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At least 865 records · Page 48Linked to original sources
PubMed2000

The effect of tamoxifen and cisplatin on the disease-free and overall survival of patients with high risk malignant melanoma.

The adjuvant treatment of high-risk malignant melanoma remains problematic. Previously we reported moderate success in the treatment of metastatic disease using tamoxifen, cisplatin, dacarbazine and carmustine. Based upon data that suggested tamoxifen and cisplatin were the active agents in this regimen, we initiated a phase II trial of this combination in the adjuvant setting. We treated 153 patients with 4 cycles of tamoxifen (160 mg day(-1), days 1-7) and cisplatin (100 mg m(-2), day 2) for 28-day intervals. Patients received an anti-nausea regimen of dexamethasone with ondansetron or granisetron. During the first 2 years of follow-up, patients were evaluated every 2 months with a history, physical exam, laboratory work and computed tomography scans of the chest, abdomen and pelvis every 4 months. Thereafter, patients were evaluated every 3 months and radiographic studies were performed if necessary. Currently, with a median follow-up of 36 months, the disease-free survival (DFS) is 68.4% and overall survival (OS) is 84.5%. Kaplan-Meier analysis predicts a 5-year DFS of 62% with an OS of 79%. Relapses after 20 months have been rare. No effect of gender or number of positive lymph nodes was noted, however, stage of disease prior treatment was a factor. The major toxicity proved to be gastrointestinal in nature with nausea the most prevalent symptom. Minimal renal, haematologic and neurologic toxicity occurred. These preliminary results suggest that there is a positive impact of tamoxifen and cisplatin on both the DFS and OS of high-risk malignant melanoma patients. The 5-year projected DFS and OS compare favourably with those reported for the ECOG 1684 trial and warrant confirmation in a prospective randomized trial.

Adult↗
PubMed1975

[The use of the brief psychiatric rating scale (BPRS) by overall and gorham for the diagnosis of acute paranoid psychoses: evaluation of a german translation of the BPRS (author's transl)].

A German translation of Overall and Gorham's "Brief Psychiatric Rating Scale" (BPRS) has been used to select patients with acute paranoid psychoses for a drug trial and to evaluate the results of the treatment. The BPRS proved very useful in screening, and as a reliable method to judge the global therapeutic outcome. The total score showed a high degree of interrater reliability; it also reflected a marked decrease of psychopathological symptoms at the end of the trial. Interrater correlation coefficients were lower than 0.7 in 9/16 items. This may be due to the somewhat unprecise and ambigous formulation of several items. The average BPRS profile of patients with "paranoid-hallucinatory schizophrenia" were similar to those published by French authors for the corresponding diagnosis.

Acute Disease↗
PubMed1982

Determination of overall insulin sensitivity in diabetic mice, KK.

A convenient methods for determining the overall insulin sensitivity of small animals was established based on the steady state plasma glucose (SSPG) concentration methods of Shen, Reaven and Farguhar (1970). Subcutaneous injection into C57BL/6 mice of saline containing epinephrine, propranolol, glucose and (3H-3)glucose with or without insulin gave steady state levels of blood glucose (SSBG), plasma insulin (SSPI) and specific activity of blood glucose (SSBG), plasma insulin (SSPI) and specific activity of blood glucose after 45 minutes. Glucose turnover (GTN) and hepatic glucose output (HGO) were computed using specific activity of blood glucose and the influx rate of injected glucose. The method was applied to diabetic and insulin resistant mice, KK. There was no difference in GTN and HGO between KK and C57BL/6 mice regardless of whether insulin was injected or not. SSPI of both strains increased in the same injected or not, SSPI of both strains increased in the same injected or not. SSPI of both strains increased in the same fashion in response to increasing doses of the hormone. SSBG of both strains fell in response to increasing SSPI level, but the response of SSBG was less prominent in KK mice. Consequently, the insulin dose-response curve of SSBG apparently shifted rightwards in KK mice.

