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Biomedical subjects

A Lang

Publications and source records attributed to A Lang.

At least 37 records · Page 2Linked to original sources
PubMed2001

Wild type p53 sensitizes soft tissue sarcoma cells to doxorubicin by down-regulating multidrug resistance-1 expression.

BACKGROUND: p53 mutations occur in almost half of all soft tissue sarcomas (STS) and may contribute to multidrug resistance (MDR) in patients with STS. Doxorubicin (Dox) is one of the most active single agents in STS but is less effective in STS with p53 mutations. The effect of reintroducing wild type (wt) p53 into STS cells harboring p53 mutations on the cytotoxicity of DOX in vitro and in vivo was studied. METHODS: The following cell lines were used in this study: SKLMS-1 STS cells, which do not express wt p53; two wt p53 stable transfectant cells derived from SKLMS-1 cells; and SKLMS-1 transfectant cells from a p53 temperature-sensitive mutant that expresses wt p53 at 32 degrees C and mutant p53 at 38 degrees C. The cytotoxicity of Dox was examined by [3-(4,5-dimethylthiazzol-2-yl)-2,5-diphenltetrazolium] (MTT) and clonogenetic assay, and the effect of reintroducing wt p53 on tumor suppression by Dox was evaluated with a tumorigenicity assay. DNA fragmentation was used to detect apoptosis. MDR-1 P-glycoprotein (P-gp) expression was detected by Western blot and immunohistochemical analyses of protein levels and by Northern blot analysis of mRNA levels, respectively. The intracellular accumulation of Dox was detected by flow cytometric analysis. RESULTS: The 50% inhibitory concentration (IC(50)) of Dox for the SKLMS-1 wt p53 transfectants decreased 16-fold compared with SKLMS-1 parental cells expressing mutant p53. Colony formation of SKLMS-1 cells after Dox treatment also was inhibited by wt p53 reintroduction. The tumorigenicity of SKLMS-1 cells was inhibited by wt p53 reintroduction alone or by Dox treatment alone and was inhibited further when p53 introduction was combined with Dox treatment in severe combined immunodeficient mice. Although no difference in DNA fragmentation, Bax expression, or Bcl-2 expression was detected among wt p53 transfectants and parental SKLMS-1 cells after Dox treatment, MDR-1 P-gp expression was decreased in wt p53 transfectants compared with parental SKLMS-1 cells. Furthermore, higher intracellular accumulations of Dox were found in wt p53 transfectants than that in SKLMS-1 cells. CONCLUSIONS: Reintroduction of wt p53 into STS cells harboring p53 mutations can enhance their chemosensitivity to Dox through the inhibition of MDR-1 P-gp expression. Thus, the combination of p53 gene therapy and chemotherapy may increase the therapeutic efficacy in the treatment of patients with STS.

Apoptosis↗
PubMed2001

Is sentinel lymph node biopsy reliable and indicated after preoperative chemotherapy in patients with breast carcinoma?

BACKGROUND: Many studies support the concept and accuracy of sentinel lymph node biopsy (SNB) for staging patients with breast carcinoma, which can be performed with low morbidity in lymph node negative patients. Preoperative chemotherapy (PC) plays an important role in the treatment of patients with operable breast carcinoma and is another approach with which to reduce radical surgery in patients with more advanced disease. It is of interest whether the sentinel lymph node accurately represents the axillary status after PC and, thus, whether the sentinel node concept can be applied to both groups. METHODS: Thirty-three patients underwent SNB after chemotherapy and prior to axillary lymph node dissection. RESULTS: The average greatest tumor dimension before chemotherapy (33 mm +/- 2 mm) was significantly larger (P = 0.000) than after therapy (20 mm +/- 3 mm). Histopathologic complete remission was seen in only three patients. One or two sentinel lymph nodes (average, 1.7 lymph nodes) were identified with certainty in 29 of 33 procedures and accurately predicted axillary lymph node status in all of these patients. Breast-conserving surgery was possible in 21 patients (64%), and axillary lymph nodes were involved in 22 patients (67%). CONCLUSIONS: Even after patients undergo PC, SNB seems to be a reliable method for accurate staging of the axilla in those more advanced breast carcinoma. Thus, axillary dissection may be avoided in certain patients. Lymph node involvement seems to be likely in women with suspicious axillary findings before chemotherapy who have no visible sentinel lymph nodes on preoperative lymphosintigraphy and in patients without recurrent tumors. Further investigation of the SNB concept in this patient group should be evaluated in larger studies.

