Biomedical subjects
Publications and source records attributed to M Roth.
We report a female patient with mitral valve replacement and preservation of subvalvular apparatus in which parts of the papillary muscle ruptured postoperatively. During systole the ruptured papillary muscle prolapsed through the native aortic valve. Echocardiographic documentation and operative procedure were demonstrated.
Many cardiac surgeons believe strongly that every effort should be made to preserve the continuity of the mitral anulus, chordae tendineae, and papillary muscles during mitral valve replacement in order to maximize ventricular function and maintain normal ventricular geometry. We treated a patient with spontaneous papillary muscle rupture after mitral valve replacement in whom efforts had been made to preserve continuity of the mitral mechanism.
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Early detection of asymptomatic subjects who are at risk for future cardiovascular events may allow for earlier medical treatment in order to prevent disease progression and future events. Electron-beam computed tomography accurately identifies people with increased coronary calcification, which is correlated with increased coronary plaque mass, increased likelihood of obstructive coronary disease, and increased likelihood of future cardiovascular events. The St. Francis Heart Study is a single-center combination study of men and women 50-70 years old that includes a natural history study of the relation between calcium scores and cardiovascular events (n = 5582), the association of calcium scores with traditional and nontraditional coronary disease risk factors (n = 1160), and a randomized clinical trial designed to assess the benefit of combination treatment with atorvastatin, vitamin C, and vitamin E, as compared to placebos, in subjects with elevated age- and gender-adjusted coronary calcification (n = 1007). Mean follow-up duration will be 4 years. The study is proceeding on schedule with anticipated completion by August 2002. It should provide important information regarding the benefits of treating asymptomatic men and women who have elevated coronary artery calcium, using cholesterol reduction and antioxidant therapy. The article describes the design of the St. Francis Heart Study.
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Thrombotic formations on atherosclerotic lesions of the thoracic aorta are potential sources of cerebral and systemic embolization. Especially younger patients without calcifications of atherosclerotic plaques or coagulation disorders have a higher risk for embolization. Magnetic resonance imaging and transesophageal echocardiography are the diagnostic methods of choice. As an alternative to anticoagulation surgical therapy is indicated to prevent severe brain damage or multiorgan failure in patients with mobile thrombotic formations. Herein we describe two patients in whom successful surgical treatment was performed in deep hypothermic circulatory arrest by excision of the aortic arch atheroma.
A 45-year-old man experienced arterial thromboembolism to the right leg requiring surgical restoration of blood flow. Transesophageal echocardiography (TEE) was performed to determine the source of embolism and identified a localized atherosclerotic lesion in the distal ascending aorta with an adherent, highly mobile thrombus. The patient underwent surgery with removal of the atherosclerotic plaque and attached thrombus, and resection of the adjacent aortic wall. This case illustrates an unusual location for a complex atherosclerotic lesion in the ascending aorta, and points out the opportunity for remedial surgery once a symptomatic embolus has occurred.
Lung fibrosis is a fatal condition of excess extracellular matrix (ECM) deposition associated with increased transforming growth factor beta (TGF-beta) activity. Although much is known about its pathological features, our understanding of the signal transduction pathways resulting in increased ECM and collagen deposition in response to TGF-beta is still incompletely defined. We have previously reported that a JunD homodimer of the transcription factor AP-1 is specifically activated by TGF-beta in lung fibroblasts. Here we demonstrate that JunD is also specifically required for TGF-beta-induced effects. Antisense against JunD, but not c-fos or c-jun, significantly inhibited collagen deposition in response to TGF-beta in primary human lung fibroblasts. We then investigated the ability of pharmacological agents to inhibit TGF-beta-induced signaling and collagen deposition. Cs-A and IFN-gamma, but not glucocorticoids, cyclophosphamide, or azathioprine, inhibited TGF-beta-induced signaling, as assessed by luciferase reporter gene assays, and collagen deposition. TGF-beta antagonism by Cs-A was associated with direct inhibition of JunD activation, as demonstrated by electrophoretic mobility shift analyses. In contrast, the effects of IFN-gamma required signal transducer and activator of transcription (STAT)-1. We thus identify the JunD isoform of AP-1 as an essential mediator of TGF-beta-induced effects in lung fibroblasts. TGF-beta-induced signaling and collagen deposition are efficiently antagonized by Cs-A and IFN-gamma treatment, both of which exhibit distinct molecular mechanisms of action. These observations therefore offer novel targets for future therapy of fibrotic lung disease.
