular overdriving (n = 13) at 200, 250 and 300 bpm for 30 s. Ventricular overdriving at 200, 250, 300 and 400 bpm for 30 s without aortic root obstruction was induced in 20 dogs. Ventricular overdriving in intact hearts produced an initial decrease in the isolated muscular artery pressure of 12.0 +/- 7.2 mmHg (p < 0.01), 9.5 +/- 5.7 mmHg (p < 0.001), 13.6 +/- 8.6 mmHg (p < 0.001) and 14.3 +/- 8.7 mmHg (p < 0.01) at 200, 250, 300 and 400 bpm respectively followed by a recovery, so that at the end of overdriving (30 s), exceeded basal values in 11.9 +/- 10.0 mmHg (p < 0.05), 21.1 +/- 12.4 mmHg (p < 0.001), 21.9 +/- 10.4 mmHg (p < 0.001) and 36.1 +/- 21.3 mmHg (p < 0.001) for each overdriving rate respectively. Aortic obstruction during spontaneous heart rate produced and initial decrease in the isolated muscular artery pressure of 12.0 +/- 7.3 mmHg (p < 0.01), when the aortic obstruction were moderate, and 31.4 +/- 15.7 mmHg (p < 0.01) when the obstructions were severe, followed by a recovery of its basal values at the end of the obstruction time. Ventricular overdriving with aortic root obstruction did not produced significant changes in the isolated muscular artery pressure except in the highest rates of overdriving, that produced an increase of isolated muscular artery pressure of 23.9 +/- 16.2 mmHg (p < 0.01). ventricular overdriving-induced hypotension in intact hearts produces an isolated muscular artery response with clear vasoconstrictor predominance. Aortic obstruction-induced hypotension does not produce a vasoconstrictor response in the isolated muscular artery but rather an initial vasodilation response which does not revert to vasoconstriction at any point during the hypotensive process. Overdriving was not capable of inducing a peripheral vasoconstriction in presence of aortic root obstruction except in the highest rates of overdriving.


[Pulmonary valvular agenesis treated with cryopreserved pulmonary homograft].

We report successful treatment of pulmonary valve agenesia with pulmonary stenosis and ventricular septal defect by infundibular resection, patch-closure of the VSD and implantation of a cryopreserved pulmonary homograft. Cases with mild to moderate hypoplasia of the pulmonary annulus are particularly well suited for direct pulmonary homograft implantation, while cases with severe hypoplasia and high right ventricular pressure after correction may be better treated with aortic homografts. Some technical aspects of homograft implantation (doing first the proximal suture, preserving the normal configuration of the valvular sinuses and using the subvalvular homograft tissue to enlarge the right ventricular outflow tract) may prevent significant valvular incompetence.


[Intraventricular transient obstruction related to bronchodilator treatment].

A 66-year-old woman with a previous history of chronic lung disease, without evidence of heart disease and without signs of left ventricular hypertrophy developed a dynamic intraventricular obstruction documented by a Doppler-derived gradient of 25 mmHg and by physical signs consisting of a brisk carotid pulse and a harsh systolic murmur while she was on treatment with theophylline and hexoprenaline. Both physical signs and Doppler-derived gradient disappeared after withdrawal of bronchodilator drugs.


[Lipomatous hypertrophy of the interatrial septum. Report of 2 cases diagnosed in vivo].

Lipomatous hypertrophy of intervenous tubercle is a clinicopathological entity characterized by an accumulation of not capsulated fatty tissue, with its thickness exceeding 15 mm, in the atrial septum, above the fossa ovalis, at the intervenous level and protruding into the right atrium. It can be clinically associated with atrial electric abnormalities such as disorders of the atrial conduction and supraventricular arrhythmias, difficulty of the venous return and sudden death. Nowadays its diagnosis is not difficult using non invasive image techniques. We present two cases of lipomatous hypertrophy of intervenous tubercle which were suspected by echocardiography. In one of them we used transthoracic echocardiography and in the other one transesophageal echocardiography. The diagnostic was latter confirmed by magnetic nuclear resonance and axial computerized tomography.


[Systemic-pulmonary shunt with autologous internal jugular vein].

We report a variant of systemic-pulmonary shunt for newborns or low-weight neonates affected with hypoplasia or atresia of pulmonary artery. An autologous internal jugular vein was used. Six months after surgery all patients referred no symptoms and a normal systemic-pulmonary shunt with an arterial oxygenation of 82-90% was present.


[Quadricuspid aortic valve. Presentation of a new case and review of the literature].

We report a case of quadricuspid aortic valve, diagnosed by two-dimensional echocardiography in a patient with scleroderma, during the course of an acute pericarditis. With regard to this observation, we review the literature published about this rare anomaly.


[The era of myocardial reperfusion].

Myocardial reperfusion is the single most useful therapeutic approach in patients with acute myocardial infarction. The thousands of lives saved each year by this treatment are the result of scientific progress in very different areas, including the biopathology of myocardial ischemia and reperfusion, the mechanisms of coronary occlusion, the pharmacology of the fibrinolytic system, and clinical research. The 30% reduction in mortality achieved by fibrinolytic treatment in patients with acute myocardial infarction does not fit, apparently, with the short time-window during which restoration of blood flow results in significant myocardial salvage in animal models with few collaterals. This discrepancy could be due to the protective effect of intermittent coronary occlusions immediately preceding stable occlusive thrombosis (ischemic preconditioning), or to other possible beneficial effects of reperfusion independent of myocardial salvage, as limitation of ventricular remodelling or reduction of the risk of cardiac rupture or severe arrhythmias. Clearly, the best approach to increase the beneficial effects of reperfusion therapy is to perform it as early as possible; the cost-effectiveness of pre-hospital treatment strategies is now under investigation. In the other hand, current reperfusion therapy cannot be considered optimal. Thrombolytic agents fail to achieve recanalization of the infarct related vessel in 20-30% of patients, and 10-15% of the successfully opened arteries present early reocclusion. In certain subgroups of patients, such in those with cardiogenic shock, failure rate is higher. Mechanical recanalization by "direct" angioplasty represent an alternative reperfusion method, which utility has been established in certain circumstances only. So, well in the "reperfusion era", many questions remain open.(ABSTRACT TRUNCATED AT 250 WORDS)


[Aspirin and heparin in the fibrinolytic treatment of acute myocardial infarction].

There is now extensive evidence of activation of platelet and the coagulation cascade with coronary thrombosis, and further activation with exogenous thrombolysis. Administration of aspirin and heparin has been shown to improve mortality when combined with thrombolytic therapy in acute myocardial infarction, probably by enhancing lysis and reducing subsequent reocclusion of infarct related artery. Most studies have evaluated the effect of aspirin or heparin in combination with streptokinase. These results can probably be extrapolated to rtPA, as it has much shorter, half live, and induces lower systemic lytic state. Although aspirin and heparin have been tested independently, they probably have a synergistic action post fibrinolysis. With current information it is mandatory to include aspirin in the treatment of AMI, with or with out thrombolytic treatment. Intravenous administration of heparin seems justified, specially if rtPA is used as fibrinolytic agent. Potent new drugs capable of inhibiting platelets an the coagulation cascade emerge as a promising future. Until their effect is clinically proven, aspirin and i.v. heparin should remain as adjunctive therapy to fibrinolytic treatment in AMI.


[Prehospital fibrinolysis: a priority objective?].

Clinical trials strongly suggest that the sooner thrombolysis is applied after the onset of chest pain, the greater are the derived benefits. Time delay between onset chest pain and initiation of therapy possesses three fundamental components: 1) the call for help; 2) the transportation to the hospital, and 3) the in-hospital delay for diagnosis and initiation of therapy. On the other hand, pre-hospital thrombolysis has been shown feasible and safe; more importantly, it has resulted in early identification of patients eligible for fibrinolysis, greatly accelerating the process of drug administration. A critical look at all measures that could result in more rapid treatment is now indicated. This include early identification of eligible patients, prompt clinical and electrocardiographic diagnosis, rapid transportation to hospital and undelayed drug administration by competent personnel. Every clinical center should investigate the practice in its community area to detect where, when and why time is lost between onset of pain and treatment application to institute the appropriate corrective measures.


[Role of angioplasty in acute myocardial infarction].

Angioplasty as the treatment of acute myocardial infarction has proven to be effective in restoring arterial patency and in reducing residual stenosis, although reocclusion and restenosis may be high. Despite the good results reported by several investigators none of the prospective randomized trials comparing thrombolytic therapy with angioplasty (either alone or associated to thrombolysis) has shown any improvement in survival, the latter strategy being associated with an excess of acute complications. However, primary angioplasty may be useful in selected subgroups such as those with cardiogenic shock or with absolute contraindications for thrombolysis. The role of rescue angioplasty still needs to be defined in properly designed studies. In conclusion, primary angioplasty in acute myocardial infarction should be restricted to patients in whom thrombolytic therapy has been shown to be harmful or ineffective.


[Treatment of cardiogenic shock with thrombolysis and coronary angioplasty].

The incidence of cardiogenic shock in patients with acute myocardial infarction can be estimated between 2 and 12%, with a mortality close to 75%. Most pathologic studies demonstrate that myocardial necrosis involves more than 40% of left ventricular mass in these patients. Severe coronary disease is the rule, with three vessel disease in nearly 70% of cases. The efficacity of fibrinolytic treatment in reducing mortality is less evident in patient with shock. In the GISSI-1 study, Killip class IV patients had 69% mortality with streptokinase and 70% without; In the GISSI-2 trial, mortality was 65% with streptokinase and 78% with tPA. The thrombolytic drug used does not seem, thus, to influence the results. In a small series of 44 patients, intracoronary streptokinase achieved recanalization in 43% of cases, less than the average for the general population of patients with acute myocardial infarction receiving conventional treatment. Mortality was 42% in successfully treated patients, less than in those not reperfused. Coronary angioplasty seems superior to conventional fibrinolytic treatment. Results are promising, with survival between 56% and 61% in successfully reperfused patients. Recanalization rate may reach 75%. Surgery offers the only alternative when shock is due to any types of cardiac rupture; in the absence of this complication, its role is not well defined yet. Survival may be estimated in 50%.


