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PubMed1982

Prognostic factors for patients with clinical stage I melanoma of intermediate thickness (1.51 - 3.39 mm). A conceptual model for tumor growth and metastasis.

Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51 - 3.39 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses greater than 6/min 2 (p = 0.0007), 2) location other than the forearm of leg) p = 0.009, 3) ulceration width greater than 3 mm (p = 0.04), 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4 degrees of freedom (p less than 10 (-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses greater than 6/mm 2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration greater than 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses less than or equal to 6/mm 2 and a location on the leg or forearm, or 2) mitoses less than or equal to 6/mm 2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration greater then 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection.

Adult↗

PubMed1999

Preoperative prognostic variables and the impact of postoperative adjuvant therapy on the outcomes of Stage IB or II cervical carcinoma patients with or without pelvic lymph node metastases: an analysis of 891 cases.

BACKGROUND: The purpose of this study was to investigate pretreatment variables that could predict prognosis and to evaluate the impact of postoperative adjuvant therapy on the outcomes of patients with Stage IB or II cervical carcinoma with or without pelvic lymph node metastases. METHODS: Eight hundred ninety-one patients with Stage IB or II cervical carcinoma who underwent radical hysterectomy and bilateral pelvic lymphadenectomy as primary treatment at a single institution were analyzed. Potential prognostic variables were studied. RESULTS: Among the variables that could be assessed before treatment, depth of cervical stromal invasion (determined by magnetic resonance imaging), clinical stage, tumor size, grade of differentiation, and DNA index (determined by flow cytometry) were independent predictors of outcome in multivariate analysis using a Cox regression model. Three distinct prognostic groups (low, intermediate, and high risk) were defined using these variables. Five-year recurrence free survival (RFS) rates for the low, intermediate, and high risk groups were 94.6%, 82.7%, and 62.3%, respectively (P = 0.0001), and overall survival (OS) rates were 98.4%, 84.5%, and 68.7%, respectively (P = 0.0001). Among patients with pelvic lymph node metastases who were free of parametrial extension, those who received postoperative chemotherapy or chemoradiotherapy had significantly better RFS (P = 0.017) and OS (P = 0.043) than those who received no adjuvant therapy. Among patients without pelvic lymph node metastases but at high risk of recurrence, those who received adjuvant radiotherapy had significantly better RFS (P = 0.015) and marginally improved OS (P = 0.087) compared with those who received no adjuvant therapy. CONCLUSIONS: A model containing assessable pretreatment variables for predicting the prognoses of patients with early stage cervical carcinoma was formulated. Subsets of patients for whom postoperative chemotherapy or radiotherapy might be beneficial were identified. The data from this retrospective review may be useful when future prospective trials of the treatment of early stage cervical carcinoma are designed.

Adult↗

PubMed1996

Variability in hepatitis B virus DNA: phylogenetic, epidemiological and clinical implications.

Hepatitis B virus has the smallest of all known human DNA virus genomes (3.2 kb) and a unique replication strategy with an intermediate reverse transcription step. The naturally occurring genetic variability between different HBV strains provides the basis for phylogenetic analysis. Four main genotypes of HBV have been found, with the possible existence of 1 or 2 more. The different genotypes largely follow a distinctive geographical distribution. Point mutations and nucleotide deletions in the genes (pre-S and S) encoding different forms of the surface protein have been shown to arise both spontaneously and after interferon treatment or vaccination. An immune escape mechanism is believed to be the reason for these mutations. The clinical implications of variations in the HBV X gene have not been widely studied, but these variations may be of importance in the development of hepatocellular carcinoma. Seroconversion from HBeAg to anti-HBe can be correlated with specific changes in the core promoter, and/or with a translational stop in precore codon 28. In both cases the production of HBeAg protein would be shut off. Mutations in the precore region may have a larger impact at another level, by inhibiting or enhancing viral replication through changes in folding of the transcript.