3-O-Methylglucose↗
PubMed1994

[Uncertainties in preliminary calculations of overall treatment costs with special reference to costs of medical risk].

This paper explains the problems in calculating global compensation for medical treatment from the physician's point of view. This new system of financing hospitals will be introduced in Germany in 1996. In routine procedures such as tonsillectomy, the costs for complications are not sufficiently included in the price calculation. Basing on "postoperative bleeding after tonsillectomy" as an example, we calculated the costs of this complication per year. A scheme for calculating these costs as well as the costs for concomitant diseases for each case is presented. Evidently the overall price does not include substantial costs, and hence foreseeable losses are inevitable.

Cost Control↗
PubMedDate not supplied

[Psychosocial care in the overall therapeutic concept of the management of children with chronic kidney diseases].

In terms of physical health, degree of rehabilitation and the personal assessment of the affected patients, kidney transplantation represents the optimal therapy for children with chronic renal insufficiency. The best results are achieved by transferring organs from relatives. However, this can only be accomplished if medical treatment is accompanied and supported by continuous psychosocial care of the patient, the family and the treatment team. The problem of noncompliance requires special attention, since it may be the reason for rejection of transplants; it can, however, be recognized by preliminary preventive investigations and prevented by appropriate therapy. Our positive overall experience concerning parenthood following kidney transplants does not appear to justify dissuading such patients from having children if they so wish. However, we consider that especially young women who already have impaired function with a transplanted kidney should be advised of the risk of further deterioration during pregnancy, and that the possibility of reduced life expectancy should be discussed with these patients as a matter of urgency.

Adolescent↗
PubMed2002

Choice of clinical outcomes in randomized trials of heart failure therapies: disease-specific or overall outcomes?

BACKGROUND: There are different views regarding the appropriateness of using cause-specific events or all events as the primary outcome of clinical trials. METHODS: This is a methodologic essay in which we discuss the pros and cons of the 2 approaches and provide illustrative examples. RESULTS: Our preference is the use of cause-specific outcomes (as long as they can be classified with reasonable reproducibility and without bias) because they are more likely to be sensitive to change, less likely to lead to spurious conclusions by random variations in categories of outcomes that are unlikely to be affected by treatment, and relatively free from confounding. Overall benefit-risk ratios can be derived by examining the impact of treatment on various categories of outcomes and then developing a general judgment. Such an approach will also allow judgments to be made regarding generalizability of results across various groups of patients who are at differing risks for an event. CONCLUSIONS: In general, cause-specific outcomes sensitive to the effects of a treatment are to be preferred as the principal outcome in trials of heart failure, as long as they are biologically sensible and can be classified without bias. Other outcomes, not expected to be affected, should also be reported separately.

Bias↗
PubMed2005

DNA lesions induced by UV A1 and B radiation in human cells: comparative analyses in the overall genome and in the p53 tumor suppressor gene.

The UV components of sunlight (UVA and UVB) are implicated in the etiology of human skin cancer. The underlying mechanism of action for UVB carcinogenicity is well defined; however, the mechanistic involvement of UVA in carcinogenesis is not fully delineated. We investigated the genotoxicity of UVA1 versus UVB in the overall genome and in the p53 tumor suppressor gene in normal human skin fibroblasts. Immuno-dot blot analysis identified the cis-syn cyclobutane pyrimidine-dimer (CPD) as a distinctive UVB-induced lesion and confirmed its formation in the genomic DNA of UVA1-irradiated cells dependent on radiation dose. HPLC/tandem MS analysis showed an induction of 8-oxo-7,8-dihydro-2'-deoxyguanosine in the genomic DNA of UVA1-irradiated cells only. Mapping of DNA damages by terminal transferase-dependent PCR revealed preferential, but not identical, formation of polymerase-blocking lesions and/or strand breaks along exons 5-8 of the p53 gene in UVB- and UVA1-irradiated cells. The UVB-induced lesions detected by terminal transferase-PCR were almost exclusively mapped to pyrimidine-rich sequences; however, the UVA1-induced lesions were mapped to purine- and pyrimidine-containing sequences along the p53 gene. Cleavage assays with lesion-specific DNA repair enzymes coupled to ligation-mediated PCR showed preferential, but not identical, formation of CPDs along the p53 gene in UVB- and UVA1-irradiated cells. Additionally, dose-dependent formation of oxidized and ring-opened purines and abasic sites was established in the p53 gene in only UVA1-irradiated cells. We conclude that UVA1 induces promutagenic CPDs and oxidative DNA damage at both the genomic and nucleotide resolution level in normal human skin fibroblasts.

