Patent foramen ovale: conservative or surgical therapy?

Notwithstanding the difficulties in definitely confirming paradoxical embolism, the association between patent foramen ovale (PFO) and cryptogenic stroke has repeatedly been demonstrated in clinical studies. Moreover, the recurrence rate of cerebral ischemia in patients with PFO and an unexplained stroke was found to be 3-4% per year in two recently published series. With the exception of right atrial pressure elevation in the setting of major pulmonary embolism, a reliable risk stratification of patients with PFO based on clinical or echocardiographic findings is not yet possible. The presence of atrial septal aneurysm, a wide opening of the defect during the cardiac cycle and a large atrial shunt have been implicated as risk factors by some investigators. Long-term prevention of paradoxical embolism with oral anticoagulants seems to be of questionable benefit. Besides, these agents are poorly tolerated and carry the risk of significant or fatal bleeding at a rate of 2-5% per year. Surgery of the atrial septum has been performed for many decades in patients with atrial septal defect and evidence accumulates that it is a safe and highly effective procedure in patients with PFO. At present, surgical closure of the PFO appears to be the treatment of choice for secondary prevention of paradoxical embolism. However, further studies are needed to define the appropriate candidates for surgical treatment. Devices for catheter-based sealing of PFO are also available and are currently being evaluated in clinical trials. However, experience with their use remains confined to specialized centers. Furthermore, further technical improvements of these systems are needed in order to optimize successful delivery and positioning, increase their long-term stability, and reduce periprocedural complications.     

mNotch1 signaling reduces proliferation of myeloid progenitor cells by altering cell-cycle kinetics

Notch receptors are involved in the regulation of cell-fate decisions, differentiation, and proliferation in many tissues. The expression of Notch receptors on hemopoietic cells and of cognate ligands on bone marrow stromal cells suggests a possible role for Notch signaling in the regulation of hemopoiesis. We were interested to assess the involvement of Notch1 signaling on cell proliferation of myeloid progenitor cells. Proliferation, cell-cycle status, and apoptosis of myeloid progenitor 32D cell lines engineered to permit the conditional induction of the constitutively active intracellular domain of mNotch1 (mN1(IC)) by the 4-hydroxytamoxifen(OHT)-inducible system were analyzed in the presence or absence of OHT.The induction of mN1(IC) by OHT resulted in reduction of proliferation (p<0.01) and accumulation of cells in the G(1)/G(0) phase of the cell cycle (p<0.001) without substantially affecting apoptosis of 32D cells. These effects were observed under culture conditions that allow differentiation and, to a lesser degree, under conditions that normally promote self-renewal in the absence of differentiated cells. Our data suggest that mNotch1 signaling suppresses proliferation of myeloid progenitor cells by altering cell-cycle kinetics.     

Major life events and risk of alcohol use disorders: a prospective cohort study

Aims

To estimate associations of individual major life events as well as accumulated major life events in childhood, adult private life and adult work life with risk of alcohol use disorders (AUD).

Design

Prospective cohort study with baseline examination in 1991–93 and linkage to national registers to identify AUD at follow‐up.

Setting

Copenhagen, Denmark.

Participants

Individuals (aged 21–93 years) who participated in the Copenhagen City Heart Study in 1991–93 (n = 8758).

Measurements

The primary outcome was first registration with AUD during follow‐up (n = 249). AUD was identified in the Danish National Patient Register, in the Danish Psychiatric Central Register and in an outpatient treatment register. Major life events were assessed by a questionnaire in the Copenhagen City Heart study. Data were analysed by Cox proportional hazards models adjusted for age, sex, educational level, household income, cohabitation status and psychiatric comorbidity.

Findings

Serious family conflicts in childhood [hazard ratio (HR) = 1.35; 95% confidence interval (CI) = 1.00, 1.83] and serious economic problems in adult life (HR = 2.22; 95% CI = 1.64, 3.01) were associated significantly with increased risk of AUD. Prospective analyses did not show consistent effects of accumulation of major life events in childhood or adult life, but an additional analysis based on all AUD registrations suggested an association between accumulated childhood events and risk of AUD.

Conclusions

Serious economic problems in adult life are associated strongly with risk of alcohol use disorders, and there may be an influence of accumulated childhood events on risk of alcohol use disorders.     