Adult↗
PubMed2001

[Homozygous form of factor V Leiden mutation as the cause of a myocardial infarction in patient with an unremarkable coronary vascular system?].

HISTORY AND ADMISSION FINDINGS: A 32-year-old smoker was referred to our hospital for the evaluation of acute chest pain. 9 years earlier he had had a non Q-wave myocardial infarction. At that time, angiography showed widely patent coronary arteries without atherosclerotic lesions. INVESTIGATIONS: Electrocardiographic as well as creatine kinase patterns were consistent with an acute transmural myocardial infarction. Cholesterol, triglyceride und homocysteine levels were normal. The patient was homozygous for the factor V Leiden mutation. TREATMENT AND COURSE: Thrombolysis was performed with streptokinase followed by coronary angiography showing a patent left coronary system and a non-occlusive thrombosis in the distal part of the right coronary artery. Body weight adapted abciximab infusion was started immediately. 9 weeks later coronary angiography was repeated. Now, in the distal part of the right coronary artery a minor dissection was seen followed by a not flow-limiting stenosis. CONCLUSION: On the evidence of this case history, we think it possible that the pronounced thrombophilia created by the homozygous factor V Leiden mutation may provoke myocardial infarction even if the atherosclerotic lesions are still too trivial to be detected by angiography.

Adult↗
PubMed2001

Criterion for determining clustering versus reentrant melting behavior for bounded interaction potentials.

We examine in full generality the phase behavior of systems whose constituent particles interact by means of potentials that do not diverge at the origin, are free of attractive parts, and decay fast enough to zero as the interparticle separation r goes to infinity. By employing a mean field-density functional theory which is shown to become exact at high temperatures and/or densities, we establish a criterion that determines whether a given system will freeze at all temperatures or it will display reentrant melting and an upper freezing temperature.

Journal Article↗
PubMed2001

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Acetamides↗
PubMed2001

The 1.8-A crystal structure of a matrix metalloproteinase 8-barbiturate inhibitor complex reveals a previously unobserved mechanism for collagenase substrate recognition.

The individual zinc endoproteinases of the tissue degrading matrix metalloproteinase (MMP) family share a common catalytic architecture but are differentiated with respect to substrate specificity, localization, and activation. Variation in domain structure and more subtle structural differences control their characteristic specificity profiles for substrates from among four distinct classes (Nagase, H., and Woessner, J. F. J. (1999) J. Biol. Chem. 274, 21491-21494). Exploitation of these differences may be decisive for the design of anticancer or other drugs, which should be highly selective for their particular MMP targets. Based on the 1.8-A crystal structure of human neutrophil collagenase (MMP-8) in complex with an active site-directed inhibitor (RO200-1770), we identify and describe new structural determinants for substrate and inhibitor recognition in addition to the primary substrate recognition sites. RO200-1770 induces a major rearrangement at a position relevant to substrate recognition near the MMP-8 active site (Ala206-Asn218). In stromelysin (MMP-3), competing stabilizing interactions at the analogous segment hinder a similar rearrangement, consistent with kinetic profiling of several MMPs. Despite the apparent dissimilarity of the inhibitors, the central 2-hydroxypyrimidine-4,6-dione (barbiturate) ring of the inhibitor RO200-1770 mimics the interactions of the hydroxamate-derived inhibitor batimastat (Grams, F., Reinemer, P., Powers, J. C., Kleine, T., Pieper, M., Tschesche, H., Huber, R., and Bode, W. (1995) Eur. J. Biochem. 228, 830-841) for binding to MMP-8. The two additional phenyl and piperidyl ring substituents of the inhibitor bind into the S1' and S2' pockets of MMP-8, respectively. The crystal lattice contains a hydrogen bond between the O(gamma) group of Ser209 and N(delta)1 of His207 of a symmetry related molecule; this interaction suggests a model for recognition of hydroxyprolines present in physiological substrates. We also identify a collagenase-characteristic cis-peptide bond, Asn188-Tyr189, on a loop essential for collagenolytic activity. The sequence conservation pattern at this position marks this cis-peptide bond as a determinant for triple-helical collagen recognition and processing.

Amino Acid Sequence↗
PubMed2001

Alternative messenger RNA splicing and enzyme forms of cathepsin B in human osteoarthritic cartilage and cultured chondrocytes.