Cells, Cultured↗
PubMed2005

Evaluation of the functional diffusion map as an early biomarker of time-to-progression and overall survival in high-grade glioma.

Diffuse malignant gliomas, the most common type of brain tumor, carry a dire prognosis and are poorly responsive to initial treatment. The response to treatment is typically evaluated by measurements obtained from radiographic images several months after the start of treatment; therefore, an early biomarker of tumor response would be useful for making early treatment decisions and for prognostic information. Thirty-four patients with malignant glioma were examined by diffusion MRI before treatment and 3 weeks later. These images were coregistered, and differences in tumor-water diffusion values were calculated as functional diffusion maps (fDM), which were correlated with the radiographic response, time-to-progression (TTP), and overall survival (OS). Changes in fDM at 3 weeks were closely associated with the radiographic response at 10 weeks. The percentage of the tumor undergoing a significant change in the diffusion of water (V(T)) was different between patients with progressive disease (PD) vs. stable disease (SD) (P < 0.001). Patients classified as PD by fDM analysis at 3 weeks were found to have a shorter TTP compared with SD (median TTP, 4.3 vs. 7.3 months; P < 0.04). By using fDM, early patient stratification also was correlated with shorter OS in the PD group compared with SD patients (median survival, 8.0 vs. 18.2 months; P < 0.01). On the basis of fDM, tumor assessment provided an early biomarker for response, TTP, and OS in patients with malignant glioma. Further evaluation of this technique is warranted to determine whether it may be useful in the individualization of treatment or evaluation of the response in clinical protocols.

Adult↗
PubMed2003

SPARC-null mice exhibit increased adiposity without significant differences in overall body weight.

Secreted protein acidic and rich in cysteine/osteonectin/BM-40 (SPARC) is a matrix-associated protein that elicits changes in cell shape, inhibits cell-cycle progression, and influences the synthesis of extracellular matrix (ECM). The absence of SPARC in mice gives rise to aberrations in the structure and composition of the ECM that result in generation of cataracts, development of severe osteopenia, and accelerated closure of dermal wounds. In this report we show that SPARC-null mice have greater deposits of s.c. fat and larger epididymal fat pads in comparison with wild-type mice. Similar to earlier studies of SPARC-null dermis, we observed a reduction in collagen I in SPARC-null fat pads in comparison with wild-type. Although elevated levels of serum leptin were observed in SPARC-null mice, their overall body weights were not significantly different from those of wild-type counterparts. The diameters of adipocytes from SPARC-null versus wild-type epididymal fat pads were 252 +/- 61 and 161 +/- 33 microm (means +/- SD), respectively, and there was an increase in adipocyte number within SPARC-null fat pads in comparison with wild-type pads. Thus the absence of SPARC appears to result in an increase in the size of individual adipocytes as well as an increase in the number of adipocytes per fat pad. In fat pads isolated from wild-type mice, SPARC mRNA was associated with both the stromal/vascular and adipocyte fractions. We propose that SPARC limits the accumulation of adipose tissue in mice in part through its demonstrated effects on the regulation of cell shape and production of ECM.

Adipose Tissue↗
PubMed1980

Simian virus 40 and polyoma virus stimulate overall cellular RNA and protein synthesis.