Disorders in the fibrinolytic and renin-angiotensin-aldosterone systems and excessive extracellular matrix (ECM) deposition are determinant factors in several pathologic manifestations of vascular and cardiac tissue. We used primary human vascular smooth muscle cells (VSMC) and studied the effects of losartan on angiotensin II (Ang II)-mediated (a) DNA synthesis, (b) secretion of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), (c) secretion of matrix metalloprotease-2 (MMP-2) activity and tissue inhibitors of MMPs (TIMPs), and (d) synthesis of glycosaminoglycans. VSMC cultures, established from human pulmonary arteries, were treated with Ang II (0.1 nM -1 microM ) and/or losartan (0.1-10 microM ), for 24 or 48 h. DNA synthesis was assessed by incorporation of 3 H-thymidine into VSMC, secreted tPA, PAI-1, and TIMPs by enzyme-linked immunosorbent assay, MMP-2 activity by gelatin zymography, and glycosaminoglycan synthesis by 3 H-glucosamine incorporation. Ang II (1 microM ) enhanced DNA synthesis and secretion of PAI-1 and glycosaminoglycans and decreased secretion of MMP-2 activity and tPA, whereas it had no effect on secretion of TIMPs and glycosaminoglycans associated with cell layers. The Ang II-mediated effects were reversed by losartan, in a concentration-dependent manner. Losartan alone increased secretion of tPA, MMP-2 activity, and TIMPs and decreased secretion of PAI-1. These results indicate that AT 1 receptors are implicated in Ang II-mediated disorders of fibrinolysis and excessive ECM deposition by VSMC.
Asthmatic airways are characterized by an increase in smooth muscle mass, due mainly to hyperplasia. Many studies suggest that extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2, respectively), one group of the mitogen-activated protein (MAP) kinase superfamily, play a key role in the signal transduction pathway leading to cell proliferation. PGE(2) and forskolin inhibited mitogen-induced ERK activation. Inhibition of MAP kinase kinases 1 and 2 (MEK1 and MEK2, respectively), which are upstream from ERK, with the specific MEK inhibitor U-0126 blocked both cell proliferation and ERK activation. In addition, U-0126 inhibited mitogen-induced activation of p90 ribosomal S6 kinase and expression of c-Fos and cyclin D1, all of which are downstream from ERK in the signaling cascade that leads to cell proliferation. Antisense oligodeoxynucleotides directed to ERK1 and -2 mRNAs reduced ERK protein and cell proliferation. These results indicate that ERK is required for human airway smooth muscle cell proliferation. Thus targeting the control of ERK activation may provide a new therapeutic approach for hyperplasia seen in asthma.
The insulin resistance syndrome, consisting of resistance to insulin and several metabolic abnormalities, is associated with an increased risk of symptomatic coronary artery disease. Asymptomatic persons with increased coronary calcification have increased coronary plaque and an increased likelihood of future cardiovascular events. Electron-beam computed tomography-derived coronary artery calcium scores, metabolic and anthropometric parameters, and fasting and stimulated concentrations of glucose and insulin were measured in 1160 asymptomatic men and women. Coronary artery calcium scores were positively correlated with glucose, insulin, and homeostasis model assessment (HOMA) insulin resistance. Calcium scores were positively correlated with intra-abdominal adiposity, age, total cholesterol/high density lipoprotein (HDL) ratio, low density lipoprotein, triglycerides, blood pressure, and HOMA beta cell function and inversely correlated with HDL and peripheral fat. These correlations, except for 2-hour glucose, remained significant for all subjects with fasting serum glucose <126 mg/dL or all subjects with fasting serum glucose 110 mg/dL. In a multivariate analysis, age, sex, family history of premature coronary artery disease, intra-abdominal adiposity, low density lipoprotein, and smoking independently predicted calcium scores. Blood pressure, HDL, triglycerides, glucose, insulin, and HOMA insulin resistance or beta cell function were not independently correlated with coronary artery calcium scores. Asymptomatic individuals with insulin resistance have elevated coronary calcium scores. The association between insulin resistance and coronary calcification persists with impaired glucose tolerance and normal fasting serum glucose. Central/visceral adiposity may be a determinant of insulin resistance and atherosclerosis even in asymptomatic nondiabetic persons.
The worldwide increase in asthma incidences and the impact of the disease on public health care have led to new investigations of the cause of the disease. Besides well-defined environmental causes, accumulating evidence suggests that respiratory tract infections play an important role in the pathogenesis of asthma. Among these microorganisms Chlamydia pneumoniae is an intracellular pathogen causing persistent infection. Chlamydia pneumoniae infection has been discussed as possibly inducing the development of asthma. This study was designed to investigate the presence of C. pneumoniae-specific IgG, IgA, and IgM antibodies in serum samples of 33 adults with a clinical history of asthma, positive methacholine test, and reduced FEV(1). Patients with asthma were compared with age-, sex-, and locality-matched control subjects (n = 33). We observed no acute infection either in patients with asthma or in control subjects, but 63% of all investigated individuals had signs of past infection. Chlamydia pneumoniae-specific IgA was detected in 52% of the patients with asthma and in 15% of the healthy control subjects (p < 0.01). Serological evidence of chronic infection with C. pneumoniae (high IgG [> pr = 1:512] and high IgA [> or = 1:40]) was more frequent in patients with asthma (18.2%) compared with control subjects (3.0%) (p < 0.01). Our results provide further evidence that chronic infection with C. pneumoniae is linked to asthma.