DNA, Viral↗

PubMed1983

Lymphocytotoxic antibody is a predictor of response to random donor platelet transfusion.

The transfusion records of 189 patients with acute leukemia were analyzed to correlate lymphocytotoxic antibody (LCTAb) levels with response to a series of random-donor platelet transfusions (Tx). Twenty-one patients were studied twice at times of different LCTAb levels. All transfusions were given when patients were clinically stable without disseminated intravascular coagulation, bleeding, temperature greater than 101 degrees F, or splenomegaly. The mean 1-hr and 24-hr corrected count increments (CCI) for all patients with negative LCTAb were 16,100 and 12,000, and values for patients with positive LCTAb were 5,600 and 2,600 (P less than 0.0005). Thirteen patients had intermediate LCTAb (10-20%) and a variable response to Tx. Of the 137 patients with negative LCTAb levels 106 (77%) had good mean CCI of greater than 10,000 at 1 hr and greater than 7,500 at 24 hr following transfusion. In contrast of 60 patients with positive LCTAb (greater than 20% cytotoxicity), 53 (88%) had poor CCI of less than 10,000 at 1 hr and less than 7,500 at 24 hr after transfusion. Only 4 patients with positive LCTAb had a good response to random donor platelets at both 1 and 24 hrs. Eighteen patients had negative LCTAb with a high 1-hr and low 24-hr CCI. Thirteen of these had a history of positive LCTAb and in 9 there was an anamnestic rise following transfusion. Nine of 137 patients had negative LCTAb with low 1-hr and 24-hr CCI. LCTAb is highly predictive of response to random donor platelets. Cytotoxicity to greater than 20% of tested lymphocytes virtually precludes a good CCI at 1 and 24 hr.

Acute Disease↗

PubMed2003

Catalysis of oxo transfer to prochiral sulfides by oxovanadium(v) compounds that model the active center of haloperoxidases.

The catalytic properties of a new class of chiral vanadium compounds--[(S,S,S)-VO(OMe)L1] (5), [(S,S)-VO(OMe)L2] (6), [(S,S)-VO(OMe)L3] (7), and [(R,R,R)-VO(OMe)L4] (8), as well as the system VO(OiPr)(3)/(R,R,R)-H(2)L4 [H(2)L1=(S,S)-bis(2-hydroxypropyl)-(S)-1-phenylethylamine, 1; H(2)L2=(S,S)-bis(2-hydroxypropyl)benzylamine, 2; H(2)L3=(S,S)-bis(2-hydroxypropyl)isopropylamine), 3; (H(2)L4)=(R,R)-bis(2-phenylethanol)-(R)-1-phenylethylamine, 4]--in the asymmetric oxidation of prochiral sulfides by organic hydroperoxides have been investigated. Particular attention has been paid to the factors that guide the discrimination between the two prochiral faces of the sulfides (methyl p-tolyl sulfide and benzyl phenyl sulfide), to steric implications stemming from the oxidant (cumyl hydroperoxide and tert-butyl hydroperoxide), and to the specific complex used. As an example, (S)-methyl p-tolyl sulfoxide was obtained in a 31 % enantiomeric excess by use of cumyl hydroperoxide as oxidant and complex 5 as the catalyst, after 150 min at 0 degrees C and with 100 % conversion of the sulfide. The crystal and molecular structures of 5 and 6 reveal the close relationship between these complexes and the active center of vanadate-dependent haloperoxidases: the vanadium is in a slightly distorted trigonal-bipyramidal environment with the nitrogen and the methoxy group in the axial positions, and the oxo and alkoxide functions of L2 and L3 are the plane. The presence and equilibrium situation of isomers of the catalysts in solution has been investigated by (51)V EXSY and variable-temperature multinuclear NMR spectroscopy. An intermediately formed peroxo (ROO(-)) vanadium complex was detected by (51)V NMR spectroscopy.

Binding Sites↗

PubMed2002

Urbanization's impact on timber harvesting in the south central United States.

