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Biomedical subjects

A Lang

Publications and source records attributed to A Lang.

At least 55 records · Page 3Linked to original sources
PubMed2000

Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression.

Our recent studies (R. Pollock et al., Clin. Cancer Res., 4: 1985-1994, 1998; M. Milas et al., Cancer Gene Ther., in press, 2000) have shown that the restoration of wild-type (wt) p53 enhances cell cycle control in vitro and inhibits the growth of human soft-tissue sarcoma in severe combined immunodeficient mice. We hypothesized that the antitumor effect of wt p53 overexpression in sarcoma cells is attributable not only to enhanced cell cycle control but also to inhibition of angiogenesis. We evaluated the effect of restoring wt p53 function on angiogenesis in human soft-tissue sarcoma harboring mutant p53. Restoration of wt p53 expression in human leiomyosarcoma SKLMS-1 cells that contain mutant p53 markedly inhibited angiogenesis induced by tumor cells in vivo. Angiogenesis assays using an in vivo Matrigel plug assay demonstrated that less neovascularization in severe combined immunodeficient mice was observed with conditioned medium (CM) from human synovial sarcoma cells expressing wt p53 compared with CM from human synovial sarcoma cells expressing mutant p53. Microvessel density and microvessel counts were lower in tumor xenografts from cells containing wt p53 than in tumor xenografts from cells containing mutant p53. The growth and migration of murine lung endothelial cells were decreased when cells were treated with CM from sarcoma cells expressing wt p53 compared with CM from sarcoma cells expressing mutant p53. The introduction of wt p53 into sarcoma cells containing mutant p53 significantly reduced the expression of vascular endothelial growth factor (VEGF), which is a key mediator of tumor angiogenesis. Stimulation of endothelial cell migration by CM from cells expressing mutant p53 was significantly reduced after anti-VEGF neutralizing antibody was added to the CM. Using luciferase as the reporter of VEGF promoter activity, we found that wt p53 inhibited VEGF promoter activity in SKLMS-1 cells. Deletion analysis defined an 87-bp region (bp -135 to -48) in the VEGF promoter that is necessary for inhibiting VEGF promoter activity by wt p53. The transcription factor Sp1 may be involved in the repression of VEGF promoter activity by wt p53 in SKLMS-1 cells. These data indicated that wt p53 can suppress angiogenesis in human soft-tissue sarcomas by transcriptional repression of VEGF expression.

Animals↗
PubMed2000

[Outpatient treatment of patients with cardiovascular diseases].

In Germany, cardiovascular disturbances belong to the diseases most frequently treated in the offices of general practitioners and internal specialists. With comprehensive monitoring and the taking of adequate therapeutic measures, the average mortality age of the majority of the 18 million patients suffering from circulatory diseases lies at 79.4 years. In the age group of over 70 years, 70 to 80% of the patients receive treatment against cardiovascular disturbances, most of them against hypertension. One of the most important goals of monitoring and intervention in the outpatient sector is the treatment of hypertension, especially in connection with measures taken against disturbances in lipometabolism in order to prevent secondary diseases. The success of treatment is shown by the decreasing age standardized rate of cardiac infarctions, especially among men, and the decreasing mortality rate of patients below 65. The increasing treatment in the outpatient sector is accompanied by additional interventions, especially by bypass surgery in the hospital sector. The concerted actions in both the outpatient and the inpatient sector result in a higher service provision to come to a higher quality of life in the patients and to prevent early death.

Adult↗
PubMed2000

Nuclear factor kappaB in proliferation, activation, and apoptosis in rat hepatic stellate cells.