Platelet function tests predict bleeding in patients with acute myeloid leukemia and thrombocytopenia

Bleeding is frequent among patients with thrombocytopenia. We studied whether in vitro platelet function predicts future bleeding in patients with acute myeloid leukemia (AML), and thrombocytopenia. Adult AML patients with platelet count <5.0 × 10¹⁰/L were included. Detailed bleeding history and blood samples were collected at inclusion and every 7 days. We analyzed hematology and coagulation parameters. With flow cytometry we evaluated platelet activation (activated GPIIb/IIIa, P-selectin, and CD63 expression), and platelet aggregation. Agonists were thrombin-receptor activating peptide (TRAP) and collagen-related peptide (CRP-XL). During 18 months, sixty participants were enrolled and followed for a total of 114 weeks. Bleeding occurred in 52 weeks, and was not associated with clinical, hematology or coagulation parameters. Predictors of bleeding were assessed using multivariate logistic regression, adjusted for platelet count, sex, and age. Bleeding history and receiver operating curves were compared using c-index. Reduced TRAP-induced platelet aggregation had Odds ratio 3.00 (95% confidence interval [CI] 1.38-6.60). Reduced CRP-XL-induced platelet aggregation had Odds ratio 4.00 (95%-CI 1.70-9.20) for bleeding. Overall, C-index was 0.71 for the models including platelet aggregation results, 0.72 for activated GPIIb/IIIa-positive platelets after stimulation with TRAP, 0.68 for percent P-selectin positive platelets with TRAP and 0.63 for the platelet count. Among patients receiving no platelet transfusion, C-index was 0.83–0.91 for bleeding; highest for models using platelet aggregation. Change in platelet aggregation did not correlate with the number of platelet concentrates administered. In conclusion, platelet aggregation and platelet activation results predict bleeding better than platelet count alone, among AML patients with thrombocytopenia.     

Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism.

OBJECTIVE: To investigate the prognostic value of echocardiographic findings in patients who present with symptoms suggestive of acute pulmonary embolism. DESIGN: 317 patients with clinically suspected pulmonary embolism were prospectively evaluated by echocardiography for the presence of right ventricular afterload stress and right heart or pulmonary artery thrombi. Objective confirmation of pulmonary embolism by lung scan or pulmonary angiography was obtained in 164 (52%). The presence of deep venous thrombosis was established in 90 of 158 patients (57%) who underwent phlebographic or Doppler sonographic studies. RESULTS: Right ventricular afterload stress was diagnosed in 87 patients (27%). Objective confirmation of pulmonary embolism and diagnosis of deep venous thrombosis was more common in patients with right ventricular afterload stress than in those without (83% v 40% and 46% v 22%, respectively; P < 0.001). This was also true for the detection of thrombi in the right heart and major pulmonary arteries (12 patients v 1 patient; P < 0.001) as well as for the in-hospital mortality from venous thromboembolism (13% v 0.9%; P < 0.001). One year mortality from pulmonary embolism was 13% in patients with right ventricular afterload stress at presentation compared with 1.3% in those without (P < 0.001). CONCLUSIONS: The presence of right ventricular afterload stress detected by echocardiography is a major determinant of short term prognosis in patients with clinically suspected acute pulmonary embolism.     

Diagnostik kardiovaskulärer Erkrankungen mit Hilfe der suprasternalen M-mode Echokardiographie

Summary The suprasternal approach can be used to image the aortic arch, the right pulmonary artery and the left atrium. Dilatation or dissections involving the aortic arch were detected echocardiographically from the suprasternal notch. The echocardiogram of the right pulmonary artery is altered in cases of acute and chronic pulmonary hypertension. Intrapulmonary thrombi in patients with acute pulmonary embolism were visualized with this technique. A volume overloading of the pulmonary circulation due to a congenital left to right shunt, as well as a decreased pulmonary blood flow due to a congenital right to left shunt causes characteristic changes in the wall motion pattern of the right pulmonary artery. Hypoplasia or aplasia of the central pulmonary arteries can be diagnosed as well. Imaging of the left atrium from the suprasternal notch may help to differentiate between supraventricular and ventricular rhythm disturbances. The suprasternal approach is therefore recommended to be used as a routine part of each echocardiographic examination.

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Abkürzungen AO_d enddiastolischer Diameter der Aorta - AO_s mittsystolischer Diameter der Aorta - ASD Vorhofseptumdefekt - AO Aorta - DCM dilative Kardiomyopathie - F₄ Fallot'sche Tetralogie - LA linker Vorhof - NP Normalperson - PH pulmonale Hypertonie - PI Pulmonalinsuffizienz - PSE_AO prozentuale systolische Erweiterung der Aorta - PSE_RPA prozentuale systolische Erweiterung der rechten Pulmonalarterie - PAD_m mittlerer Pulmonalarteriendruck - PC praecordial - Q_RPA maximale Zunahme der Querschnittsfläche der rechten Pulmonalarterie während der Systole - RPA_d end-diastolischer Diameter der rechten Pulmonalarterie - RPA_s mittsystolischer Diameter der rechten Pulmonalarterie - SS suprasternal - SX subxiphoidal Teile der Arbeit wurden durch das BMFT-Projekt 01ZSO31-ZA/NT02 gefördert     

Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept

Botulinum neurotoxins (BoNTs) cause muscle paralysis by selectively cleaving core components of the vesicular fusion machinery within motoneurons. Complex gangliosides initially bind into a pocket that is conserved among the seven BoNTs and tetanus neurotoxin. Productive neurotoxin uptake also requires protein receptors. The interaction site of the protein receptor within the neurotoxin is currently unknown. We report the identification and characterization of the protein receptor binding site of BoNT/B and BoNT/G. Their protein receptors, synaptotagmins I and II, bind to a pocket at the tip of their H(CC) (C-terminal domain of the C-terminal fragment of the heavy chain) that corresponds to the unique second carbohydrate binding site of tetanus neurotoxin, the sialic acid binding site. Substitution of amino acids in this region impaired binding to synaptotagmins and drastically decreased toxicity at mouse phrenic nerve preparations; CD-spectroscopic analyses evidenced that the secondary structure of the mutated neurotoxins was unaltered. Deactivation of the synaptotagmin binding site by single mutations led to virtually inactive BoNT/B and BoNT/G when assayed at phrenic nerve preparations of complex-ganglioside-deficient mice. Analogously, a BoNT B mutant with deactivated ganglioside and synaptotagmin binding sites lacked appreciable activity at wild-type mouse phrenic nerve preparations. Thus, these data exclude relevant contributions of any cell surface molecule other than one ganglioside and one protein receptor to the entry process of BoNTs, which substantiates the double-receptor concept. The molecular characterization of the synaptotagmin binding site provides the basis for designing a novel class of potent binding inhibitors.     

Recommendations for personal respiratory protection in tuberculosis

These recommendations of the German Central Committee against Tuberculosis give an overview of the current scientific knowledge on the tuberculosis risk of health service employees and on the risk of infection in individual areas of work. The efficacy of face masks and their benefit in tuberculosis control is discussed. There are no reliable data on the efficacy of face masks in preventing infection with M. tuberculosis, nor can such data be expected in the near future, due to the complex interaction of infection-preventing measures. As rapid case finding, isolation, and immediate, effective treatment of infected patients already greatly diminish the risk of transmission, we consider face masks to be of limited use in reducing this risk. However, they may be beneficial in certain areas of work and in certain situations, particularly in the presence of elevated aerosol concentrations. The benefit of face masks depends largely on their correct application. The choice of a particular type of mask requires knowledge of the current epidemiological situation, and a competent assessment of the risk in the area of work for which it is chosen, taking into account the closeness of contact with potentially infectious tuberculosis patients.     

Susceptibilities of Candida spp. to antifungal agents visualized by two-dimensional scatterplots of relative growth.

The growth of 811 clinical yeast isolates in the presence of single concentrations of antifungal agents was measured spectrophotometrically and expressed as a percentage of growth in inhibitor-free control cultures. Two-dimensional scatterplots of the relative growth data allowed for the simple visual determination of some susceptibility trends, including correlations in relative growth between different agents and in relative susceptibilities between different yeast species. A positive susceptibility correlation was found for relative growth results with the azole antifungal agents fluconazole, itraconazole, and ketoconazole for 504 Candida albicans isolates. The relative growth scatterplots for fluconazole versus itraconazole showed that 50 (9.9%) of 504 C. albicans isolates were outliers with respect to the 95% confidence limits for a line of correlated relative growth established with an initial test panel of 59 isolates of this species. The outlying isolates were relatively less susceptible to fluconazole than to itraconazole under the conditions of the test. Most of the outliers were received in 1993 and 1994; only 3.9% of the isolates received in 1991 and 1992 and 1.7% of the isolates received before 1991 showed this differential susceptibility. In addition, most of the outliers came from patients with human immunodeficiency virus infections. The relative growth scatterplots confirmed the known high susceptibility of most Candida parapsilosis isolates to both fluconazole and itraconazole and the specifically low susceptibility of Candida krusei isolates to fluconazole. The scatterplots also illustrated a tendency towards lower (and correlative) relative growth among oral isolates obtained from AIDS patients who responded to azole antifungal treatment than among isolates from clinical nonresponders.     

Conservative management of post-intubation tracheal tears—report of three cases

Iatrogenic tracheal rupture is a rare complication after intubation. We present three patients with tracheal tears. In all of these patients, a common finding was a lesion of the posterior tracheal wall with postoperative subcutaneous and emphysema as the first clinical sign of the rupture. Diagnosis and follow-up were based on clinical and endoscopic findings and chest computed tomography (CT) scans. In our cases with progressive subcutaneous and mediastinal emphysema or dyspnea, we performed a tracheotomy and bypassed the lesion with a tracheostomy tube to avoid an increase in air leakage into the mediastinum. Under broad-spectrum antibiotic therapy, no mediastinitis occurred and all patients survived without sequelae. Closure of tracheostomy was scheduled for 1-2 months after tracheal injury. Analysis of surgical and anesthesiological procedures revealed no abnormalities and the accumulation of tracheal injuries was considered as accidental. We found that in clinically stable patients with spontaneous breathing and with no mediastinitis, a conservative management of tracheal tears is a safe procedure.