The impact of urbanization on timber harvesting in the south central United States was investigated. Geo-referenced Census and Forest Inventory Analysis (FIA) data were combined using a geographic information system (GIS) in order to examine the effects of various demographic and biophysical forest inventory characteristics on timber harvesting. These effects were estimated for intermediate and final harvests using a multinomial logit model. The probability for both types of harvests decreased with increasing population density, decreasing forest size, and decreasing distance to urban areas; however, the reduction in intermediate harvests was greater for each variable. Harvesting rates decreased by as much as 19% as population densities increased or distance to urban areas decreased. The results indicated that active forest management is curtailed far beyond the urban boundary. In order to model the impact of urbanization adequately, timber supply projections must also account for its impact on harvesting frequencies in surrounding areas.

Cities↗

PubMed1984

A Golgi analysis of unlayered polymicrogyria.

The cytoarchitectonics of the cerebral unlayered polymicrogyria located at the borders of a bilateral porencephalic defect is characterized by minute convolutions not exteriorized by sulci, in which blood vessels and increased numbers of fibrillary astrocytes are present in the fused molecular layers. The cellular organization, based on the analysis of Golgi sections, differs among gyral, intermediate, and sulcal regions and represents variable degree of cellular damage and structural organization of the cerebral mantle injured approximately in gestational month 5. Polymicrogyria may be produced by incomplete ischemia of radial territories vascularized by cortical blood vessels penetrating at right angles from the surface which is the result of the imbalance between the impaired cerebral blood flow of occluded large prerolandic arteries, responsible for the porencephalic defect, and the arterial meningeal anastomoses. Abnormal folding in polymicrogyria may be generated by lateral differences in the cortical thickness of adjoining areas, and by the imbalance in growth rates of laterally contiguous cortical regions.

Cerebral Cortex↗

PubMed1990

Linear calibration of radiographic mineral density using video-digitizing methods.

Radiographic images can provide quantitative as well as qualitative information if they are subjected to densitometric analysis. Using modern video-digitizing techniques, such densitometry can be readily accomplished using relatively inexpensive computer systems. However, such analyses are made more difficult by the fact that the density values read from the radiography have a complex, nonlinear relationship to bone mineral content. This article derives the relationship between these variables from the nature of the intermediate physical processes, and presents a simple mathematical method for obtaining a linear calibration function using a step wedge or other standard.

Animals↗

PubMed2006

Analysis of the utility of diffusion-weighted MRI and apparent diffusion coefficient values in distinguishing central nervous system toxoplasmosis from lymphoma.

INTRODUCTION: Toxoplasmosis and lymphoma are common lesions of the central nervous system in patients with AIDS. It is often difficult to distinguish between these lesions both clinically and radiographically. Previous research has demonstrated restricted diffusion within cerebral lymphomas and bacterial abscesses. However, little work has been done to evaluate the diffusion characteristics of toxoplasmosis lesions. This study was designed to explore further the utility of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps and values in making the distinction between toxoplasmosis and lymphoma. METHODS: The magnetic resonance imaging (MRI) studies of 36 patients, including 22 with toxoplasmosis (all of whom had AIDS) and 14 with lymphoma (8 of whom had AIDS), at two institutions were reviewed retrospectively. The characteristics of the lesions on DWI were evaluated, and the ADC ratios of the lesions were calculated and compared. RESULTS: There was significant overlap of the ADC ratios of toxoplasma and lymphoma, most notably in the intermediate (1.0-1.6) range. There was variability in ADC ratios even among different lesions in the same patient. In only a minority of the lymphoma patients were the ADC ratios low enough to suggest the correct diagnosis. CONCLUSION: Our study showed that toxoplasmosis exhibits a wide spectrum of diffusion characteristics with ADC ratios which have significant overlap with those of lymphoma. Therefore, in the majority of patients, ADC ratios are not definitive in making the distinction between toxoplasmosis and lymphoma.