In lytic infection with simian virus 40 and polyoma virus of monkey and mouse cells in tissue culture, synthesis of the viral tumor (T) antigens (T antigens) is rapidly followed by a mitogenic response of the host cell. The latter begins with virus-induced stimulation of overall cellular RNA and protein synthesis, leading to a substantial increase in cytoplasmic and nuclear RNA and protein. Stimulation begins within 1 hr after onset of T-antigen synthesis and also occurs if virus-induced DNA synthesis is blocked by metabolic inhibitors. The broad spectrum of biological and molecular effects induced by simian virus 40 and polyoma virus is, at least phenotypically, reminescent of the pleiotropic impact exerted on target cells by nonviral mitogens and by certain growth-promoting steroid and polypeptide hormones.

Antigens, Neoplasm↗
PubMed1990

Changing the invariant proline-30 of rat and Drosophila melanogaster cytochromes c to alanine or valine destabilizes the heme crevice more than the overall conformation.

Drosophila melanogaster and rat cytochromes c in which proline-30 was converted to alanine or valine were expressed in a strain of baker's yeast, Saccharomyces cerevisiae, where they sustained aerobic growth. The mutations had no significant effect on the spectra or redox potentials but altered drastically the stability of the bond between the methionine-80 sulfur and the heme iron, as judged by four criteria: (i) the alkaline pKa values of the 695-nm band of the ferric form of the mutant proteins decreased by almost 1 pH unit as compared to the wild types; (ii) the acid pKa values increased by 0.5 to 1.2 pH units; (iii) the 695-nm band half-disappeared at temperatures 10-20 degrees C lower in the mutant proteins than in the wild types; and (iv) the 695-nm band of the mutant proteins was susceptible to concentrations of urea that had little influence on their overall structure. The valine-substituted rat cytochrome c had properties intermediate between those of the wild type and the alanine mutant. The destabilized coordinative bond is located in space a long distance from the mutation site. It is suggested that the mutations weaken the hydrogen bond between the carbonyl of residue 30 and the imino group of the imidazole of histidine-18, modifying the bonding of the heme iron by that imidazole, which, in turn, through a trans effect, weakens the bond between the heme iron and the other axial ligand, the sulfur of methionine-80. Alternatively, the effect of the mutations may be propagated allosterically along the peptide chain.

Alanine↗
PubMed1991

Structural similarities in glutaminyl- and methionyl-tRNA synthetases suggest a common overall orientation of tRNA binding.

Detailed comparisons between the structures of the tRNA-bound Escherichia coli glutaminyl-tRNA (Gln-tRNA) synthetase [L-glutamine:tRNA(Gln) ligase (AMP-forming), EC 6.1.1.18] and recently refined E. coli methionyl-tRNA (Met-tRNA) synthetase [L-methionine:tRNA(Met) ligase (AMP-forming), EC 6.1.1.10] reveal significant similarities beyond the anticipated correspondence of their respective dinucleotide-fold domains. One similarity comprises a 23-amino acid alpha-helix-turn-beta-strand motif found in each enzyme within a domain that is inserted between the two halves of the dinucleotide binding fold. A second correspondence, which consists of two alpha-helices connected by a large loop and beta-strand, is located in the Gln-tRNA synthetase within a region that binds the inside corner of the "L"-shaped tRNA molecule. This structural motif contains a long alpha-helix, which extends along the entire length of the D and anticodon stems of the complexed tRNA. We suggest that the positioning of this helix relative to the dinucleotide fold plays a critical role in ensuring the proper global orientation of tRNA(Gln) on the surface of the enzyme. The structural correspondences suggest a similar overall orientation of binding of tRNA(Met) and tRNA(Gln) to their respective synthetases.

Amino Acyl-tRNA Synthetases↗
PubMed1995

Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity.