BACKGROUND/AIMS: Activation of the transcription factor NFkappaB has been demonstrated in activated hepatic stellate cells (HSCs). We investigated the role of NFkappaB in proliferation, in activation, and in TNFalpha-induced apoptosis of HSCs. METHODS: NFkappaB activation was inhibited using an adenovirus expressing an IkappaB dominant negative protein (Ad5IkappaB) in both quiescent and activated HSCs. Quiescent HSCs were infected with Ad5IkappaB or an adenovirus expressing beta-galactosidase (Ad5LacZ). The cells were cultured for 7 days. HSCs activation was determined by cell morphology, smooth muscle alpha-actin (alpha-sma) expression, and steady-state mRNA levels of alpha1(I) collagen as assessed by Western blot and RNase protection assay, respectively. Proliferation was determined in culture-activated HSCs by 3H-thymidine incorporation and direct cell counting. Apoptosis was analyzed by infecting quiescent or activated HSCs with Ad5IkappaB or Ad5LacZ, and then treating with TNFalpha. Apoptosis was demonstrated by determining cell number, assessing nuclear morphology, TUNEL assay and caspase 3 activity. RESULTS: After 7 days in culture no differences were noted between the Ad5IkappaB- and the Ad5LacZ-infected cells in the morphology, alpha-sma expression or in alpha1(I) collagen mRNA levels. Ad5IkappaB infection did not modify proliferation in activated HSCs. TNFalpha induced apoptosis only in Ad5IkappaB-infected activated, but not quiescent HSCs. Apoptosis was initially demonstrated 12 h after exposure to TNFalpha. Twenty-four h after the TNFalpha treatment, 60% of the activated HSCs were apoptotic. CONCLUSION: NFkappaB activity is not required for proliferation or activation of HSCs; however, NFkappaB protects activated HSCs against TNFalpha-induced apoptosis.

Adenoviridae Infections↗
PubMed2000

Response types in Collembola towards copper in the microenvironment.

Laboratory studies were carried out to cast light on differences in density responses among collembolan species to copper (Cu)-polluted environments. In a recolonisation experiment, mesofauna originating from a copper (Cupolluted arable field were allowed to colonise defaunated Cu-contaminated and uncontaminated soil cores for 3 months. The abundances of Pseudosinella alba and gamasid mites were higher in the uncontaminated soil, whereas the majority of other collembolans tended to be more abundant in the Cu-enriched soil. Behavioural experiments were conducted to test the ability of single Collembola species to distinguish between filter paper and food soaked in water, Cu, and calcium (Ca) solutions. Onychiurus armatus avoided both Cu and Ca, whereas Folsomia quadrioculata and Folsomia manolachei showed a significant preference for Cu. Isotomurus palustris was not able to distinguish between Cu and water. The results are compared and discussed with regard to other studies on the occurrence and behaviour of Collembola in Cu-contaminated environments. We suggest that microsite selection according to preference or avoidance of high salinity of pore water may partly explain the community structure of Collembola in Cu-polluted soils which are characterised by an increase of euedaphic species. More studies have to be carried out to generalise this concept and to explore to what extent reduced predation by gamasid mites contribute to the success of certain Collembola in Cu-contaminated sites.

Journal Article↗
PubMed2000

Adenovirus-mediated p53 gene therapy inhibits human sarcoma tumorigenicity.

Mutations of the p53 tumor-suppressor gene are the most frequent genetic abnormality in soft tissue sarcomas. Because these rare tumors also respond poorly to standard chemotherapy and bear a 50% 5-year mortality rate, we investigated the possible therapeutic benefits of p53 gene restoration in sarcomas. We constructed Ad5p53, which is an E1A-deleted, replication-deficient adenovirus expressing a cytomegalovirus promoter-driven wild-type p53 cDNA with a Flag sequence tag. SKLMS-1 human leiomyosarcoma cells containing a mis-sense p53 point mutation were effectively transduced with Ad5p53. Increasing levels of Flag-p53 protein, as well as dose-dependent p21Cip1 induction, were observed through a dose range of 10-500 plaque-forming units (PFU)/cell. In vitro administration of Ad5p53 as a single 100 PFU/cell dose caused 40-60% growth inhibition of SKLMS-1 cells at posttreatment days 4, 6, and 8 compared with untreated or viral control treated-cells (P < .05, Student's t test). Relative to these same controls, in vivo treatment of SKLMS-1-bearing severe combined immunodeficient mice with 6 x 10(9) PFU of Ad5p53 by intratumoral injection resulted in a 35-day tumor growth delay and complete tumor regression in 40% of mice (P < .05, Student's t test). The expression of virally derived p53 mRNA in Ad5p53-treated tumor tissues was detected in treated tumor specimens by reverse transcriptase polymerase chain reaction. Reduced intratumoral cellularity and the presence of p53 staining in adjacent normal tissue, consistent with delivery of exogenous p53 to the tumor target, were evident only in Ad5p53-treated tumors after immunohistochemical staining for p53. These results indicate that wild-type p53 gene restoration in sarcomas retards tumor growth and may come to be usefully applied to the clinical treatment of this disease as a single regimen or in combination with conventional therapies.