AIDS-Related Opportunistic Infections↗

PubMed2005

70 Gy or more: which dose for which prostate cancer?

INTRODUCTION: Radical prostatectomy and radiotherapy are currently accepted treatment modalities for localized prostate cancer. Regarding radiotherapy, current evidence suggests that favorable treatment outcome critically depends on adequate radiation doses. However, the exact role of dose in relation to the individual risk profile is complex. In order to evaluate available data on radiation dose response relationships, in prostate cancer, a thorough and critical literature analysis was performed. MATERIAL AND METHODS: Studies on dose response relationships from randomized trials, dose escalation trials, retrospective subgroup analyses and pooled data were identified by Pubmed and ISI web of sciences searches and were critically reviewed. RESULTS AND CONCLUSION: All available data suggest a clear dose response relationship for radiotherapy for localized prostate cancer. In low risk cases, most studies suggest that doses of 70-72 Gy are adequate. Dose escalations up to 78-80 Gy seem to be beneficial for intermediate risk patients. Due to confounding variables, the dose response curves for high-risk patients are less steep. The integration of dose escalation into a more comprehensive treatment protocol is difficult, since trials on the relative impact of either hormonal ablation or inclusion of adjuvant nodal regions on dose escalation are missing.

Clinical Trials as Topic↗

PubMed1992

Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and antifolates.

Two membrane folate receptor (MFR) isoforms are present in human tissues i.e. MFR-1 (e.g. placenta) and MFR-2 (e.g. placenta, KB cells, CaCo-2 cells). MFR-1 was expressed in COS-1 cells and the resulting protein had the same polypeptide molecular weight as the native protein. The affinities of (6S) and (6R) diastereoisomers of N5-methyltetrahydrofolate, N5-formyltetrahydrofolate, and 5,10-dideazatetrahydrofolate as well as folic acid and methotrexate to MFR-1, MFR-2 and placental MFR (MFR-1 plus MFR-2) were determined in terms of the Ki values for their competitive inhibition of the binding of [3H]folic acid to these proteins. The results indicated a striking difference in the stereospecificity of MFR-1 and MFR-2 for reduced folate coenzymes; MFR-2 preferentially bound to the physiological (6S) diastereoisomers and MFR-1 bound preferentially to the unphysiological (6R) diastereoisomers, while dideazatetrahydrofolate did not show significant stereospecificity for MFR-1. Furthermore, MFR-2 displayed significantly (2- to 100-fold) greater affinities for all the compounds tested compared to MFR-1. Purified placental MFR, a natural source of MFR-1 which contains variable amounts of MFR-2, showed intermediate Ki values for the compounds tested compared with MFR-1 and MFR-2 and stereospecificities similar to MFR-1. These observations demonstrate striking differences in the ligand binding sites of MFR-1 and MFR-2 which could potentially be exploited in the design of MFR isoform specific antifolates.

Animals↗

PubMed1994

Intrahepatic peribiliary vascular plexus in various hepatobiliary diseases: a histological survey.

The peribiliary vascular plexus (PVP) plays an important role in the pathophysiology of the biliary tree. We histologically examined vascular endothelial cells of the intrahepatic PVP in various hepatobiliary diseases by immunohistochemistry and lectin histochemistry with antibodies to factor VIII-related antigens (F-VIII-R-Ag) and Ulex europaeus agglutinin I (UEA-I). The PVP around the intrahepatic large bile ducts (LBDs) and septal bile ducts (SBDs) in normal livers consists of three layers: inner layer vessels immediately adjacent to the epithelium, intermediate layer vessels within the ductal wall, and outer layer vessels outside the ductal wall. In some bile ducts that show active inflammation in hepatolithiasis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and extrahepatic biliary obstruction (EBO), vessels in the intermediate layer and, to a lesser degree, in the inner layer, are increased in number. In sclerotic bile ducts of PSC, EBO, and hepatolithiasis, the number of inner and intermediate layer vessels are markedly and variably reduced, respectively. In liver cirrhosis or chronic advanced liver diseases, the vessels in all three layers, particularly those in the outer layer, are increased in number and dilated, probably reflecting intrahepatic microcirculatory disturbance. The PVP showed several types of numerical and luminal changes, each of which may be related to disease processes in the intrahepatic biliary tree as well as to intrahepatic microcirculatory disturbance.