Affinity maturation of IgG antibodies in adaptive immune responses is a well-accepted mechanism to improve effector functions of IgG within 2 weeks to several months of antigen encounter. This concept has been defined mainly for IgG responses against chemically defined haptens. We have evaluated this concept in a viral system and analyzed neutralizing IgG antibody responses against vesicular stomatitis virus (a close relative of rabies virus) with a panel of monoclonal antibodies obtained early (day 6 or 12) and late (day 150) after hyperimmunization. These neutralizing IgG antibodies recognize a single major antigenic site with high affinities (Ka of 10(8)-10(10) liter.mol-1) and with rapid on-rates already on day 6 of a primary response and with no evidence for further antigen dose- and time-dependent overall improvement of affinity. This type of IgG response is probably representative for viruses or bacterial toxins which are crucially controlled by neutralizing antibodies.

Animals↗
PubMed1995

Effects of overall oxidation state on infrared spectra of heme a3 cyanide in bovine heart cytochrome c oxidase. Evidence of novel mechanistic roles for CuB.

Effects of changes in oxidation state at the other metal centers on oxidized heme a3 cyanide of bovine heart cytochrome c oxidase have been investigated. Only one CN- binds, giving Fe3+a3CN, in fully-oxidized cytochrome c oxidase and its 1-, 2-, and 3-electron reduction products. Soret/visible spectra for the heme a3 cyanide are independent of overall redox level, whereas distinct shifts in C-N infrared stretch band frequency occur upon reduction, reflecting changes in the polarity of the ligand (CN-) environment. Catalysis of O2 reduction can be critically dependent upon such changes in polarity at the reduction site. These findings indicate that CuB, when reduced, exists in two forms whose relative stabilities are independent of Fea and CuA oxidation states and, when oxidized, is in only one stable form. These results are consistent with the oxidation of Cu+B triggering proton pumping and with the involvement of a CuB ligand in respiratory control. Electron equivalents introduced into the enzyme are distributed equally among Fea, CuA, and CuB, which raises the possibility that all four electrons used in O2 reduction are donated via Cu+B, which is favorably positioned with respect to Fea3 (the O2 binding site) in order to carry out this role in electron transfers.

Animals↗
PubMed2001

The overall conformation of conventional kinesins studied by small angle X-ray and neutron scattering.

The quaternary structures of several monomeric and dimeric kinesin constructs from Homo sapiens and Drosophila melanogaster were analyzed using small angle x-ray and neutron scattering. The experimental scattering curves of these proteins were compared with simulated scattering curves calculated from available crystallographic coordinates. These comparisons indicate that the overall conformations of the solution structures of D. melanogaster and H. sapiens kinesin heavy chain dimers are compatible with the crystal structure of dimeric kinesin from Rattus norvegicus. This suggests that the unusual asymmetric conformation of dimeric kinesin in the microtubule-independent ADP state is likely to be a general feature of the kinesin heavy chain subfamily. An intermediate length Drosophila construct (365 residues) is mostly monomeric at low protein concentration whereas at higher concentrations it is dimeric with a tendency to form higher oligomers.

Amino Acid Sequence↗
PubMed2005

Nitrile pathway involving acyl-CoA synthetase: overall metabolic gene organization and purification and characterization of the enzyme.

Two open reading frames (nhpS and acsA) were identified immediately downstream of the previously described Pseudomonas chlororaphis B23 nitrile hydratase (NHase) gene cluster (encoding aldoxime dehydratase, amidase, the two NHase subunits, and an uncharacterized protein). The amino acid sequence deduced from acsA shows similarity to that of acyl-CoA synthetase (AcsA). The acsA gene product expressed in Escherichia coli showed acyl-CoA synthetase activity toward butyric acid and CoA as substrates, with butyryl-CoA being synthesized. From the E. coli transformant, AcsA was purified to homogeneity and characterized. The quality of the recombinant protein was verified by the NH2-terminal amino acid sequence and the results of matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The apparent Km values for butyric acid, CoA, and ATP were 0.32 +/- 0.04, 0.37 +/- 0.02, and 0.22 +/- 0.02 mm, respectively. AcsA was shown to be a short-chain acyl-CoA synthetase, according to the catalytic efficiencies (kcat/Km) for various acids. The substrate specificity of AcsA was similar to those of aldoxime dehydratase, NHase, and amidase, the genes of which coexist in the same orientation in the gene cluster. P. chlororaphis B23 grew when cultured in a medium containing butyraldoxime as the sole carbon and nitrogen source. The activities of aldoxime dehydratase, NHase, and amidase were detected together with that of acyl-CoA synthetase under the culture conditions used. Moreover, on culture in a medium containing butyric acid as the sole carbon source, acyl-CoA synthetase activity was also detected. Together with the adjacent locations of the aldoxime dehydratase, NHase, amidase, and acyl-CoA synthetase genes, these findings suggest that the four enzymes are sequentially correlated with one another in vivo to utilize butyraldoxime as a carbon and nitrogen source. This is the first report of an overall "nitrile pathway" (aldoxime-->nitrile-->amide-->acid-->acyl-CoA) comprising these enzymes.