[Elective coronary angioplasty in recurrent ischemia after successful fibrinolysis in myocardial infarction. Comparison with results of angioplasty in the acute phase].

To assess the initial and long-term results of 149 percutaneous transluminal coronary angioplasty (PTCA) procedures performed within 1 month of an acute myocardial infarction (AMI), 83 of them because of recurrent ischemia (post-infarction angina) after thrombolytic therapy with initial reperfusion success in the AMI (100 lesions attempted) (group I) and 66 PTCAs (69 lesions) performed during the acute phase of the AMI (group II). Mean age was 56 +/- 14 and 127 (85%) patients were male. Although successful dilation was obtained in 151 (89%) of the 169 attempted lesions, (96[96%] in group I vs 55[78%] in group II), clinical success was obtained in only 123 (82%) (76[92%] vs 64[77%] in both groups, respectively). Late occlusion occurred in 14 (9%) of the 151 lesions successfully dilated (6[6%] and 8[15%], respectively) and reinfarction was documented in 7 (5%) patients (5[5%] and 2[3%]). One patient in group I underwent coronary bypass surgery. There were 4 (3%) hospital deaths (1[1%] and 3[4%]) in group I and II, respectively). Event-free (no occurrence of death, AMI, coronary surgery, repeat PTCA or angina recurrence) survival rate was 76%, 73% and 67% in group I versus 62%, 57% and 40% in group II, at 1, 2 and 4 years respectively. During follow-up, 1 (1%) patient of the group I and 4 of the group II died. At last follow-up, 63 (78%) of the 81 patients alive vs 33 (67%) of the 59 patients in the group I and II respectively remained asymptomatic. In conclusion, in our experience elective PTCA performed in the subacute phase after an AMI provides better initial and long-term outcome than that performed in the acute phase. Therefore, the procedure would be delayed whenever possible.


[Reperfusion arrhythmias during coronary thrombolysis: clinical reality or experimental curiosity?].

To determine the arrhythmogenic impact of the fibrinolytic therapy during acute myocardial infarction, we have revised 9 clinical series published between 1983 and 1992 including a total number of 2,091 patients, and we have discussed the data according to the factors that modulate the incidence of reperfusion arrhythmias. All patients had an acute myocardial infarction that began 3 to 6 hours before admission and in all instances fibrinolytic treatment consisted of intravenous or intracoronary streptokinase infusion. Ventricular fibrillation (VF) during thrombolytic therapy occurred in 8 (4%) out of 188 patients with angiographically documented reopening of the occluded coronary artery. The mean incidence of VF was 0-17% among all series. The overall incidence of sustained ventricular tachycardia (VT) was 19%, whereas that the incidence of slow VT (idioventricular rhythm) was 39%. Sinus bradycardia was not systematically analyzed in the present series, but the presence of sinus bradycardia and arterial hypotension (Bezold-Jarisch reflex) was considered to be indicative of myocardial reperfusion specially in cases of acute inferior myocardial infarction. We conclude that in contrast to experimental models of coronary reperfusion, fibrinolytic therapy in patients with acute myocardial infarction has a low arrhythmogenic potential.


[Does reperfusion modify the risk of heart rupture? Effects of early reperfusion].

The goal of this study was to evaluate whether early fibrinolytic therapy could reduce in-hospital mortality caused by cardiac rupture in patients with acute myocardial infarction (AMI). Based on the strong correlation between occurrence of left ventricular free wall rupture and development of sudden electromechanical dissociation (EMD) in patients with a first TAMI without relevant heart failure, we compare the incidence of this mechanism of death in patients treated with streptokinase and in those from a control group. The study included 406 patients with a first transmural AMI younger than 71 years who received intravenous streptokinase (SK) with 104 similar patients not treated with fibrinolytic agents. Mortality rate in patients treated with SK was 6% compared to 11% in those from the control group. Patients treated with SK presented a lower incidence of EMD than those from the control group (17% vs 72%; p < 0.002). A necropsy study carried out in 33% of cases, confirmed the existence of left ventricular free wall rupture in each of the 7 cases who presented EMD but in none of the 6 who died in shock. We conclude that left ventricular free wall rupture is the principal cause of mortality in patients admitted to a Coronary Care Unit with a first transmural AMI, and that fibrinolytic treatment reduces mortality mainly by reducing development of cardiac rupture.


[Detecting reperfusion in patients with acute myocardial infarction].

The patency of the infarct-related coronary artery seems to be an important prognostic factor after an acute myocardial infarction. It is not only related to short term prognosis, specially in the context of cardiogenic shock, but also to long-term prognosis, due to its influence on ventricular remodelling. On the other hand, the assessment of new fibrinolytic treatments require large numbers of patients in multicenter trials for documenting a benefit, when mortality is used as the endpoint. Accordingly, new endpoints will have to be developed, as the patency of the infarct-related coronary artery. Coronary angiography has been used until now to assess coronary patency. However, it is an invasive procedure and its optimal timing after fibrinolytic treatment has not been established. The classic non-invasive methods, like resolution of chest pain, reperfusion arrhythmias, normalization of ST segment elevation and enzymatic determinations, are not very useful, although the combined analysis of these markers increases their accuracy. The imaging methods, specially isotopic but also magnetic resonance imaging, offer interesting possibilities, but they are expensive and not universally available. The usefulness of contrast echocardiography has not been well established. Thus, the diagnosis of myocardial reperfusion by a non-invasive method, sensitive, specific and with a good temporal and spatial resolution, is still an unsolved problem.


[The future of fibrinolysis: from fibrinolytic treatment to reperfusion therapy].

Fibrinolytic therapy is aimed at dissolving the fibrin clot. Its use now represents the optimal therapy for an acute evolving myocardial infarction. Although improved fibrinolytic agents are now being developed, the next frontier appears to be thrombolytic therapy which will combine fibrinolysis to platelet active drugs and specific inhibitors of blood coagulation, targetting the blood clot formation process itself. The most promising agents in this regard are inhibitors of the platelet glycoprotein IIb-IIIa receptors and specific thrombin inhibitors active on clot bound thrombin. This should result in more complete control of the thrombogenicity of the culprit coronary artery lesion. The comprehensive approach for the management of acute myocardial infarction should however ultimately be reperfusion therapy combining to thrombolytic therapy measures that will preserve the acutely ischemic myocardium and prevent the long-term deleterious effect of infarct expansion and left ventricular remodelling.


[Comparison of clinical efficacy of thrombolytic drugs in patients with acute myocardial infarction].

Thrombolytic therapy has prove to be effective to recanalize the occluded coronary artery in patients with acute myocardial infarction, reducing infarct size, preserving ventricular function and improving short and long term survival. In a number of studies the relative efficacy of the available thrombolytic agents has been studied an are discussed in this revision of the comparative, randomized trials. Some differences have been found in the relative efficacy of streptokinase, APSAC, urokinase and tPA to recanalized the occluded infarct related coronary artery. Reocclusion is probably highest with tPA and lowest with urokinase or the combination of urokinase and tPA. No differences were found in the reduction of infarct size and improving of left ventricular function. The mortality rate of patients treated with streptokinase, APSAC or tPA was found to be similar in two multicentric studies: GISSI-2 and ISIS-3. Major complications related with the use of thrombolytics include systemic or cerebral haemorrhage, allergic reactions, hypotension and probably heart rupture. Systemic and cerebral hemorrhages are more frequently associated with the use of tPA and APSAC than with streptokinase. Allergic reactions are more frequent after administration of streptokinase and APSAC than after tPA or urokinase and the same occurs with hypotension requiring treatment. The analysis of the available data from the comparative studies do not offer enough clinical evidence to consider any of the thrombolytic agents as the drug of choice in most patients with acute myocardial infarction.


Replication of mini-F plasmids during the bacterial division cycle.

The cell-cycle replication patterns of two mini-F plasmids have been examined using the membrane-elution technique (to produce cells labelled at different times during the division cycle) and scintillation counting (for quantitative analysis of radioactivity incorporated into plasmid DNA). The mini-F plasmid pML31, which contains the oriV and oriS origins of replication, replicates in a cell-cycle-specific manner with a pattern and cell-cycle timing similar to the parental F plasmid. The mini-F plasmid pMF21, deleted for the region containing the oriV origin of replication, replicates more randomly throughout the division cycle. These results suggest that the oriV origin of replication may be related to cell-cycle-specific replication of the F plasmid.


Introduction of the emm6 gene into an emm-deleted strain of Streptococcus pyogenes restores its ability to resist phagocytosis.

To complete the formal proof that the M protein functions to protect the group A streptococcus from phagocytosis and to lay the groundwork for the molecular genetic dissection of this major virulence factor, we have reintroduced a wild-type allele of the M protein gene (emm) into the chromosome of a strain from which it had previously been deleted. For this purpose, we used homologous recombination with an engineered plasmid that was introduced into the Streptococcus pyogenes chromosome by an electroporation technique that we developed. The plasmid pJRS120E was constructed in Escherichia coli and contains the structural gene for the antiphagocytic M6 protein (emm6) of S. pyogenes JRS4 and a selectable marker (ermAM) between the chromosomal regions that flank emm6 in S. pyogenes. This plasmid was introduced into S. pyogenes strain JRS75, a strain that is not resistant to phagocytosis as a result of the allelic replacement of the emm6 gene by a kanamycin resistance gene (aphA3). DNA hybridization analysis indicated that in erythromycin-resistant strain JRS115, homologous recombination resulted in the replacement of the aphA3 gene of JRS75 with the introduced emm6 allele. Strain JRS115 produces approximately the same amount of M6 as does the parental emm6+ strain JRS4, as assayed by Western blot analysis, and is resistant to phagocytosis.