Adenoviruses, Human↗
PubMed2000

[Initial effects of the 1998 revised narcotic law in substitute drug treatment of narcotic dependent patients--results of a physician survey].

UNLABELLED: To study the consequences of the last revision of the German narcotics act (1998, which forbids prescribing codeines as substitutes), a survey was carried out several months after implementation with 639 physicians, who gave substitution treatment. It could be determined how far codeine patients were ready to change their substitute, how content physicians said their patients were after changing the substitute and which were the attitudes of physicians to the revision in question. RESULTS: The majority of patients (70%) who were formerly substituted by means of codeine accepted methadone as a substitute. After the method of substitution had been changed, 51% of patients had been classified as "very content" and 35% as "reasonably content". Especially those physicians who prescribed codeines in the past, unlike physicians who used methadone for substitution treatment only, criticised the revision in question and feared that many patients should be without medical care as a consequence of the new situation.

Attitude of Health Personnel↗
PubMed2000

[Helicobacter pylori and coronary heart diseases--hypotheses and facts].

In 1994 Mendall et al. (9) have suggested that there might be a correlation between Helicobacter pylori (HP) infection and coronary heart disease (CHD), mediated by a chronic low-grade acute phase reaction with mildly raised serum or plasma concentrations of C-reactive protein and fibrinogen. According to this hypothesis, a gastric HP colonization might be an additional risk factor for CHD. In the meantime, 35 studies have examined whether HP seropositivity is associated with CHD occurrence. However, in 8 publications only CHD was definitively proven (in CHD+ patients) or excluded (in the corresponding control groups) by coronary artery angiography, and in only 2 of them (1 abstract, 1 full-length publication) a significant association between HP positivity (serologically proven) and CHD was ascertained. Additionally, a metaanalysis of 18 studies including 10,000 patients could not demonstrate any correlations between HP seropositivity and different acute phase proteins (66). Thus, a positive correlation between gastric HP colonization and CHD is far from being proven. Further proposed links between HP infection and CHD such as hyperhomocysteinemia (67) or autoimmune mechanisms (71) due to cross-reacting antibodies to HP HSP60/65 (heat shock protein) with human endothel-derived HSP60/65 need further confirmation.

Acute-Phase Reaction↗
PubMed2000

Botulinum toxin for essential tremor of the voice with multiple anatomical sites of tremor: a crossover design study of unilateral versus bilateral injection.

OBJECTIVES/HYPOTHESIS: To evaluate the relative efficacy of unilateral and bilateral injections of botulinum toxin injection (BOTOX) in the treatment of essential tremor of the voice (ETV). STUDY DESIGN: Prospective open-label crossover study. METHODS: Patients referred to the Neurolaryngology Clinic at Toronto General Hospital with a diagnosis of ETV were eligible for the study. Patients were sequentially assigned to receive BOTOX as either a bilateral 2.5-U or a unilateral 15-U electromyography-guided injection, followed by the alternative injection 16 to 18 weeks later. Acoustic, aerodynamic, and nasopharyngoscopic data were collected approximately 2, 6, 10, and 16 weeks after each injection. Patients were asked to provide a perceptual evaluation of BOTOX effects at the conclusion of the study. RESULTS: Three of 10 patients demonstrated an objective reduction in tremor severity with bilateral injection, and 2 of 9 with unilateral injection. However, 8 of 10 patients wished to be re-injected at the conclusion of the study. A reduction in vocal effort appeared to be coincident with reduction in laryngeal airway resistance after BOTOX injection. CONCLUSIONS: Using objective acoustic measures, only a small proportion of patients achieved benefit from BOTOX injection for ETV. However, a majority of patients in our study benefited from a subjective reduction in vocal effort that may have been attributable to reduced laryngeal airway resistance.