Adult↗

PubMed1988

Prediction of successful suppression of sustained ventricular tachyarrhythmias by serial drug testing from data derived at the initial electrophysiologic study.

This study investigated whether data available after the initial electrophysiologic study in patients with sustained ventricular tachyarrhythmia could identify those patients in whom serial drug testing is likely to be efficacious. One hundred six patients with inducible sustained ventricular tachyarrhythmia, whose initial study included short-term drug testing with intravenous procainamide, were evaluated. The baseline arrhythmia induced (in the absence of all antiarrhythmic drugs) was monomorphic tachycardia with a cycle length greater than 200 ms in 81 patients and ventricular flutter or fibrillation in the remaining 25 patients. After intravenous infusion of procainamide (1,250 +/- 300 mg), a ventricular tachyarrhythmia could still be induced in 80 patients during testing with up to three extrastimuli. Serial drug testing with one to four trials of oral conventional and investigational agents was then undertaken. Evaluation of 15 clinical, hemodynamic and electrophysiologic variables by stepwise logistic regression identified two independent predictors of successful response to oral antiarrhythmic drugs: 1) noninducibility of ventricular tachycardia after intravenous procainamide (p less than 0.001), and 2) left ventricular ejection fraction greater than or equal to 40% (p less than 0.05). Subgroup analysis combining each of these variables identified patients with a high, intermediate or low probability of finding a successful oral drug regimen. Patients whose arrhythmia was suppressed by intravenous procainamide had a 100% likelihood (if left ventricular ejection fraction was greater than or equal to 40%) or an 87% likelihood (if ejection fraction was less than 40%) of responding to an oral regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

NMR analysis of the conformational properties of the trapped on-pathway folding intermediate of the bacterial immunity protein Im7.

Previous work shows that the transiently populated, on-pathway intermediate in Im7 folding contains three of the four native alpha-helices docked around a core stabilised by native and non-native interactions. To determine the structure and dynamic properties of this species in more detail, we have used protein engineering to trap the intermediate at equilibrium and analysed the resulting proteins using NMR spectroscopy and small angle X-ray scattering. Four variants were created. In L53AI54A, two hydrophobic residues within helix III are truncated, preventing helix III from docking stably onto the developing hydrophobic core. In two other variants, the six residues encompassing the native helix III were replaced with three (H3G3) or six (H3G6) glycine residues. In the fourth variant, YY, two native tyrosine residues (Tyr55 and Tyr56) were re-introduced into H3G6 to examine their role in determining the properties of the intermediate ensemble. All four variants show variable peak intensities and broad peak widths, consistent with these proteins being conformationally dynamic. Chemical shift analyses demonstrated that L53AI54A and YY contain native-like secondary structure in helices I and IV, while helix II is partly formed and helix III is absent. Lack of NOEs and rapid NH exchange for L53AI54A, combined with detailed analysis of the backbone dynamics, indicated that the hydrophobic core of this variant is not uniquely structured, but fluctuates on the NMR timescale. The results demonstrate that though much of the native-like secondary structure of Im7 is present in the variants, their hydrophobic cores remain relatively fluid. The comparison of H3G3/H3G6 and L53AI54A/YY suggests that Tyr55 and/or Tyr56 interact with the three-helix core, leading other residues in this region of the protein to dock with the core as folding progresses. In this respect, the three-helix bundle acts as a template for formation of helix III and the creation of the native fold.

Amino Acid Sequence↗

PubMed1998

Rationale for use of non-high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy.