OBJECTIVE: In previous studies, we suggested that cathepsin B, which is present at sites of cartilage remodeling in osteoarthritis (OA), may act as an antagonist of cartilage repair, an enhancer of the action of metalloproteinases, and a mediator of cartilage neovascularization and mineralization. Alternative splicing of cathepsin B pre-messenger RNA (pre-mRNA) and/or mRNA overexpression is a plausible regulatory mechanism. In the present study, we investigated the abundance of cathepsin B transcripts and the properties of cathepsin B protein in normal and OA cartilage, osteophytes, and cultured chondrocytes. METHODS: Cathepsin B mRNA splice variants containing the full-length transcript (CB) and the variants lacking either exon 2 (CB[-2]) or lacking exons 2 and 3 (CB[-2,3]) were measured by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot assays and were localized by in situ RT-PCR. Cathepsin B protein was analyzed by electrophoretic, Western blot, and chromatographic methods. RESULTS: The relative content of CB, CB(-2), and CB(-2,3) varied considerably in OA cartilage and osteophytes, with less variation in normal cartilage. The mean cathepsin B mRNA level was significantly higher in OA cartilage and osteophytes than in normal cartilage. Normal cultured chondrocytes attained cathepsin B mRNA levels similar to those in OA cartilage. Enzyme overexpression resulted in the secretion of procathepsin B, followed by activation to the proteolytically active form. CONCLUSION: The high levels of CB and CB(-2) are consistent with an overproduction of secreted procathepsin B in OA. Up-regulation of chondrocyte cathepsin B, which takes place at both the transcriptional and the translational level, suggests a leading role of the enzyme in the progression of OA.

Aged↗
PubMed2001

Functional correlates of pallidal stimulation for Parkinson's disease.

We measured regional cerebral blood flow with H2 15O and positron emission tomography (PET) scanning at rest and during a motor task to study the mechanism of motor improvement induced by deep brain stimulation of the internal globus pallidus in Parkinson's disease. Six right-handed patients with Parkinson's disease were scanned while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed ON and OFF stimulation in a medication-free state. Internal globus pallidus deep brain stimulation improved off-state United Parkinson's Disease Rating Scale motor ratings (37%, p < 0.002) and reduced timing errors (movement onset time, 55%, p < 0.01) as well as spatial errors (10%, p < 0.02). Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex (Brodmann area [BA] 4), bilaterally in the supplementary motor area (BA 6), and in the right anterior cingulate cortex (BA 24/32). Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation. With internal globus pallidus deep brain stimulation, improved movement initiation correlated with regional cerebral blood flow increases in the left sensorimotor cortex and ventrolateral thalamus and in the contralateral cerebellum. By contrast, improved spatial accuracy correlated with regional cerebral blood flow increases in both cerebellar hemispheres and in the left sensorimotor cortex. These results suggest that internal globus pallidus deep brain stimulation may selectively improve different aspects of motor performance. Multiple, overlapping neural pathways may be modulated by this intervention.

Adult↗
PubMed2001

Comparison of antimicrobial use and resistance of bacterial isolates in a haematology ward and an intensive care unit.

The objective of the study presented here was to compare antimicrobial use and resistance of bacterial isolates in the haematology ward and the intensive care unit of Bolzano General Hospital. The bacterial organisms isolated most frequently from patients in the two wards (coagulase-negative staphylococci, Enterococcus spp., and Pseudomonas aeruginosa) were investigated for antimicrobial resistance. Isolates obtained from patients in the haematology ward were more often resistant to antimicrobial agents than isolates obtained from patients in the intensive care unit, and the agents against which the highest rates of resistance were found were third- and fourth-generation cephalosporins, carbapenems and monobactams, quinolones, aminoglycosides, and trimethoprim-sulfamethoxazole. These classes of antimicrobial agents were also used more frequently in the haematology ward than in the intensive care unit. Conversely, penicillinic beta-lactam antibiotics, rifamycins, macrolides and lincosamides were used less frequently in the haematology ward than in the intensive care unit, and the rates of resistance against these classes of antimicrobial agents were significantly lower in the haematology ward than in the intensive care unit. The results support the hypothesis that a causal relationship exists between antimicrobial use and the development of resistance and indicate that careful monitoring of antimicrobial use in hospitals is required to identify situations in which prescription patterns are contributing to the development of resistance.

Anti-Bacterial Agents↗
PubMed2001

Subcellular site of superoxide dismutase expression differentially controls AP-1 activity and injury in mouse liver following ischemia/reperfusion.