Aged↗
PubMed2000

Expression of small heat shock protein alphaB-crystallin is induced after hepatic stellate cell activation.

Using the differential PCR display method to select cDNA fragments that are differentially expressed after hepatic stellate cell (HSC) activation, we have isolated from activated HSCs a cDNA that corresponds to rat alphaB-crystallin. Northern blots confirmed expression of alphaB-crystallin in culture-activated HSCs but not in quiescent HSCs. Western blot analysis and immunocytochemical staining confirmed expression of alphaB-crystallin protein in activated but not quiescent HSCs. alphaB-crystallin is induced as early as 6 h after plating HSCs on plastic and continues to be expressed for 14 days in culture. Expression of alphaB-crystallin was also induced in vivo in activated HSCs from experimental cholestatic liver fibrosis. Confocal microscopy demonstrated a cytoplasmic distribution of alphaB-crystallin in a cytoskeletal pattern. Heat shock treatment resulted in an immediate perinuclear redistribution that in time returned to a normal cytoskeletal distribution. The expression pattern of alphaB-crystallin was similar to that of HSP25, another small heat shock protein, but differed from the classic heat shock protein HSP70. Therefore, alphaB-crystallin represents an early marker for HSC activation.

Animals↗
PubMed2000

[Assisted living for former long-term hospitalized psychiatric patients].

OBJECTIVES: The aim of the study is the evaluation of essential characteristics of patients who entered the sheltered group homes of the Psychosozialen Dienst (PSD) in the city of Vienna after the establishment of sectorized psychiatric out-patient care facilities. METHOD: Eighty patients who lived in these group homes on the first key day, June 30th 1993, were investigated. Any change in their living situation and rate of hospitalization was ascertained at follow-up, 3.5 years after the first key day. RESULTS: The patients had an average period of hospitalization of 240.5 days per year before entry to a group home, which decreased to 12.4 days per year after entry to a sheltered group home. At follow-up more than half of all patients (65%) were still able to live in the community successfully. The number and the length of hospitalizations between the first key day and the follow-up were lowest for patients who had moved to private homes. CONCLUSIONS: Sheltered group homes play an essential role in the process of rehabilitation towards independent living within the community. The results demonstrate that rehabilitation in private apartments can be possible even after 5.7 years of residence in sheltered group homes.

Adult↗
PubMed2000

[Quality of life of the mentally ill].

Object of this research project was to study the subjective quality of life of psychiatric patients. The vulnerability of 424 out- and inpatients was assessed. The Vulnerability Index, composed of: marital status, income, health, life conditions, occupation, and risk factors in childhood was used. According to their vulnerability, two groups of patients were differentiated: patients with high and low vulnerability. We compared these objective criteria of vulnerability with the subjective quality of life (Q-LES-Q). Quality of life was also compared with diagnosis, severity of illness, and treatment (first contact/long-term contacts). Quality of life of 250 patients was analysed after one year follow up. Patients with a low vulnerability score are more satisfied with 'social relations' than patients with a high vulnerability score. In-patients are more satisfied with 'social relations' than out-patients. Out-patients are more satisfied with their 'physical health', 'subjective feelings', 'leisure time activities', and 'overall life satisfaction' than in-patients. Patients with a mild affective disorder have a better 'life satisfaction' than patients with severe affective disorder. Quality of life of schizophrenics and of patients with anxiety and adjustment disorders has improved significantly after one year.