The plasma level of low-density lipoprotein (LDL) cholesterol is the "gold standard" for estimating the lipoprotein-related risk for complications of atherosclerotic vascular disease. LDL cholesterol concentrations are commonly estimated by the Friedewald formula that requires only the measurement (after overnight fasting) of plasma cholesterol and triglycerides along with high-density lipoprotein (HDL) cholesterol. This value, however, is not in fact a true estimate of LDL cholesterol but rather of LDL cholesterol along with variable, usually smaller, amounts of intermediate-density lipoprotein (IDL) cholesterol and lipoprotein(a). Estimation of LDL cholesterol levels by the Friedewald formula becomes progressively less accurate as plasma triglyceride concentrations increase, and the formula is generally considered inapplicable when triglyceride levels exceed 400 mg/dL. We believe that a very simple measurement-non-HDL cholesterol (serum cholesterol minus HDL cholesterol)-has considerable potential as a screening tool for identifying dyslipoproteinemias, for risk assessment, and for assessing the results of hypolipidemic therapy. Unlike the estimation of LDL cholesterol levels by the Friedewald formula, the estimation of non-HDL cholesterol concentrations requires no assumptions about the relation of very-low-density (VLDL) cholesterol levels to plasma triglyceride concentrations. This method includes all of the cholesterol present in lipoprotein particles now considered to be potentially atherogenic [VLDL, IDL, LDL, and lipoprotein(a)]. This article provides examples of the utility of non-HDL cholesterol concentrations in clinical medicine.

Apolipoproteins B↗

PubMed1984

The pursuit of a total data processing system free of language and programming.

The interactive system FLXFL has been reconstructed as a versatile tool for data analysis. The system now allows the user to carry out such step-by-step analysis as multivariate analysis, converting input data, changing the combination of variables, or making use of the intermediate result, all in an interactive mode. Another new feature is the interactive form designing facility for record output. This unique function provides flexibility in the output style without forcing laborious programming work on the user. Retaining the principle of operational simplicity, all the processes are consistently carried out based on menu-selection. The system has processed as many as 50,000 records in the past, and currently it runs at three clinical institutions. Through experience with FLXFL, it is concluded that in the medical environment the simplicity of the menu-based operation fully offsets the restrictions imposed.

Computers↗

PubMed1980

Holocarboxylase synthetase deficiency: a biotin-responsive organic acidemia.

The clinical and biochemical features of an infant affected by holocarboxylase synthetase deficiency are presented. The patient was the sibling of the deceased child in whose cultured skin fibroblasts the precise enzymatic disorder was first determined. This fact permitted administration of specific therapy in the form of oral biotin, resulting in immediate improvement from impending respiratory failure and shock. The clinical response to biotin was accompanied by recovery of the biochemical mechanisms known to be biotin-dependent, as manifested by disappearance of intermediates in urine and blood. The variability of biotin responsiveness and the diversity of clinical presentation in the patients originally thought to have a deficiency of beta methylcrotonylCoA carboxylase, a biotin-dependent enzyme, raises the question of a separate, specific apocarboxylase defect.

Amino Acid Metabolism, Inborn Errors↗

PubMed1988

A self-organized chemical model and reaction cascade.

Some reaction cascades in biological systems are analyzed by a self-organized chemical model, an autocatalytic reaction. This model is described by the coupling of a primary system which stabilizes the initial stage of the reaction rapidly and a partial system which controls the primary system slowly. By the internal force caused by a trigger above the threshold, the coupled system in near-equilibrium is broken and changed into a new state. From the rate equation for the coupled system, a dimensionless nonlinear state equation, n = -n3 - un - v, is derived, where n is the concentration of intermediate, and u, v are dynamic variables of the system. This equation is similar to a nonequilibrium tri-molecular reaction. By using this chemical network theory, fibrin polymerization. F + F----fm----fp + X, where F is a fibrinogen molecule, fm is a fibrin monomer, fp is fibrin polymer, and X is small peptides released from fibrinogen, is discussed as an excellent example of the enzyme reaction cascade.

Blood Coagulation↗