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PubMed1989

Computer-assisted evaluation of polydisperse two-dimensional gel patterns of polysaccharide-protein conjugate preparations with regard to size and net charge.

Native Hemophilus influenzae polysaccharide-protein conjugate particles were analyzed by a two-dimensional agarose electrophoresis procedure. In view of their preparation by random chemical crosslinking, the conjugates necessarily exhibit a polydisperse two-dimensional gel pattern which varies depending on the conditions of the particular preparation. The polydisperse patterns were interpreted with regard to the size and surface net charge density of the conjugate on the basis of the extended Ogston model. Data processing was performed by a new program, designated ZWEIDI.DO, written in the language of M-LAB (modeling laboratory). The program computes particle and gel fiber specific parameters from the positions of standards and unknown(s) on the two-dimensional gel using a simultaneous linear least-square curve fitting routine. Based on these calculations, the program serves to compute a nomogram of iso-size and iso-free-mobility profiles. Superimposing these profiles on the gel patterns, the size and free mobility range of the polydisperse conjugate mixtures is obtained. Potentially, the procedure could serve as a tool for quality control in the production of conjugates as vaccines and for the physical characterization of polydisperse subcellular particles and vesicles.

Bacterial Proteins↗
PubMed1985

A new dosing regimen in renal insufficiency: application to cephalexin.

We describe a new method of drug dosage adjustment. The method simultaneously considers glomerular and tubular functions as parameters, because nonparallel decreases in both functions limit the use of the conventional endogenous creatinine clearance (CLCR) method for dosage adjustment. In the new method, CLCR and the 15-minute phenolsulfonphthalein (PSP15') test were used and applied to patients with renal insufficiency with cephalexin (CEX) as a model drug for renal tubular secretion. The results clearly demonstrate good control of plasma CEX concentrations by the CLCR-PSP15' method, whereas there were marked changes in plasma CEX levels with the CLCR method alone. Our method appears to be more useful for patients with renal impairment than the conventional CLCR method for CEX, which is mainly excreted in urine by renal tubular secretion. A nomogram for the CEX dosing interval is proposed for application to clinical practice.

Absorption↗
PubMed2000

Population pharmacokinetics of tobramycin in hospitalized patients receiving once-daily dosing regimen.

The population pharmacokinetics of tobramycin was investigated in a group of 327 adult hospitalized patients receiving once-daily administration of tobramycin at a dose of 7 mg kg(-1). The patients had an average age of 57+/-18 y and an average weight of 65+/-14 kg; 153 of the patients were female. Data, comprised of 575 serum concentrations, were analyzed using a nonlinear mixed-effect model (NONMEM) with a first-order conditional estimation method and were best described with a one-compartment model. The patient covariates including body weight, gender, age and creatinine clearance (CL(CR)) were added in a stepwise fashion to identify their potential influences on tobramycin pharmacokinetics. Results showed that tobramycin clearance (CL) was linearly correlated with CL(CR) (proportionality constant: 0.066+/-0.002 x CL(CR) (ml min(-1))) and the volume of distribution (Vd) was linearly related to body weight (proportionality constant: 0.40+/-0.024 x body weight (1 kg(-1))). The mean population estimates for CL and Vd were 4.53 l h(-1) and 27.3 l, respectively. The half-life of tobramycin was estimated to be 4.2 h. The inter-individual variability in CL and Vd were 37.0 and 28.5%, respectively. The residual error was 1.2 mg l(-1). Based on the results, optimal dosing intervals for renal impaired patients were calculated and were comparable with the intervals derived from the previous established nomogram.

Adolescent↗
PubMed1975

Digoxin pharmacokinetics: role of renal failure in dosage regimen design.

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2-compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady-state volumes of distribution (V-ss-D equals 195 to 489 liters/1.73 m-minus2) and t1/2beta values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant V-ss-D and a rigorous relationship between t1/2beta and creatinine clearance (Cl-CR). Body clearance (Cl-B) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between Cl-B and renal clearance of digoxin or Cl-CR was found and was used to develop a model-independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady-state serum concentrations of digoxin (C-ss-p) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of C-ss-p is obtained by use of digoxin renal and body clearances. Variability in the digoxin:creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.

Adult↗
PubMed2026

Stratifying lung adenocarcinoma: a novel prognostic model based on mitochondrial outer membrane permeabilization activity.