Acute damage following ischemia and reperfusion (I/R) in the liver is in part caused by the generation of reactive oxygen species, such as superoxides, during the reperfusion event. Gene therapy directed at attenuating mitochondrial superoxide production following warm I/R injury in the liver has demonstrated great promise in reducing acute hepatocellular damage. In the present study, we have compared the therapeutic effects of ectopic expression of mitochondrial (MnSOD) and cytoplasmic (Cu/ZnSOD) superoxide dismutase using recombinant adenoviral vectors for reducing I/R damage in the liver. Consistent with previous observations, recombinant adenoviral delivery of MnSOD to the liver significantly attenuated both acute liver damage and AP-1 activation following I/R injury to the livers of mice. However, ectopic expression of Cu/ZnSOD diminished neither I/R-induced elevations in serum alanine transaminase (ALT) nor AP-1 activation. Interestingly, baseline activation of AP-1 before I/R-induced injury was seen in livers infected with recombinant Ad.Cu/ZnSOD, but not Ad.MnSOD or Ad.LacZ, vectors. The level of Cu/ZnSOD-induced AP-1 activation was significantly reduced by ablation of Kupffer cells or by coexpression of catalase, suggesting that increased H(2)O(2) production facilitated by Cu/ZnSOD in hepatocytes and/or Kupffer cells may be responsible for AP-1 activation. In vitro reconstitution studies using hepatocyte and macrophage cell lines demonstrated that Cu/ZnSOD overexpression induces AP-1 in both cell types, and that secretion of a Cu/ZnSOD-induced macrophage factor is capable of elevating AP-1 in hepatocytes. In summary, our findings demonstrate that subcellular sites of superoxide production in the liver can differentially affect the outcome of I/R injury in the liver and selectively influence AP-1 activation.

Animals↗
PubMed2001

Weathering the storm of perinatal bereavement via hardiness.

Hardiness is a personal resource that can potentially diminish negative effects of life stress. To increase understanding of the role that it can have on the health protection and promotion of bereaved parents following a perinatal loss, this article uses J. Wilson's (1969) method to present a concept analysis of hardiness. This analysis provides not only a fresh perspective for understanding the experience of perinatal loss but has also induced the development of a hardiness instrument. Knowledge development in this area is paramount for professionals interested in enabling bereaved parents to draw on and develop their hardiness, not only to transcend the experience but ultimately to gain a sense of personal growth following their loss.

Adaptation, Psychological↗
PubMed2001

Costs of asthma treatment in Estonia.

BACKGROUND: The aim of this study was to describe the distribution of the direct costs of asthma in Estonia by the type of treatment received and to differentiate the costs by age of patients. METHODS: Data were obtained from the databases of national health insurance offices. Persons who had been in a hospital or visited a doctor because of asthma and who also purchased anti-asthmatic drugs during 1997 were identified. The bills of all direct costs of health insurance for each asthma patient could thus be summarised. The data on all purchases of drugs were used to follow the patterns of drug treatment of asthma. RESULTS: The mean annual treatment costs of one asthma patient were 118 EUR. The costs of hospital care accounted for 27%, costs of ambulatory care for 20% and costs of pharmacotherapy for 53% of all treatment costs. Beta-agonists and corticosteroids for inhalation accounted for more than 80% of prescriptions and 90% of pharmacotherapy costs in patients under 45 years. The users of oral corticosteroids had twice as high per capita annual asthma treatment costs as compared to non-users. CONCLUSIONS: The frequency of out-patient visits, hospital admissions, number of prescriptions, total costs and costs of pharmaceuticals increased in parallel with age. The total estimated direct costs of asthma diagnosis and treatment during 1997, as extrapolated from the study population, were 2.1 million EUR, and accounted for 1.4% of direct health care costs in Estonia.

Adolescent↗
PubMed2001

Color discrimination in heterozygous deutan carriers.

PURPOSE: The color discrimination abilities of heterozygous deutan female carriers were measured using color mixture thresholds and compared with those of suspected nonheterozygous normal subjects. METHODS: Eight test subjects and 26 control subjects were run on a computer-controlled color test (color mixture thresholds) that presented 1 degree diameter spots on a color television monitor for 1/60 of a second. A QUEST procedure was used to determine visual thresholds for spots varying in brightness and/or color. Individual data points were graphed on an X/Y plot and fitted with an ellipse. The major and minor diameters of the ellipse represent the color and brightness thresholds, respectively. RESULTS: The mean axis angle of the ellipse for the heterozygous carriers did not differ from that for the controls (15.75 degrees vs. 14.93 degrees, p = 0.428, Mann-Whitney test). The carriers did show, however, a larger mean major axis length (68.79 vs. 46.78, p = 0.0218, Mann-Whitney test). Additionally, the length-to-width ratios for the carriers were higher than the controls (9.34 vs. 6.80, p = 0.0403, Mann-Whitney test). CONCLUSIONS: Deutan-carriers do show reduced color purity discrimination as measured using color mixture thresholds compared with nonheterozygous, color vision normals.