Adaptation, Psychological↗
PubMed2000

[Expectations of psychiatric patients from their outpatient and inpatient treatment].

OBJECTIVE: This study describes patient evaluations about treatment interventions and the subjective value of specific treatment expectations. METHOD: A random sample of 425 out-patients and in-patients was assessed to evaluate importance of treatment interventions and specific expectations of psychiatric treatment. RESULTS: Preferences regarding treatment interventions varied among diagnostic groups. Psychiatric patients ranked medication and supporting therapeutic conversations the highest. Sociodemographic characteristics, numbers of previous hospitalizations, quality of life and social abilities influenced treatment expectations. A patient's perception of dissatisfying quality of life and high social vulnerability increased the need for social assistance. CONCLUSION: Subjective treatment expectations of psychiatric patients should be the start-out for every treatment-regime. Socially vulnerable patients should be identified and specific treatment plans should be developed at treatment-start.

Adult↗
PubMed2000

The relative importance of cysteine peptidases in osteoarthritis.

OBJECTIVE: To assess the activity of cysteine peptidases in cultured human articular chondrocytes as well as in osteoarthritic (OA) cartilage and subchondral bone, and to interpret their relative importance in cartilage destruction and remodeling of the subchondral region. METHODS: Intracellular and secreted cysteine peptidase activity was measured in chondrocytes using fluorimetric assays, and enzymes were immunolocalized using monospecific antibodies. Enzyme histochemistry in normal and OA femoral heads was used to characterize enzymatic activity in full thickness samples containing cartilage and subchondral bone. The zonal distribution of cathepsin activity was measured in tissue slices of normal and OA femoral heads cut parallel to the joint surface, using fluorogenic substrates. RESULTS: Cathepsins B and L were localized by immunohistochemistry with lysosome-like structures in dedifferentiated chondrocytes. Free cysteine peptidase activity (i.e., not requiring prior activation), secreted and intracellularly stored by chondrocytes, was due to cathepsin B, while cathepsin L contributed a minor fraction of the total activity, and was seen only after activation at acidic pH. Histochemistry and activity measurements confirmed cathepsin B as the major, active cysteine peptidase in OA cartilage, particularly at sites where matrix neosynthesis took place. However, free cathepsin L and/or cathepsin K activity was found subchondrally in association with cathepsin B in osteophytes, in zones undergoing bone remodeling, and at sites of inflammation. CONCLUSION: Cathepsin B, not cathepsin L or cathepsin K, is a candidate for articular cartilage catabolism in OA. While cathepsin K is the major osteoclastic cysteine peptidase, cathepsin L and cathepsin B may also participate in the remodeling processes of bone as well as in bone erosion by inflammatory cells.

Adult↗
PubMed2000

[Social vulnerability, social isolation of chronic psychiatric patients].

Social vulnerability and social isolation as to different, light and severe grades of chronically ill psychiatric patients were evaluated. A social vulnerability index, composed out of marital status, income, health, living conditions, occupation, and risk factors in childhood was used. The vulnerability of 64 severely chronically ill patients and of 84 chronically ill patients was assessed. According to their vulnerability, the patients were divided into a group of highly vulnerable and a group of less vulnerable patients. The social isolation of the two groups (severely chronically und chronically ill patients) was compared and assessed. We used objective criteria (such as living alone, no friends, no contact to family members) and subjective criteria (feeling isolated). Social Vulnerability and social isolation are higher in severely chronically ill patients compared to chronically ill patients. The severely sick group is significantly more affected by objective and/or by subjective isolation than the less sick group. In both groups patients have more difficulties in social relationships than non-isolated patients. There is no significant correlation between objective isolation and subjective isolation.

Adolescent↗
PubMed1999

Coagulation factor IXa: the relaxed conformation of Tyr99 blocks substrate binding.