A degU-containing SP beta prophage complements superactivator mutations affecting the Bacillus subtilis degSU operon.

The Bacillus subtilis degSU two-gene operon encodes a two-component regulatory system which positively controls expression of a variety of genes encoding degradative enzymes. Point superactivator mutations in either degS or degU increase the production of these enzymes. A specialized transducing SP beta phage which partially complements several of these mutations was isolated from a phage library of the B. subtilis chromosome. This phage was shown to contain the degU (wild-type) gene. This unexpected co-dominance is discussed.


Purification and characterization of Kanagawa haemolysin from Vibrio parahaemolyticus.

The haemolysin of a Kanagawa-phenomenon-positive Vibrio parahaemolyticus strain was purified to apparent homogeneity by acid precipitation, DEAE-Trisacryl, hydroxyapatite and FPLC (Mono-Q) columns: 1.4 micrograms of protein gave a single band on conventional SDS-PAGE with silver staining. The haemolysin was not inactivated by heating for 10 min at 100 degrees C. It was a monomeric protein with a molecular weight estimated to be 29 kDa by PAGE under denaturing and non-denaturing conditions. The haemolysin caused fluid accumulation in the ligated mouse ileum, was cytolytic against cultured mammalian cells and also lysed erythrocytes of various animal species (equine erythrocytes being the most resistant).


Antigenic variation and strain heterogeneity in Borrelia spp.

Antigenic variation and strain heterogeneity have been demonstrated for the pathogenic Borrelia species, i.e. B. burgdorferi and the relapsing fever borreliae. In relapsing fever, new borrelia serotypes emerge at a high rate spontaneously, a mechanism that is caused by DNA rearrangements on linear plasmid translocating genes coding for variable major proteins from previous silent to expression sites (i.e. from inner sites to telomeric sites of the plasmid). As a result of this variation, the borreliae escape the immune response of the host, thus leading to the relapse phenomenon. In B. burgdorferi, which is the causative agent of the multisystem disorder Lyme borreliosis, there is also a growing body of findings that antigenic variation is involved in pathogenesis of the disease. Phenotypic variation of strains in vitro concerns the size and the amount of surface-associated proteins (OspA, OspB and pC). There are indications that OspA and OspB truncations are due to deletions within the ospAB operon caused by recombination events, and that OspA/OspB-less mutants lack the 49-kb plasmid that bears the ospAB operon. With the increasing number of isolates obtained from various geographic and biological sources, it became apparent that B. burgdorferi is immunologically and genetically more heterogeneous, as previously believed. The major outer surface proteins OspA and OspB (which have been efficient antigens in vaccine studies) are heterogeneous at a genetic level. The same degree of genetic non-identity was observed for the pC protein. Other proteins like flagellin and the highly specific immunodominant p100 range protein show a lower degree of non-identity. Recombinant OspA, pC, p100 range protein and flagellin have been hyperexpressed in E. coli and these proteins are immunologically reactive. This allows further research for development of vaccines and diagnostic tools. B. burgdorferi isolates have been investigated with genotyping (DNA hybridization, PCR and 16S rRNA analysis) as well as serotyping by various authors. Comparison of the different methods has shown good agreement when the same strains have been investigated. No correlation could be found between different phenotypic and genotypic groups with respect to the ability to cause arthritis in SCID mice. A serotyping system based on immunological differences in OspA detected by a panel of monoclonal antibodies has been proposed. Serotyping a large number of B. burgdorferi isolates has shown a striking predominance of the OspA serotype 2 among European isolates from human skin, in contrast to isolates from ticks or CSF.(ABSTRACT TRUNCATED AT 400 WORDS)


Spirochete chemotaxis, motility, and the structure of the spirochetal periplasmic flagella.

Spirochetes have a unique motility system that is characterized by flagellar filaments contained within the outer membrane sheath. Direct evidence using video microscopy has recently been obtained which indicates that these periplasmic flagella (PF) rotate in several spirochetal species. This rotation generates thrust. As shown for one spirochete, Spirochaeta aurantia, motility is driven by a proton motive force. Spirochete chemotaxis has been most thoroughly studied in S. aurantia. This spirochete exhibits three distinct behaviours, runs of smooth swimming, reversals and flexing. These behaviours are modulated by addition of attractants such that S. aurantia swims towards higher concentrations of attractants in a spatial gradient. Unlike the prototypical bacterium, Escherichia coli, chemotaxis in S. aurantia involves fluctuations in membrane potential. The PF of a number of spirochetes have been examined in considerable detail. For most species, the PF filaments are complex, consisting of an assembly of several different polypeptides. There are several antigenically related core polypeptides surrounded by an outer layer consisting of a different polypeptide. Borrelia burgdorferi and Spirochaeta zuelzerae represent exceptions where the filaments are composed of a single major polypeptide species. The genes encoding the filament polypeptides from several spirochete species have been cloned and analysed. Apparently, the outer layer polypeptides of S. aurantia, Treponema pallidum and Serpulina hyodysenteriae are transcribed from sigma-70-like promoters, whereas the core polypeptide genes are transcribed from sigma-28-like promoters. A gene encoding the hook polypeptide in Treponema phagedenis has been cloned and analysed. The product of this gene shows significant similarity to the E. coli hook protein, FlgE, and homologs have been identified in T. pallidum and B. burgdorferi.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of phenothiazine on contractions induced by prostaglandin F2 alpha and 5-hydroxytryptamine in normal and spastic canine cerebral artery.

We have investigated the effect of phenothiazine, a compound known to inhibit calmodulin, on the responses of normal and spastic cerebral arteries, using the canine "two hemorrhage" model of cerebrovascular spasm. Ring preparations from control vessels or vessels removed three or seven days after injection of blood, were contracted with either 5-hydroxytryptamine (5-HT) or prostaglandin F2 alpha (PGF2 alpha) and then exposed to increasing concentrations of phenothiazine. In normal arteries, low concentrations of phenothiazine enhanced the response to PGF2 alpha, while higher concentrations caused relaxation. Responses to 5-HT were inhibited by all concentrations of phenothiazine tested. When normal arteries were compared with arteries from animals injected with blood, in the case of 5-HT, phenothiazine was a less effective antagonist at low doses, but equieffective at higher doses. Similar experiments conducted with PGF2 alpha showed that phenothiazine was a more effective antagonist in spastic vessels. We conclude that 5-HT and PGF2 alpha have significant differences in the mechanism by which they produce contraction of cerebral vessels, that phenothiazine has secondary effects on contraction independent of inhibition of calmodulin, and, finally that the effects of phenothiazine in clinical vasospasm may be insufficient to reverse the condition, despite the observation that vessels in spasm may be more sensitive to this agent.


Central arrhythmogenic effects of N-methyl-D-aspartate (NMDA) in anesthetized rats: influence of the denervation of the carotid-sinus baroreceptors on the susceptibility to arrhythmias.

The intracerebroventricular (i.c.v.) administration of NMDA into urethane anesthetized rats could induce centrogenic cardiac arrhythmias. There were some important differences between sodium glutamate- and NMDA-induced arrhythmias which rendered it difficult to accept the assumption that glutamate-induced arrhythmias were due to the stimulation of only NMDA receptors. Denervation of the carotid-sinus baroreceptor zones enhanced the central arrhythmogenic activity of both sodium glutamate and NMDA.


Genetic approaches to cell biology and metabolism of spirochetes.

Genetic analysis and methodology have only comparatively recently been applied to the study of spirochetes. Although genetic transfer procedures for spirochetes are not widely available, there are several examples of progress in genetic analysis of spirochetes by other approaches. Some examples of these approaches are the following. 1) Genes for synthetic pathways in Treponema and Leptospira have been cloned by complementation of Escherichia coli serving as plasmid hosts. 2) The OspA protein of Borrelia burgdorferi has been overexpressed in E. coli without the signal peptide; the recombinant product has been suitable for circular dichroism as well as other biochemical analyses. 3) The heat shock proteins of B. burgdorferi are homologous to heat shock proteins of E. coli. 4) Enzyme activity profiles of B. burgdorferi and other spirochetes show strain heterogeneity and also indicate which biosynthetic and enzymatic activities are conserved within different spirochetes. 5) The gene organization of rRNA genes have revealed differences between spirochetes and other types of bacteria.


Extrachromosomal elements of spirochetes.

The spirochetes include some important pathogenic bacteria, Treponema, Borrelia and Leptospira. The pathogeneses of these spirochetes are very diverse. In an attempt to learn more about the virulence factors among the spirochetes, their genetic organization and capacity have been studied. Structural analysis of the genome in Borrelia has shown that the genome is composed of one linear maxi-chromosome with additional linear minichromosomes as well as several supercoiled circular plasmids. Moreover, the molecular analysis of the terminal ends of one of the linear minichromosomes has revealed that this unique replicon has sequence similarities with poxviruses and particularly the viral agent of African swine fever. The presence of nucleic-acid-containing vesicles and its possible role in mediating DNA transfer between borreliae is an additional, very interesting feature of these organisms. Treponema does not contain any linear DNA, chromosomal or extrachromosomal, however molecular characterization of a 2.6-kb plasmid of Treponema denticola has been performed with the aim of establishing cloning vehicles to study the virulence properties of the genus Treponema.


Changes in the xanthine dehydrogenase/xanthine oxidase ratio in the rat kidney subjected to ischemia-reperfusion stress: preventive effect of some flavonoids.