Adolescent↗
PubMed2001

Satisfaction of inpatients and outpatients with staff, environment, and other patients.

The study described here compared levels of satisfaction with staff, environment, and other patients among 420 first-time and long-term patients in psychiatric outpatient and inpatient settings. The demographic, clinical, and outcome variables associated with satisfaction were explored. Patient satisfaction was related to quality of life, social functioning, treatment expectations, and one-year psychological and physical prognoses. Perceptions of other patients were significantly more positive among long-term patients than among first-time patients. The concerns of first-time patients about other patients are of special importance, and they should be addressed during initial treatment.

Adult↗
PubMed2001

Appearance of images through a multifocal intraocular lens.

The appearance of images through a multifocal intraocular lens (IOL) was simulated. The optical transfer function (OTF) of a model eye containing the multifocal lens was measured and divided by the OTF of the model eye with a monofocal IOL. This ratio was used to filter digital images, generating simulations that represent the retinal images seen through a multifocal intraocular lens when viewed through an eye with a monofocal lens. A dichoptic side-by-side display was used to present the original image to one eye, implanted with the multifocal lens, while the other eye, implanted with monofocal lens, viewed the simulations and variations on the simulations to derive a point of subjective equivalence. Four subjects with such bilateral lens implants were tested for near and distance vision. The results validate the test methodology and the simulations. Referenced to the nominal theoretical filter, the prediction was within a 0.25-diopter (D) blur for distance simulation and within a 0.50-D blur for the near-vision simulation.

Aged↗
PubMed2001

Antimicrobial use and susceptibility rates in isolates from intensive care unit and other nosocomial inpatient and outpatient areas.

Our objective was to evaluate the relation between antimicrobial use and susceptibility in the intensive care unit (ICU) and non-ICU inpatient areas in the Bolzano regional hospital. For the isolates of S. aureus, coagulase negative staphylococci, Enterococcus sp., P. aeruginosa and E. coli we found a pattern of significant stepwise decrease in the frequency of antimicrobial susceptibility to penicilloic beta-lactam antibiotics and first generation cephalosporins; the highest senitivity rates occurred among isolates from outpatients, followed in decreasing order by rates among isolates from non-ICU inpatients and from ICU-patients; the rate of use of this group of antimicrobial agents was relatively high in the intensive care unit (13,1%). For P. aeruginosa we observed significantly lower susceptibility-rates to second, third and fourth generation cephalosporins, carbapenems and monobactams for non-ICU inpatient areas than for outpatient or ICU areas; this paralleled with the low use of this group of agents in the ICU area (4,9%). Also, for P. aeruginosa the prevalence of susceptibility to ciprofloxacin and norfloxacin in inpatient areas was lower than in the outpatient or ICU-areas; the rate of quinolone-use was relatively low in the ICU area (4,2%).

Ambulatory Care Facilities↗
PubMed2001

A novel mutation in the M1S1 gene responsible for gelatinous droplike corneal dystrophy.

PURPOSE: To identify the genetic defect in the M1S1 gene causing gelatinous droplike corneal dystrophy (GDLD) in an Estonian family. METHODS: DNA was extracted from members of a GDLD-affected family and control persons. Polymerase chain reaction followed by direct sequencing was used to detect mutations in the M1S1 gene. Sequencing results were confirmed with restriction analysis. RESULTS: Sequencing of the M1S1 gene revealed a novel mutation and a common polymorphism. All patients with GDLD were found to be homozygous for the insertion of nucleotide C in position 520 in M1S1. The mutation leads to formation of truncated protein. The mutation was excluded in 103 normal, unaffected individuals. Very close to the location where the mutation was identified in the M1S1 gene, a single-nucleotide polymorphism (518A/C) was found, changing aspartic acid to alanine at codon 173. CONCLUSIONS: The data indicate that mutation ins520C in the M1S1 gene is the primary cause of GDLD in the family studied.

Antigens, Neoplasm↗