BACKGROUND: Among the S1 family of serine proteinases, the blood coagulation factor IXa (fIXa) is uniquely inefficient against synthetic peptide substrates. Mutagenesis studies show that a loop of residues at the S2-S4 substrate-binding cleft (the 99-loop) contributes to the low efficiency. The crystal structure of porcine fIXa in complex with the inhibitor D-Phe-Pro-Arg-chloromethylketone (PPACK) was unable to directly clarify the role of the 99-loop, as the doubly covalent inhibitor induced an active conformation of fIXa. RESULTS: The crystal structure of a recombinant two-domain construct of human fIXa in complex with p-aminobenzamidine shows that the Tyr99 sidechain adopts an atypical conformation in the absence of substrate interactions. In this conformation, the hydroxyl group occupies the volume corresponding to the mainchain of a canonically bound substrate P2 residue. To accommodate substrate binding, Tyr99 must adopt a higher energy conformation that creates the S2 pocket and restricts the S4 pocket, as in fIXa-PPACK. The energy cost may contribute significantly to the poor K(M) values of fIXa for chromogenic substrates. In homologs, such as factor Xa and tissue plasminogen activator, the different conformation of the 99-loop leaves Tyr99 in low-energy conformations in both bound and unbound states. CONCLUSIONS: Molecular recognition of substrates by fIXa seems to be determined by the action of the 99-loop on Tyr99. This is in contrast to other coagulation enzymes where, in general, the chemical nature of residue 99 determines molecular recognition in S2 and S3-S4. This dominant role on substrate interaction suggests that the 99-loop may be rearranged in the physiological fX activation complex of fIXa, fVIIIa, and fX.

Amino Acid Sequence↗
PubMed1999

Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases.

The tissue inhibitors of matrix metalloproteinases (MMPs), TIMP-1 and TIMP-2, are also angiogenesis inhibitors. Cathepsin B and MMPs are found at sites of neovascularization in pathologies such as cancer and osteoarthritis. Treatment of TIMP-1, TIMP-2, and of a mixture of both inhibitors from human articular chondrocytes with cathepsin B resulted in their fragmentation, whereby they lost their MMP-inhibitory and anti-angiogenic activities. Our data suggest that, besides directly participating in tissue destruction, cathepsin B can be harmful for two further reasons: it raises the activity of the MMPs also in the absence of mechanisms up-regulating these enzymes, and it stimulates angiogenesis. This is a prerequisite for blood vessel invasion in a variety of pathological situations of which cancer and osteoarthritis are prominent examples.

Cartilage, Articular↗
PubMed1999

[Meningococcal sepsis in 3 young men].

HISTORY AND CLINICAL FINDINGS: Three young men became ill one after the other with fever, headaches, vomiting, arthralgias and muscle pain. One day after beginning of symptoms all three patients developed a haemorrhagic rash with petechial and ecchymotic lesions most intense on distal extremities. 24 hours later patient no. 1 and 3 were in septic shock. INVESTIGATIONS: Laboratory tests showed signs of systemic infection, disseminated intravascular coagulation and renal failure. On the day of admission to the hospital blood cultures showed Neisseria meningitidis in patient no. 1 and 3. In patient no. 2 blood cultures were negative. TREATMENT AND COURSE: Intravenous antibiotic therapy was started immediately after admission. In patient no. 1 and 3 purpura fulminans with multiple organ failure demanded intensive care treatment. Patient no. 1 recovered. Necrotic toes made amputations necessary. Patient no. 2 was never critically ill. Patient no. 3, whose course was complicated by a long lasting disseminated intravascular coagulation, died from massive cerebral bleeding 6 days after admission. Patient no. 2, who was treated with ciprofloxacin after symptoms began was never critically ill. CONCLUSION: Neisseria meningitidis sepsis has a high mortality rate. Rapid admission to the hospital and beginning of an antibiotic therapy with penicillin G or a third-generation cephalosporin is a priority when meningococcal disease is suspected. Chemoprophylaxis should be offered to close contacts of patients.

Acute Disease↗