The enzyme xanthine oxidase has been implicated in the tissue oxidative injury after ischemia-reperfusion. This enzyme, which is a source of oxygen free radicals, is formed from a dehydrogenase form during ischemia. The ratio dehydrogenase/oxidase of rat kidney homogenates decreases during the ischemia and the reperfusion. Two flavonoids, quercetin and silybin, characterized as free radical scavengers, exert a protective effect preventing the decrease in the dehydrogenase/oxidase ratio observed during ischemia-reperfusion. The mechanism of this effect and the role of flavonoids in the ischemia-reperfusion tissue damage is discussed.


Interaction of spirochetes with the host.

The success of an invading organism must depend on several cytoplasmic, surface-associated and secreted factors. The technical difficulties in handling pathogenic spirochetes like Treponema pallidum and Borrelia burgdorferi have made it difficult to define specific factors involved in entry and long-term survival. The problem of defining virulence factors has been attacked by several strategies: T. pallidum secretes a number of immunogenic low molecular mass proteins. The most predominant are of molecular weight 15.5 and 22 kDa. Preliminary data suggest that antibodies against these proteins induce protective immunity in rabbits experimentally infected with T. pallidum. Many potentially important surface-associated antigens of T. pallidum have now been cloned and characterized. Two of these, TpD and TpE, are lipoproteins which exhibit characteristic size heterogeneity. The apparent molecular weight of TpE from T. pallidum and T. pertenue are different. The clinical symptoms in syphilis and yaws are very different, but sequence analysis of TpE has shown that the TpE proteins are indeed very similar in the two strains. This observation makes it unlikely that heterogeneity of TpE can account for the different clinical symptoms of syphilis and yaws. Sequence data for another newly sequenced surface-associated antigen of T. pallidum (molecular weight 41 kDa) indicate that this protein is involved in glucose transport and chemotaxis/motility. Intracellular factors like the molecular chaperonin GroEL have been documented both in treponemes and borreliae. This stress protein is involved in cellular repair processes and folding/assembly of protein subunits. Indirect evidence suggests that GroEL affects the ability of spirochetes to survive in the stressful environment of the infected host. Several lines of evidence suggest that the Osp proteins of Borrelia are important for host/parasite interaction. Further support for this idea has come from studies of a series of monoclonal antibodies against OspA. A monoclonal antibody against OspA (9B3D) is able to block attachment of B. burgdorferi to a cell monolayer. Borrelia loses infectivity after several passages in vitro. The loss of pathogenicity is associated with loss of specific plasmids and proteins. One of the low-passage-associated proteins (Lap30) has been cloned and sequenced. Lap30 is a lipoprotein encoded by a 38-kb plasmid, not present in high passage B. burgdorferi. Aberrant immunological processes induced by the lipopolysaccharide component of Treponema hyodysenteriae could explain the dramatic intestinal lesions in swine dysenteriae. But analysis by TLC reveals that the LPS of this treponeme is different from classical Salmonella LPS.(ABSTRACT TRUNCATED AT 400 WORDS)


Spirochetes: vaccines, animal models and diagnostics.

The detailed characterization of various proteins from spirochetes using molecular biology techniques has made possible new approaches to vaccine and diagnostic development that are described in this session. The importance of animal models was emphasized and illustrated.


1,25-Dihydroxyvitamin D3 inhibits thromboxane release from activated macrophages.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) in concentrations from 0.1 to 10 nM suppressed immunoreactive thromboxane B2 (iTXB2) release from Propionibacterium acnes (P. acnes)-elicited liver adherent cells stimulated with lipopolysaccharide (LPS, 1 microgram/ml). These suppressive effects of 1,25-(OH)2D3 were also observed in oyster glycogen-elicited peritoneal macrophages. On the contrary, it did not inhibit iTXB2 release from both resident Kupffer cells and peritoneal macrophages stimulated with the same concentration of LPS. Furthermore, 1,24(R)-dihydroxyvitamin D3 (1,24(R)-(OH)2D3), a vitamin D3 analogue, also inhibited iTXB2 release from liver adherent cells, but, another synthesized vitamin D3 analogue, 1 alpha-hydroxyvitamin D3 (1 alpha-OH-D3) tended to decrease iTXB2 release only at higher concentrations. These results suggest that active vitamin D3 analogues inhibit iTXB2 release from activated macrophages.


In vitro and in vivo activities of the novel antiplatelet agent alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide.

In an effort to develop compounds with high antithrombotic activity and minimal toxicity, our laboratory has synthesized a number of nipecotamides. The effectiveness of one of these compounds, alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide (A-1), in inhibiting both in vitro and in vivo platelet aggregation is reported here, along with its acute toxicity. The IC50 of A-1 in in vitro ADP- and PAF-induced platelet aggregation was 44.5 microM and 21.2 microM, respectively. Suppression of intraplatelet [Ca2+] is suggested as a likely mediator of the aggregation-inhibitory properties of A-1, since both the release of cytosolic Ca2+ and the influx of extracellular Ca2+ were decreased. The ED50 of A-1 in protecting mice against thromboembolism induced by a collagen-epinephrine challenge was 164 mumol/kg. The measurement of the acute toxicity of this compound as the LD50 was 691 mumol/kg, with the therapeutic index being 4.2. These data indicate that compounds in this family hold promise as clinically effective antithrombotic agents.


The influence of renal failure on the kinetics of intravenous midazolam: an "in vitro" and "in vivo" study.

The effect of renal failure upon the "in vitro" binding of midazolam, a new water-soluble short-acting benzodiazepine, has been studied in man. An increase of its free fraction (ranging from 2.52 to 5.17%) in serum from uremic patients was observed. A similar situation was originated in rabbits by administering uranyl nitrate (2 mg/Kg i.v.) and posterior hypnosis with midazolam. Uremic rabbits showed a marked increase in the free concentration of midazolam in serum (ranging from 8.9 to 13.7 micrograms/ml) and in midazolam brain levels (156.2 micrograms/g in cortex vs 84.5 micrograms/g in control animals). A positive correlation between brain and serum free concentration of midazolam was also observed. It is concluded that in renal patients more unbound drug is available to produce central nervous system effects, and a decrease in intravenous dose of midazolam could be recommended in this clinical situation.


Morphometric analysis of renal cortex changes induced by diethylstilbestrol (DES) in Syrian hamsters.

Estrogen-induced renal adenocarcinoma usually can be readily detected in castrated hamsters after 9 to 12 months of DES treatment. In the present study, we examined the morphological characteristics of the renal cortices of castrated hamsters that had received 3 months of DES treatment in order to describe early histological evidence of carcinogenesis induction. Twelve Syrian Golden hamsters, 8 to 9 weeks of age, were first castrated and then subjected to either subpannicular implantation of a 20 mg DES pellet (experiment group), or sham operation (controls). Morphological and 2-D morphometric evaluations were conducted sequentially on kidney histological sections. Numbers (N's) or area fractions (AF's) of renal components in the juxta-medullary junction of each kidney section were processed for morphometric evaluation. The DES treatment caused a 15% increase in kidney weight, but not body weight. Dysplastic foci associated with hyperplastic tubules were present in 67% of the left kidneys or 17% of the right kidneys of hamsters in the test group, but were absent in kidneys of controls. DES treatment decreased glomeruli N by 33% and increased the vasculature AF by 169% per examination field. DES also increased AF's of glomeruli, proximal tubules, distal tubules, and vasculature by 17, 81, 53 and 346% per nephron, respectively. Our results showed that, after the first three months of DES-treatment, hamster kidneys developed dysplastic foci and their masses were greater than controls. Increased renal components in the juxta-medullary junction region included glomeruli, tubules, and vasculature. The dysplastic foci may be sites of subsequent malignancies, whereas the increased renal mass might be a result of functional adaptation/expression to exogenous estrogen which might contribute to the carcinogenic process.


Cystic fibrosis and pulmonary involvement from multiple perspectives.

The pulmonary involvement in cystic fibrosis (CF) is discussed from several perspectives including historical, current treatment, and possible future therapies. The clinical realities that have limited and frustrated the successful control of the pulmonary progression are reviewed. A variety of pending new therapies are briefly presented including antiinflammatory agents, protease inhibitors, ion transport inhibitors, antiviscosity agents, chloride channel modifiers, and immunomodifiers. An appeal is made for more effective down-regulation of the overstimulated local and systemic immune responses to the chronic inflammatory processes. More attention needs to be paid to improvement of current methods of aerosol administration that will be of critical importance for living cell/viral/gene/liposome delivery. Other means of buying additional survival time are urgently needed such as improvements in lung transplantation and better treatment of cor pulmonale. The explosion of molecular genetics progress in CF basic research is an exciting and encouraging dynamic that may lead to a cure for patients with CF in spite of the more than 200 known genetic variations known to date. The survival of CF patients has increased 1 year for 1 year during the past 10 years and now is 29.4 years in 1991. If this progress can be maintained, the hope is that advances in molecular genetics and cell electrophysiology can soon be brought to clinical application in an effective fashion. A magnificent choice of new treatment directions is becoming available, leading to very realistic hope and optimism for the future for patients with CF.


The cystic fibrosis gene and relationships to clinical status.

Cystic fibrosis (CF) is a disease characterized by significant variability in both presentation and clinical course. The genetic and environmental factors responsible for the phenotypic expression of CF are most likely legion, and their relationship to the disease complex. Therefore, it was not until the isolation and characterization of the CF gene and the ability to genotype individual patients that further elucidation of the genotype-phenotype relationship in CF was possible. Currently, the pancreatic status of CF patients appears to be primarily determined by genetic factors and patients homozygous for the most common mutation, delta F508 are, as a rule, pancreatic insufficient. Other specific alleles that confer pancreatic sufficiency have been identified. Patients having these alternative alleles remain pancreatic sufficient, are diagnosed later, have lower sweat chloride values, milder respiratory disease, and a better prognosis than patients with alleles associated with pancreatic insufficiency. Other clinical manifestations, including meconium ileus and the presence of liver disease, appear to be associated with pancreatic insufficiency. The variability in the pulmonary course for homozygous delta F508 patients suggests that genetic heterogeneity at other loci or environmental factors are important. Therefore, the CF genotype does not precisely predict pulmonary status.