Air microbubbles mostly occur unnoticed during cardiopulmonary bypass and are predominantly responsible for serious postoperative psychoneurological dysfunction. A dynamic bubble trap (DBT), which removes air microbubbles from the arterial blood, was tested in a clinical study. The aim was to evaluate the efficiency of microbubble removal under clinical conditions. As blood passes through the DBT, which is placed in the arterial line between the arterial filter and arterial cannula, it is converted into a rotating stream. The bubbles are directed to the centre of the blood flow and are collected in the distal end of the DBT, from where they are returned to the cardiotomy reservoir. Doppler ultrasonography was used to detect the microbubbles before and after the DBT, and also the number of high-intensity transient signals (HITS) in the right and left middle cerebral artery during extracorporeal circulation. A significant reduction of microbubbles in the arterial line (3,990 before DBT, 537 after, p < 0.001) and HITS in the brain (51 in the DBT group, 77 in the placebo group, p = 0.04) was measured.
Employing a two-dimensional simulation model, this paper presents a suitable design for an experiment to study metallization of hydrogen in a heavy-ion beam imploded multilayered cylindrical target that contains a layer of frozen hydrogen. Such an experiment will be carried out at the upgraded heavy-ion synchrotron facility (SIS-18) at the Gesellschaft für Schwerionenforschung, Darmstadt by the end of the year 2001. In these calculations we consider a uranium beam that will be available at the upgraded SIS-18. Our calculations show that it may be possible to achieve theoretically predicted physical conditions necessary to create metallic hydrogen in such experiments. These include a density of about 1 g/cm(3), a pressure of 3-5 Mbar, and a temperature of a few 0.1 eV.
A specifically tailored plasma lens could shape a high-energy, heavy-ion beam into the form of a hollow cylinder without loss of beam intensity. It has been experimentally confirmed that both a positive as well as a negative radial gradient of the current density in the active plasma lens can be the underlying principle. Calculations were performed that yield the ideal current density distribution for both cases. A numerical simulation of an experiment with an intense ion beam highlights that the shaping of the beam increases the achievable compression in a lead sample.
An intense collimated beam of high-energy protons is emitted normal to the rear surface of thin solid targets irradiated at 1 PW power and peak intensity 3x10(20) W cm(-2). Up to 48 J ( 12%) of the laser energy is transferred to 2x10(13) protons of energy >10 MeV. The energy spectrum exhibits a sharp high-energy cutoff as high as 58 MeV on the axis of the beam which decreases in energy with increasing off axis angle. Proton induced nuclear processes have been observed and used to characterize the beam.
Quantitative measurement of mechanical properties of biologic tissues may have several applications for diagnosis or biomechanic modeling in sports medicine, traumatology, or computer-guided surgery. The magnetic resonance imaging (MRI) methods previously tested for these applications all required synchronization between MRI acquisition pulses and the mechanical stimulation. A new unsynchronized method operating with no prior knowledge of intensity, direction, and frequency of the mechanical waves is proposed. A specifically modified SPAMM (SPAtial Modulation of Magnetization) sequence has been used, operating on a 0.2-T MRI system. The experimental results obtained on test objects fit well with theoretical calculations. The new proposed method is very fast (a less than 5-second acquisition time) for routine clinical use.
Eight male volunteers were submitted to a 6-week anti-orthostatic bedrest trial followed by a 1-month reambulation period. We prospectively monitored whole-body composition by dual-energy X-ray absorptiometry, bone and connective tissue metabolism by biochemical markers and calcium regulating hormones by 1-84 parathyroid hormone and 1,25-dihydroxyvitamin D(3). Bone mineral density (BMD) did not vary significantly; however, a trend toward an increase in head BMD and a decrease in trunk, lumbar vertebrae and lower limb BMD was observed. A decrease in the lower limb lean content occurred by day 27 and was maximum by day 42 after the beginning of bedrest; it normalized by day 30 after bedrest. The serum levels of both osteocalcin and C-terminal crosslinked telopeptide of type I collagen increased as a consequence of bedrest. A slight increase in the serum levels of the N-terminal propeptide of type III collagen, a marker of connective tissue metabolism, was observed during the bedrest period. Except for the C-terminal extension propeptide of type I collagen, all markers decreased to baseline pre-immobilization levels during the 1-month recovery phase. Serum PTH and 1,25-dihydroxyvitamin D(3) levels were low during the bedrest period and rose during the reambulation phase. These results seem to reflect early changes in bone and connective tissue metabolism as a result of bedrest unloading, but their order of magnitude remains moderate, thus emphasizing the necessity to perform longer-duration trials.