Base Sequence↗
PubMed2006

The importance of the strictly conserved, C-terminal glycine residue in phosphoenolpyruvate carboxylase for overall catalysis: mutagenesis and truncation of GLY-961 in the sorghum C4 leaf isoform.

Phosphoenolpyruvate carboxylase (PEPC) is a "multifaceted," allosteric enzyme involved in C4 acid metabolism in green plants/microalgae and prokaryotes. Before the elucidation of the three-dimensional structures of maize C4 leaf and Escherichia coli PEPC, our truncation analysis of the sorghum C4 homologue revealed important roles for the enzyme's C-terminal alpha-helix and its appended QNTG961 tetrapeptide in polypeptide stability and overall catalysis, respectively. Collectively, these functional and structural observations implicate the importance of the PEPC C-terminal tetrapeptide for both catalysis and negative allosteric regulation. We have now more finely dissected this element of PEPC structure-function by modification of the absolutely conserved C-terminal glycine of the sorghum C4 isoform by site-specific mutagenesis (G961(A/V/D)) and truncation (DeltaC1/C4). Although the C4 polypeptide failed to accumulate in a PEPC- strain (XH11) of E. coli transformed with the Asp mutant, the other variants were produced at wild-type levels. Although neither of these four mutants displayed an apparent destabilization of the purified PEPC homotetramer, all were compromised catalytically in vivo and in vitro. Functional complementation of XH11 cells under selective growth conditions was restricted progressively by the Ala, DeltaC1 and Val, and DeltaC4 modifications. Likewise, steady-state kinetic analysis of the purified mutant enzymes revealed corresponding negative trends in kcat and kcat/K0.5 (phosphoenolpyruvate) but not in K0.5 or the Hill coefficient. Homology modeling of these sorghum C-terminal variants against the structure of the closely related maize C4 isoform predicted perturbations in active-site molecular cavities and/or ion-pairing with essential, invariant Arg-638. These collective observations reveal that even a modest, neutral alteration of the PEPC C-terminal hydrogen atom side chain is detrimental to enzyme function.

Allosteric Site↗
PubMed1998

Central, local, and overall ratings of perceived exertion during cycling and running by women with an external or internal locus of control.

Much research has been directed toward finding the most prominent psychological factors affecting ratings of perceived exertion during physical exercise. The one most frequently mentioned, although rarely investigated empirically, is locus of control. Findings from non-sport-related research indicate that individuals with an internal locus of control (internals) are better at using the available information than individuals with an external locus of control (externals). That finding has been attributed to the inferior information-processing capacity of the latter group, a deficit that might also affect the processing of exertional cues during physical exercise. In the present study, a group of women categorized as internals were compared with a similar group of externals during both ergometer cycling and treadmill running. The results indicated significantly different ratings between the groups not only for overall perceived exertion but also for local (muscles and joints) and central (cardiopulmonary) exertion. The observed differences were greater during ergometer cycling than during treadmill running. It is possible that the more distinct cues available during cycling, stemming mainly from the working muscles (local factors), presented more information to process, a task that the internals were better at than the externals.

Adult↗