Evolution of airway microbiology in the infant with cystic fibrosis: role of nonpseudomonal and pseudomonal pathogens.

Bacterial colonization of the airways of the infant with cystic fibrosis is usually established early in life, and, once established, is difficult to eradicate and is associated with progressive lung disease. Thus, understanding of early airway microbiology is critical to the development of appropriate early interventions such as prophylactic antibiotics, immunotherapy, and, potentially, gene therapy. The barriers to the study of infant airway microbiology are discussed, and the properties of infant lung anatomy, physiology, and immunity, which predispose the young patient to serious infection, are reviewed. We examine the natural history of lung infection in young patients, reviewing the roles of each of the main bacterial pathogens. Recent research on risk factors for early Pseudomonas aeruginosa colonization, including the potential role of respiratory viral infections, is discussed. We conclude with a discussion of the role of prophylactic antibiotic therapy.


Emergence and persistence of Pseudomonas aeruginosa in the cystic fibrosis airway.

Colonization in the respiratory tracts of cystic fibrosis (CF) patients by mucoid Pseudomonas aeruginosa correlates with the progression of bronchial airway pathology. There is a direct correlation between the incidence of Pseudomonas colonization and age, clinical score, extent of pulmonary disease, severity of radiographic changes, and level of serum immunoglobulins. The central propensity to Pseudomonas colonization in patients with CF is not freely understood, but we discuss the acquisition and persistence of P aeruginosa in the CF airway. Elucidation of pathogenetic mechanisms of CF inflammatory airways disease is the first essential step to initiating novel therapies. It has been difficult to prove that the ability of P aeruginosa to adhere to the respiratory epithelium and provide selective advantage for this gram-negative bacillus over other potential pathogens for infection in the CF airway. However, flexible filaments (pili) extending from the Pseudomonas cell wall are thought to medicate epithelial cell adherence for nonmucoid P aeruginosa, and similarly, the gelatinous exopolysaccharide alginate produced by mucoid variants of P aeruginosa seems to be the adhesive to tracheal cells. Following the signal event of adherence, this bacterial pathogen competes successfully for iron cofactor and multiplies, releasing proteases with broad substrate specificities that dramatically alter the airway antiprotease screen, and the pathogen creates defects in local antibacterial defenses. Lung inflammation in CF is characterized by massive neutrophil infiltration. Although critical to host defense, neutrophils also cause progressive airway damage by release of bioactive lipids, oxygen metabolites, and granule enzymes such as hydrolases, myeloperoxidase (MPO), lysozyme, and neutral serine proteases. The necessarily circumscribed discussion that follows will focus narrowly on the host cell-derived factors (macrophages and neutrophils) proposed as important components in this pathogenetic scheme.


Allergic bronchopulmonary mycosis complicating cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease caused by bronchial colonization with Aspergillus fumigatus that affects approximately 10% of patients with cystic fibrosis (CF). The diagnosis in CF patients is difficult because the cardinal symptoms of ABPA occur frequently in CF, ie, pulmonary infiltrates and wheezing, as well as the frequent colonization with A fumigatus that leads to humoral reactivity. If left untreated, ABPA leads to bronchiectasis and pulmonary fibrosis. The pathogenesis of ABPA seems to be a prolonged asthmatic late-phase reaction orchestrated by CD4+ Th2-like T cells in response to persistent pulmonary A fumigatus allergen exposure. Thus, polyclonal and A fumigatus-specific IgE antibodies (and IgA and IgG) and blood pulmonary eosinophilia are stimulated by Th2-derived cytokines such as IL-4 and IL-5. In addition, IL-4 would also promote pulmonary transendothelial migration of eosinophils, basophils, and lymphocytes via induction of cell adhesion molecules and their ligands. IgE mast cell interactions would also contribute to the bronchial reactivity and inflammation. Recent advances have begun to identify immunodominant A fumigatus allergens. Evaluation of the quantity of IgE antibodies (and IgA and IgG) and T-cell cytokine responses to specific A fumigatus allergens should aid in the diagnosis and immunopathogenesis of ABPA, especially in CF patients.


Chest radiographic findings in cystic fibrosis.

Radiographic imaging modalities that have been applied to the staging and prognostication of the lung lesion in cystic fibrosis (CF) include conventional chest radiographs, computed tomography (CT), and magnetic resonance imaging (MRI). Conventional chest radiographs are usually adequate to detect the salient radiographic features of CF and provide objective parameters for longitudinal disease progression. Although the lung manifestations of CF can be highly variable most patients with CF demonstrate some of the classic chest radiographic findings that reflect chronic bronchiectasis: hyperinflation, bronchial thickening and dilatation, peribronchial cuffing, mucoid impaction, cystic radiolucencies, an increase in interstitial markings, and scattered nodular densities. Complications of advanced CF include atelectasis, mucoid impaction, pneumothorax, pneumomediastinum, pulmonary hemorrhage, cardiomegaly, and enlargement of the pulmonary artery with cor pulmonale. Scoring systems have been developed to grade the chest radiograph in CF and to more accurately quantitate the severity of disease. Currently, the Brasfield system is in widest use. These radiographic scoring systems correlate well with pulmonary function data in both the pediatric and adult CF populations. High-resolution computed tomography (HRCT) is clearly more sensitive and accurate than conventional chest radiography in delineating the extent and severity of bronchiectasis and other parenchymal and airway lesions in CF. Quantifiable scoring systems using HRCT have been developed to assess disease severity in CF. The use of MRI in the clinical management of CF has been limited. MRI may be helpful in determining the cause of linear lung markings, differentiating mucous plugging, and peribronchial thickening from normal pulmonary blood vessels. MRI is an excellent imaging modality to differentiate hilar or mediastinal adenopathy from blood vessels or mediastinal fat.


Antimicrobials in cystic fibrosis: emergence of resistance and implications for treatment.

We reviewed the current literature on the role of antibiotic therapy in cystic fibrosis, concentrating on studies directing therapy at Pseudomonas aeruginosa. To highlight controversial areas, we examined studies comparing monotherapy with combination therapy, home intravenous treatment versus hospital treatment, intravenous versus oral therapy, and the role of aerosolized antibiotics. We found that all systemic therapies with antipseudomonal activity were of comparable efficacy. Data on the efficacy of aerosolized treatment were equivocal. There is a substantial body of anecdotal literature addressing the issue of antibiotic resistance complicating treatment of cystic fibrosis. This will be briefly reviewed and the responsible mechanisms will be outlined. There is a secular trend for selection of more resistant pathogens in the lungs of CF patients. In the individual patient, however, emergence of antibiotic resistance may occur without deleterious clinical effects.


Immunomodulatory therapies for cystic fibrosis.

Progressive pulmonary disease is the primary cause of morbidity and mortality in adult patients with cystic fibrosis (CF). The decrease in lung function associated with infection with Pseudomonas aeruginosa has been related to the severity of pulmonary inflammation. Thus therapies that reduce pulmonary inflammation may prove to be clinically efficacious. Therapeutic interventions that target pulmonary inflammation may be directed either at the infecting organism, especially P aeruginosa, or at host responses. Eradication of P aeruginosa from the airways of patients with CF has not been accomplished. However, reduction of the burden of P aeruginosa or modification of virulence factors are practical goals. Normalization of the host response ultimately depends on correction of the molecular defect. Until then, therapies are being investigated that may modulate pulmonary inflammation. These include therapies aimed at compensating for the defect in ion transport, down-regulating inflammatory cell responses, inhibiting host inflammatory products, or altering airway secretions. Preliminary data suggest that each of these approaches may have clinical efficacy. Large, multicenter trials addressing these issues are presently ongoing and hold the promise for continued improvement in the clinical course of patients with CF.


Lung transplantation in cystic fibrosis.

Lung transplantation has emerged in the last decade as a valid therapeutic endeavor for patients with end-stage lung disease. Although the presence of highly resistant organisms in the airway and sinuses of patients with cystic fibrosis (CF) increases the perioperative risk of infection following lung transplantation, transplant procedures can be undertaken in properly selected CF patients with acceptable morbidity and mortality at experienced centers. The introduction of a modification in the technique of double-lung transplantation has resulted in improved operative survival of CF patients undergoing lung transplantation. Whereas problems with posttransplant obliterative bronchiolitis, infection, and lymphoproliferative disorders contribute to morbidity, it is clear that lung transplantation can offer CF patients with end-stage lung disease improvement in both the quality and quantity of life. The most serious impediment to more widespread application of this therapy in CF is the inadequate number of donor organs.


The impact of molecular biology on understanding renal signal transduction.

The information that cells require to grow and prosper comes from diverse sources, adjacent to them and from considerable distances. Through evolution, cells have developed multiple mechanisms to acquire and process information. When a signaling mechanism has been successful, it has been used repeatedly with relatively minor modifications, and consequently is seen throughout biology. Specificity comes from using precise combinations of signaling molecules to achieve different ends in different cell types. Among the signaling systems that fit this description include the receptor and nonreceptor tyrosine kinases, G protein-coupled receptors, cell attachment receptors, guanylate cyclases, ligand-gated ion channels, the second messenger dependent and independent protein kinases and phosphatases, and transcription factors. The consequence of this conservation of molecular mechanisms is that many basic regulatory systems, which cannot be dissected free of the complexity of mammals, can be understood in relatively simple, manipulable experimental systems. With information from simple systems and the tools of genetics and molecular biology, complex problems such as human physiology and disease may be understood and eventually controlled.


Molecular physiology of renal potassium channels.

The application of patch-clamp technique to the study of ion channels showed the enormous diversity of K channels. In the kidney, K channels play an major role in transepithelial K transport, in the regulation of vascular tone, and in cellular proliferation. In the last 5 years, the use of powerful genetic and molecular biological techniques has provided an understanding of the molecular structure of some types of K channels. Although much work remains to be done in this area, the greater challenge will be to integrate the molecular information with the extensive physiological data already available. Finally, the rapidly accumulating knowledge of K channel structure, and the recent appreciation of their possible role in important disease states, such as hypertension, make the study of K channels very exciting.


Asthmatic drugs and competitive sport. An update.

Almost all asthmatics are prone to asthma triggered by moderate to severe exercise. Fortunately there are a number of pharmaceutical agents now available which can prevent and/or reverse exercise-induced asthma (EIA) and allow many asthmatics to participate in vigorous physical activities with minimum respiratory disadvantage. Regular exercise is an accepted part of the management of asthma and EIA can now be controlled so successfully that a number of elite sportspersons, in almost all types of sporting events, are asthmatic. This control of EIA, which is essential if asthmatics are to participate safely, requires that the patient and his/her doctor initiate a strategy to manage the disease during sport and other physical activities. In recent years the mortality and morbidity from asthma have been increasing and this has indicated the need to improve patient care. One of the most important innovations aiming to improve the control and treatment of asthma has been the recent development of the 6 point asthma management plan which is a strategy to simplify and optimise the long term management of asthma. It aims to improve the quality of life of most asthmatics and more importantly, prevent deaths due to asthma. Because antidoping controls operate in many high performance sports it is essential that the EIA management plan rely on those medications which are permitted. The list of allowable drugs is in continual flux as new ones are added and others are challenged on the grounds of possible ergogenicity. All aerosol beta 2-agonists except fenoterol, the khellin derivatives, theophylline, ipratropium bromide and the aerosol corticosteroids are currently permitted. Some nonasthmatic athletes who are aware of the improved performance of asthmatic athletes when using pre-exercise medication have been known to take antiasthma medication in the hope that it might improve their performance. Current evidence indicates, however, that the permitted medications are not ergogenic and do not give the asthmatic any advantage over the nonasthmatic athlete but merely removes the respiratory disadvantage under which he/she competes.


Cardiac rehabilitation following myocardial infarction. A practical approach.

The concept of cardiac rehabilitation following myocardial infarction is not a new one but is now at last gaining acceptance as an essential part of the service to the coronary patient. Its aim is to restore the effectiveness of post-infarct patients by ensuring that they are well adjusted, well educated and fit and thereby best able to cope with the long term consequences of their ischaemic heart disease. The first essential factor for good rehabilitation is patient education. Studies have shown high levels of distress and anxiety after infarction and to a large extent this is related to lack of information. Where patients have been given adequate information concerning their condition and treatment there is a high level of patient satisfaction and greater compliance. It must be appreciated that stress and anxiety impair the patient's ability to assimilate information and therefore repeated reinforcement is necessary. During the in-hospital period, the staff who are caring for the patient are constantly changing and while there is a role for all to educate the patient, the use of a cardiac liaison sister provides a continuity throughout the early recovery period to ensure that the education process is adequate. The use of written material and both audio and video tapes is also helpful. It is also important for the liaison sister to extend her role to the patient's immediate family, who also require information, and finally the liaison sister can provide a link into the post discharge phase, to answer the many questions that arise at this time, and to provide encouragement to the patient who is attempting to modify his lifestyle by stopping smoking, changing his diet and taking regular exercise. The use of exercise training is the second vital ingredient for adequate rehabilitation. This begins in earnest after the 6-week assessment, which can provide information on which to base an exercise prescription. The majority of patients enrolled within exercise programmes are medically stable and relatively symptom-free. There is increasing evidence that those with extensive myocardial damage, left ventricular dysfunction or failure, and ongoing myocardial ischaemia may also benefit. Traditional training programmes have been hospital based and have used mainly aerobic exercise. However, home based programmes should not be discounted where they may be more economical, more convenient, and improve patient compliance. Similarly, circuit training with weights has been shown to improve aerobic endurance and muscle strength and to have additional benefits in improved treadmill time compared with traditional aerobic programmes.(ABSTRACT TRUNCATED AT 400 WORDS)


Applied physiology of tennis.

Studies in anthropometry showed that more research is needed in the area of physical development and its relationship to playing tennis. Muscle activity patterns have been studied for the different strokes, although more data are available relative to the service. During the service, skilled tennis players were found to display more consistent muscular activity with shorter periods of activation, implying a higher level of coordination than less skilled players. In profiling players, positive correlations were found between tournament play and a number of fitness parameters. More research is needed to develop assessment measures that are tennis specific. Also, longitudinal studies will provide greater insight into player profiles. The general consensus on fitness development was that tennis players should incorporate flexibility, strength and endurance training in their programmes to minimise asymmetry and injuries, while simultaneously enhancing performance. Tennis was found to have both aerobic and anaerobic components, with the predominant energy supply coming from phosphagen energy system. These findings suggest training programmes should be designed specific to the actual energy and muscular demands of the game. The need for further research in all areas certainly still exists in order to gain a better understanding of the game.


An overview of common soccer injuries. Management and prevention.

The most common injuries in soccer involve the ankle and knee joints, and the muscles and ligaments of the thigh and calf. Rehabilitation to restore strength and endurance after healing is extremely important to prevent a recurrence of the injury, which is much more severe and disabling than the initial injury. Sprains and strains of the hamstring and quadriceps, and injuries to the external and internal structures of the knee joints are frequent and relatively more disabling. Recent progress in the technical aspect of investigative medicine, such as magnetic resonance (MRI) imaging/quantitative only computer tomography (CT) scanning, ultrasonic imaging of soft tissues and isokinetic measurement of muscle characteristics, lead to better diagnosis and management of soccer injuries. Appropriate nutritional and physiological preparation, maintaining fluid and electrolytes during the game and restoration of the reserves following completion of exhaustive activities will help to minimise injuries.


[The difficult diagnosis of tuberculosis].

In spite of alarming reports from third world and industrialized countries, no increase in the incidence of tuberculosis has been seen in Switzerland. This is mainly attributable to the consistently performed initial treatment with a multiple-drug combination and the good compliance of our patients. In Switzerland the diagnosis of tuberculosis is difficult, because of its low incidence (1990: 1229 reported cases), as well as its nonspecific initial symptoms. Screening tests are only indicated in high risk-populations with direct contact to infectious tuberculosis cases, inhabitants of centres for homeless or immigrants, foreign workers and HIV-positives. The fast introduction of the gene amplification method with the polymerase chain reaction (PCR) would allow bacteriologic diagnosis within 48 hours. This would be of great practical relevance, allowing a quicker initiation of therapy and with that, a decrease of infection risk for physicians and medical staff, especially in endoscopy-rooms, emergency- and intensive care units. In Switzerland the multiple-drug resistance of mycobacteria (against insoniazid, rifampicin and other antimycobacterial agents) is seen only rarely (0.7 to 1.3% of cases). In patients with origin from countries with frequent drug-resistance to isoniazid and even more in case of suspected multiple drug-resistance or high initial bacterial count (cavernous tuberculosis), an initial combination therapy with four different antimycobacterial drugs should be applied, until the result of the susceptibility-tests is available.


[The current treatment of trigeminal neuralgia. Experience in 162 thermorhizotomies].

The neuralgia of the trigeminal nerve is the most frequent neuralgia of the cranial nerves. It is mostly seen in the elderly. In younger patients it must always be suspected as a symptomatic neuralgia. The course is recurrent and progressive. Spontaneous temporary remissions are usual. Later the pain becomes more frequent, unbearable and disabling. At first the therapy is a conservative one, the drug of choice is Carbamazepin, alternatively Phenytoin and Baclofen. If the conservative therapy fails, the only possible treatment is a neurosurgical one. Nowadays all methods aim at the Gasserian ganglion. In use are several percutaneous transoval procedures or the microvascular decompression through a craniotomy. Our surgical procedure of choice is the percutaneous thermorhizotomy in the Gasserian ganglion and the nerve root, where the pain-conducting fibers are destroyed, preserving tactile sensibility. This procedure is practically without vital hazards for the patient. It is applied in local anesthesia and a short intravenous analgesia. The recurrence rate of 32% is considerable, but the procedure can be repeated. The success cannot be deduced from the recurrence rate alone but must take into account the side effects of the procedure. These are mainly a loss of sensibility to touch by too aggressive rhizotomy and anesthesia of the cornea. By the criteria explained in the text we achieved a good result in 44%, a fair one in 25%, an indifferent one in 10% and a poor result in 7%. In 14% the result is unknown.


[Methods in continuing professional education. Results of a pilot survey of physicians].

There is not enough evidence, that formal continuing education can improve the quality of patient care. A model to support the work of quality circles by improving the acquisition of new knowledge and skills through problem-based learning in small groups was suggested in 1991. The results of a pilot survey carried out in three different groups of physicians and professional health care workers gave evidence that the model is acceptable in Germany, where problem-based learning is virtually unknown. Attributes of study groups like inclusion of nonphysicians, who would also be accepted as moderators, were indicated by a great majority. Topics and groups should be chosen by the individual and not be imposed by a central organization. Of the four methods suggested for problem-solving-presentation of the solution by an expert, solving the problem in group work, advice from an external expert, use of electronic publications--at least three were selected by 62, 65 and 96% of the responders in the three different groups. 30% of the total of 108 responders favor all four methods. Three of the four tasks of organizations responsible for continuing education are accepted: 1. support of local study groups, 2. provision of consulting experts, 3. instillation of information centers using modern information technology. Production and application of case simulations to be used in the study groups were only accepted by 23%. The differences between groups could have been caused by external influence such as experience with case presentations. The results justify a survey with improved and extended methodology in a sample of doctors representative for the physicians working within the frame work of social insurance.


Periodic leg movements during sleep before and after heart transplantation.

We report the association between periodic leg movements (PLM) during sleep and congestive heart failure (CHF) in a patient who had a successful heart transplant. Pretransplant, the patient had chronic insomnia and CHF. Overnight polysomnography revealed severe PLM disorder and sleep disruption. Three months following transplantation his insomnia had resolved associated with a dramatic reduction in PLM.


Self-reported sleep disturbances in employed women.

To explore the incidence and types of sleep disturbances in employed women, 760 registered nurses completed a health survey that included questions about their sleep patterns and sleep quality. Comparisons are made between those nurses working permanent day, permanent evening, permanent night, and rotating shifts. As expected, there were higher incidences of sleep disturbances and excessive sleepiness for women working night and rotating shifts, but age and family factors, rather than caffeine and alcohol intake, contributed to the differences in types of sleep disturbances these women experienced.


Treatment of sleep apnea with prosthetic mandibular advancement (PMA).

Nine males with sleep apnea DOES syndrome and three males with sleep apnea DIMS syndrome were treated with prosthetic mandibular advancement (PMA). The method uses a prosthesis, which is designed to advance the mandible 3-5 mm to prevent upper airway occlusion during sleep. The apnea index in the obstructive-type apnea and the percentage of time spent in obstructive apnea decreased significantly with PMA. Although the apnea index showed merely a tendency to decrease in central apnea (p < 0.1), the percentage of time spent in central apnea decreased significantly with PMA. A marked improvement in sleep structures was observed with PMA; a significant increase was seen in total sleep time, percent slow wave sleep (SWS) and percent rapid eye movement (REM) sleep, and the time spent in intra-sleep awakening decreased remarkably. PMA had excellent effects on snoring, and daytime hypersomnolence was reduced in almost all patients. Moreover, a survey on the therapeutic effects of PMA on sleep apnea syndrome and problems associated with wearing PMA was performed with a questionnaire for the sample of nine DOES patients and an additional 22 patients who were treated over a long time. The therapeutic effects could be maintained without any problems in about 2/3 of these patients. The therapeutic mechanisms of PMA in its reduction of both obstructive and central apnea are discussed.


Autonomic stress tests in obstructive sleep apnea syndrome and snoring.

Apneic events in the obstructive sleep apnea syndrome (OSAS) are associated with cardiovascular responses mediated through the autonomic nervous system. We examined autonomic cardiovascular responses in 33 patients (median age = 50 years, range = 20-72 years) undergoing polysomnography for suspected OSAS. We examined these responses in the evening and at arousal in the morning. Tests consisted of heart rate responses to Valsalva maneuver, deep breathing and change from lying down to standing. In addition, systolic blood pressure (BP) response to standing and diastolic BP response to handgrip were studied. Each abnormal test scored +1 and each marginal result +0.5. Autonomic nervous system (ANS) test results were scored as abnormal if a subject had a score > 1 which included at least one abnormal test. The total scores for evening and morning tests combined showed 11/24 sets of scores > 1 in 12 severe OSAS patients [median RDI (apnea+hypopnea per hour slept) = 44 (range = 31-74)] compared to 3/22 in non-OSAS (p = 0.04). The response to deep breathing, expressed as an expiratory to inspiratory ratio (E/I), was the test most often found abnormal. A significant difference between normal abnormal autonomic stress test (AST) groups was observed in the evening and the morning as regards cumulative time spent under 90% SaO2 and minimal SaO2. We conclude that abnormal autonomic stress responses are common in OSAS and are probably a secondary defect.


Delta sleep-inducing-peptide-like immunoreactivity (DSIP-LI) and delta sleep in schizophrenic volunteers.

Delta sleep-inducing-peptide (DSIP) has been reported to increase sleep in subjects with insomnia. The authors studied cerebrospinal fluid (CSF) DSIP-like immunoreactivity (DSIP-LI) in 15 drug-free male subjects with a DSM-IIIR diagnosis of schizophrenia. The subjects underwent a lumbar puncture and three nights of polysomnography. CSF DSIP-LI was significantly correlated with polysomnography the night before the LP: with stage 3 sleep (p = 0.05), stage 3 and delta (stages 3 + 4) sleep during the first nonrapid eye movement NREM period (p = 0.02 and p = 0.05, respectively) and the ratio of the first and second NREM period (p < 0.05), and negatively with stage 2% sleep (p < 0.05). Whether this first report of a potential relationship between CSF DSIP-LI and slow-wave sleep in man might be generalized to sleep in nonpsychiatric subjects awaits further study.


Caffeine use as a model of acute and chronic insomnia.

It was hypothesized that the metabolic effects of caffeine, which can be objectively measured (i.e. physiological, "arousal"), could be used to develop a physiological arousal model of chronic insomnia in a group of normal young adults. Twelve normal young adult males participated for 11 nights after laboratory adaptation. Subjects received 400 mg of caffeine three times a day for 7 nights and days. As predicted, the use of caffeine resulted in increased metabolic rate. Sleep efficiency was significantly reduced by caffeine and multiple sleep latency tests (MSLTs) were significantly increased. Some adaptation to the metabolic, sleep efficiency, and MSLT effects of caffeine was seen over the week of administration. Withdrawal effects (i.e. rebound sleep or sleepiness) were not seen for metabolic, MSLT or sleep variables. The data indicated that caffeine was effective in producing significant metabolic and sleep effects and that those effects were related. The results were consistent with the interpretation that a chronic decrease in sleep efficiency associated with increased physiological arousal, although producing subjective dysphoria, does not produce a physiological sleep debt.


Sleep deprivation in the rat: XVI. Effects in a light-dark cycle.

To avoid a possible confound between the effects of sleep loss and disturbed circadian rhythms in previous studies of total sleep deprivation (TSD) by the disk-over-water method, TSD rats and their yoked control (TSC) rats had been maintained in constant light both before and during the experiment. With circadian rhythms of both groups flattened by constant light, group differences in outcome measures could be attributed to sleep loss. However, the constant light control entailed the possibility that the sleep loss effects might obtain only in constant light. To evaluate this possibility, three TSD-TSC rat pairs maintained on a 12 hour light: 12 hour dark (LD) schedule were studied. TSC rats showed only minor changes during the deprivation period. As in previous studies, TSD rats showed increased food intake; decreased weight; increased energy expenditure; debilitated appearance; lesions on the tail and paws; an initial increase followed by a large decrease in body temperature; impending death; and recovery sleep, which featured large, selective, sustained rebounds of paradoxical sleep and a reversal of all observed TSD-induced changes. Thus, TSD produced the same changes during an LD schedule as during constant light. The amplitude of the diurnal body temperature rhythm declined over the course of TSD and then almost completely recovered during the first day of recovery sleep. The decline was interpreted as the result of deprivation-induced thermoregulatory changes.


Self-reported sleep quality in college students: a repeated measures approach.

A longitudinal assessment of sleep quality is presented. Undergraduates provided two levels of repeated measures data. Sleep log information was gathered across the 7 days of the week, in three replications, over a semester. There were several new findings. Across the week, students spent significantly more time in bed on weekend days as compared with weekdays. Further, a new measure for quality of sleep covaried with the amount of time spent in bed during the week. The students enjoyed their sleep more on the weekends. Finally, both the amount of time in bed and the number of awakenings reported dropped significantly as the semester progressed.


Changes in the waking EEG as a consequence of sleep and sleep deprivation.

Electroencephalographic (EEG) activity was monopolarly recorded during resting wakefulness in 10 volunteers under the following conditions: at night before going to sleep, at night before total sleep deprivation, in the morning after waking, in the morning after sleep deprivation and at night after having slept during the day. Absolute and relative power and inter- and intrahemispheric correlation were established. After diurnal and nocturnal sleep as compared to sleep deprivation, we obtained the following significant results: interhemispheric correlations were higher; intrahemispheric correlations were lower; absolute power of alpha 2, beta 1 and beta 2 was lower; and relative power of alpha 2 and beta 2 was lower. EEG changes as a consequence of sleep or lack of sleep are dependent on prior sleep and/or wakefulness and not on circadian phase. EEG activity during wakefulness is a sensitive parameter and a useful tool to assess the consequences of sleep on brain functional organization.


Distribution of period-analyzed delta activity during sleep.

The distribution of delta EEG activity was evaluated during sleep in eight healthy adults. Digital period analysis, including an amplitude measurement, was used to quantify delta activity. The average percentages of delta half- and full-wave zero-crosses, mean delta power, and mean total power were computed for each nonrapid eye movement (NREM) period. The distribution of these delta measures was examined across NREM periods (NREMPs). No significant linear trends were evident in the zero-cross or power measures. Four subjects showed the highest delta power and greatest incidence of delta in the second rather than first NREMP. Regression analyses of individual delta incidence data revealed that only 62.5% of recording nights could be described with an exponential equation. Exponential regressions described 81% of delta amplitude cases. Further, delta activity in some subjects could be described by either linear or exponential regression. The findings suggest that the temporal changes of delta activity may not be entirely systematic across NREMPs and are variable across subjects.


Slow wave sleep dreaming.

Fifty volunteers slept two nonconsecutive nights in a sleep laboratory under electropolygraphic control. They were awakened for one report per night. Awakenings were made, in counterbalanced order, from slow wave sleep (SWS--stage 3-4 and stage 4) and rapid eye movement (REM) sleep. Following dream reporting, subjects were asked to identify memory sources of their dream imagery. Two independent judges reliably rated mentation reports for temporal units and for several content and structural dimensions. The same judges also categorized memory sources as autobiographical episodes, abstract self-references, or semantic knowledge. We found that REM reports were significantly longer than SWS reports. Minor content SWS-REM differences were also detected. Moreover, semantic knowledge was more frequently mentioned as a dream source for REM than for SWS dream reports. These findings are interpreted as supporting the hypothesis that dreaming is a continuous process that is not unique to REM sleep. Different levels of engagement of the cognitive system are responsible for the few SWS-REM differences that have been detected.


An inexpensive alternative for recording middle ear muscle activity (MEMA) during sleep.

In past studies of middle ear muscle activity (MEMA) in sleep, one of two methods of recording has been used: an acoustic impedance bridge (AIB) or a miniaturized pressure transducer (MPT). A low-cost and less fragile piezoresistive pressure transducer was tested to determine its practicality in recording MEMA during sleep in humans. A specialized ear mold accommodating both types of pressure transducer was custom-fitted for six subjects. The sleep of each subject was analyzed epoch by epoch for one night to determine comparability of the two transducers. In no case did either transducer indicate a MEMA without confirmation by the other. It is recommended that this type of transducer would be practical for researchers interested in recording MEMA in sleep.


Concordance between habitual sleep times and laboratory recording schedules.

The validity of laboratory-based studies of sleep depends, in part, upon good concordance between habitual sleep schedule and laboratory recording schedule. Without good concordance, error variance due to the circadian misplacement of sleep and to different amounts of time in bed is probable. In an assessment of scheduling concordance in 1,762 research patient nights over two time intervals, we observed good concordance (< 30-minute discrepancy) in 71.2-77.3% of bedtimes and waketimes, discrepancy (difference of > or = 30 minutes) in 14.9-24.2% of bedtimes and waketimes, and missing data in 4.6-7.5% of times. Waketime differences were consistently in the direction of earlier laboratory than habitual waketimes, whereas differences in bedtime were about equally divided between earlier and later (laboratory vs. habitual). Subjects with schedule discordance averaged 19.5 minutes less time in bed during laboratory sessions as compared with their habitual sleep schedule, whereas subjects with schedule concordance averaged only 3.6 minutes less (p < 0.001). Our experience suggests that it may be more difficult to achieve higher rates of concordance among young adult and middle-aged subjects than among elders and that patient requests related to external constraints on scheduling were a frequent reason for discrepancy. We strongly recommend a policy of routinely including data on laboratory versus habitual sleep times in peer-reviewed publications.


Histopathologic observations in weanling B6C3F1 mice and F344/N rats and their adult parental strains.

Weanling Fischer 344/N (F344) rats and the first filial hybrid of C57BL/6 x C3H (B6C3F1) mice and retired breeders from the parental stocks of these strains were monitored over a 5-yr-period by examining the histopathology of selected organs and comparing those results to viral and mycoplasmal serology and the intestinal tract bacterial flora of each animal on an individual basis. Serology gave no evidence of viral infection, but Mycoplasma arthriditis antibodies were detected. Reactivity of serum of adult C57BL/6 female mice with control cells or media (tissue culture, TC) was seen in a significant number of mice. TC reactivity correlated positively with lymphoid perivascular infiltrates, predominantly of the lungs, suggesting an allergic response in development of the lesions. Other lesions of note consisted of Harderian gland inflammation of rats, focal necrotizing lesions of the liver of both species, and thickening of the pleura and adjacent pulmonary interstitium of weanling rats. Embolization of bacteria from the gastrointestinal tract to the liver was considered a possible cause of the liver necrosis in both species. Although lesions of the lung and Harderian gland of the rats are similar to those caused by known viral agents, the cause of the latter could not be determined as these animals were negative for viral antibodies and the former was considered to be related to incomplete pulmonary development in the young rat. Features differentiating the lesions observed in animals of this survey from those caused by viral infection are discussed.


Cephaloridine-induced renal pathological and biochemical changes in female rabbits and isolated proximal tubules in suspension.

Cephaloridine (Cld) is a nephrotoxic cephalosporin antibiotic. The intracellular biochemical changes that occur leading to Cld-induced nephrotoxicity may involve lipid peroxidation and/or mitochondrial injury. The purpose of this report was to examine and correlate the biochemical changes induced by Cld in vivo and in vitro with the observed pathological changes in an attempt to understand better the mechanisms of beta-lactam-induced nephrotoxicity. Cld treatment (500 mg/kg sc) caused elevations in blood urea nitrogen and decreases in the accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) by renal cortical slices. Histopathological alterations, characterized by individual cell necrosis of tubular epithelial cells, were first seen 6 hr after treatment in the pars recta of the outer stripe of the medulla. Ultrastructural alterations involved the straight (S2 and S3) segments of the proximal tubules. Mitochondrial morphology was, for the most part, unaffected by Cld exposure. Cld did not cause any significant changes in tissue malondialdehyde (MDA) content in vivo at any of the time points examined, but it did cause a depletion of GSH to approximately 40% of control by 1 hr after dosing that recovered toward control by 6 hr. Significant changes were observed in renal ATP content beginning at 6 hr after treatment; however, this change mirrored the onset of histological evidence of necrosis. In isolated tubules in vitro, the onset of glutathione (GSH) depletion and MDA formation clearly preceded lactate dehydrogenase (LDH) leakage, whereas ATP depletion was a mirror image of cell death. These data demonstrate that isolated proximal tubules in vitro are a reasonable model for Cld nephrotoxicity in vivo. Cld-induced mitochondrial alterations leading to ATP depletion and cell injury were not observed in this study.


Pulmonary neoplasms in rats that inhaled cerium-144 dioxide.

The lung neoplasms induced in rats by inhaled, internally deposited 144CeO2 were described and classified using histologic criteria. F344 rats were exposed once or repeatedly by inhalation to 144CeO2 and observed for their life span. There was significant life shortening only in those rats with the highest radiation doses. In these rats, there was a high percentage of squamous cell carcinomas of the lung, as well as much lower percentages of adenocarcinomas of the lung, hemangiosarcomas of the lung, and pleural mesotheliomas. At lower doses, adenocarcinomas were the most predominant tumor. These adenocarcinomas were subdivided based on their histologic pattern: alveolar, papillary, tubular, or undifferentiated. Neither the mode of exposure (single or repeated) nor the sex of the rat influenced the lung tumor incidence or tumor type. The lung neoplasms induced by this beta-emitting radionuclide are similar in nature to those induced by alpha-emitting radionuclides deposited in the lung in rats. However, the radiation-induced squamous cell carcinomas of the lung differ from those induced by heavy particle loads of nonradioactive compounds. The radiation-induced squamous cell carcinomas occur in higher incidence and have a more malignant behavior than those induced by heavy particle loads.


Ultrastructural alterations in liver of medaka (Oryzias latipes) exposed to diethylnitrosamine.

Liver cytotoxic alterations of adult medaka (Oryzias latipes) following short-term bath exposure (48 hr) to 500 mg/L diethylnitrosamine (DEN) were studied (days 3-21) by electron microscopy and cytochemistry. Control medaka displayed hepatic sexual dimorphism as described for other sexually active fish. Following DEN exposure, decreased glycogen stores with loss of cellular compartmentation obscured sexual dimorphism. A spectrum of organelle alterations, previously not reported in livers of fish, was seen. Early changes in hepatocytes included: nuclear lipid inclusions, nucleolar changes, decreased amounts of granular endoplasmic reticulum (GER), increased fractionation and steatosis of GER, proliferation of smooth ER and lysosomes, reduction in number and content of particulate lipoproteins and vitellogenin in Golgi vesicles, and reduction in number and staining intensity of peroxisomes. At day 14 and/or 21, partial to complete reversal of the above alterations indicated hepatic recovery, and fewer necrotic cells were seen at day 21 versus day 14. Lesions that did not resolve during this study were altered mitochondria and areas of spongiosis hepatis that developed at day 8 and continued to increase throughout the study. Infiltration of lymphocytes, granulocytes, and large numbers of macrophages were late changes. The description, timing, and duration of lesions are of value for consideration as biomarkers of exposure and effect in aquatic toxicology.


Dose-dependent renal tubular toxicity of harman and norharman in male F344 rats.

The renal toxicity of harman and norharman, administered for 2 or 4 weeks at dietary levels of 1,000, 500, or 0 parts per million (ppm), was investigated in 6-week-old male F344/DuCrj rats. Although rats fed 1,000 ppm harman or norharman, but not the 500 ppm level, demonstrated marked body weight retardation from 1 week to termination, no mortalities occurred. Marked elevation of water consumption was evident in rats given harman or norharman at 1,000 ppm, but not at 500 ppm, together with large increases in urine of low specific gravity. Urinary lysosomal enzymes (N-acetyl-beta-D-glucosaminidase, NAG, and lactate dehydrogenase, LDH) and sugar levels were increased, and the brush border enzymes (gamma-glutamyl transpeptidase, GGT, and alkaline phosphatase, ALP) decreased. Furthermore, serum biochemistry revealed clear elevation of parameters indicating renal toxicity in these rats. Histopathologically, rats fed 1,000 ppm harman or norharman, but not 500 ppm, demonstrated focal toxic renal degenerative/necrotic and regenerative lesions in proximal, distal, and collecting tubules. These changes were associated with a clearly increased labeling index (LI) of the nuclei of renal tubular epithelial cells on immunohistochemical staining for 5-bromo-2'-deoxyuridine (BrdU). Chemical specific crystal formation within tubular lumina was evident in rats fed 1,000 ppm, but not 500 ppm, this being considered the cause of the renal tubular lesions. It was concluded that harman and norharman exert renal toxicity at the dietary level of 1,000 ppm, but not 500 ppm, in male F344 rats.