UNLABELLED: Mitochondrial outer membrane permeabilization (MOMP) is a core apoptotic regulatory event that dictates mitochondrial integrity, where full activation drives cell death and sublethal dysregulation contributes to tumor genomic instability. We used the Cancer Genome Atlas lung adenocarcinoma cohort (TCGA-LUAD) as the training cohort and the Gene Expression Omnibus dataset GSE42127 as the validation cohort to identify prognostic genes related to MOMP activity in lung adenocarcinoma (LUAD) and to evaluate their potential biological significance. By intersecting MOMP-related genes with differentially expressed genes, combined with survival analysis, Mendelian randomization analysis, and 101 machine-learning algorithm combinations, seven prognostic genes, namely BIRC5, PSMD11, TNFRSF13C, YWHAZ, YWHAG, CYCS, and LTB, were identified. Next, an optimal prognostic model was constructed based on the gradient boosting machine (GBM) algorithm. Based on the risk score, LUAD patients were stratified into high- and low-risk groups, and patients in the high-risk group exhibited poorer overall survival in both the training and validation cohorts. Furthermore, a nomogram integrating the risk score and clinicopathological factors was developed and showed favorable predictive performance for 1-, 3-, and 5-year survival. Meanwhile, functional and immune analyses revealed that the high-risk group was enriched in DNA replication-related pathways and demonstrated a higher tumor mutation burden (TMB). Correlation analysis indicated that TNFRSF13C was positively correlated with activated B cells, whereas BIRC5 was negatively correlated with eosinophils, suggesting that MOMP-related genes might be involved in remodeling the immune microenvironment of LUAD. Drug sensitivity analysis showed differences in predicted half-maximal inhibitory concentration (IC50) values between the risk groups, suggesting the potential value of this model in assisting therapeutic stratification. Single-cell RNA sequencing (scRNA-seq) further identified T lymphocytes as a key cell type, with numerous prognostic genes exhibiting differential expression in T cells or dynamic changes during differentiation. We suggest that the MOMP-related signature established in this study may provide a reference for prognostic stratification in LUAD and offers candidate prognostic genes for subsequent experimental and clinical validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05058-6.

Lung adenocarcinoma↗
PubMed1997

Doppler echocardiographic reference values for healthy rhesus monkeys under ketamine hydrochloride sedation.

Cardiac ultrasound is a noninvasive technique that is commonly used to serially evaluate cardiac structure and function. Recent advances in Doppler-Echocardiography enable the ultrasonographer to perform a sophisticated noninvasive assessment of cardiovascular physiology. The Rhesus monkey is a frequently used non-human primate animal model of human cardiovascular disease because this species closely models human anatomy and physiology. However, while this species is frequently used in cardiovascular research, standardized echocardiographic values generated from large numbers of normal Rhesus are not available. In the present study, we performed cardiac ultrasound imaging on 28 healthy Rhesus monkeys to obtain normal reference values of cardiovascular structure and function in this species. Nomograms were generated from these data by plotting parameters of cardiovascular geometry and function with body weight. These normal reference data were compared to previously reported values obtained from prior studies that used noninvasive, invasive, and morphometric techniques.

Anesthetics, Dissociative↗
PubMed1977

Clinical evaluation of high-frequency positive-pressure ventilation (HFPPV) in laryngoscoy under general anaesthesia.

A technique for automatic ventilation during laryngoscopy under general anaesthesia was evaluated in a lung model and in 5 patients (3--57 y) submitted for routine laryngoscopy. this technique has been given the name laryngoscopic HFPPV and utilizes an insufflation frequency (f) of 60 per min and a relative insufflation time (t%) of 22%. Ventilation is given via a nasotracheal insufflation catheter. Laryngoscopic HFPPV permits laryngeal surgery with a virtually unobstructed surgical field under complete muscular relaxation. The alveolar ventilation of the patient may be controlled by adjustment of the pressure of the anaesthetic gas mixture and there is no air entrainment through the larynx during insufflation. This makes possible use of O2/N2O mixtures and the oxygenation of the patient may be controlled by adjustment of the oxygen concentration of the anaesthetic gas mixture. As there is a continuous upward has flow through the larynx, blood or pieces of loose tissue are not sucked down into the trachea. A simple ventilation nomogram for clinical use is proposed. Adequately used, this nomogram guarantees safe ventilation during laryngoscopic HFPPV. An Fio2 of 0.3--0.4 gives adequate arterial oxygenation.

Anesthesia, General↗
PubMed1997

Effect of weight, sex, age, clinical diagnosis, and thromboplastin reagent on steady-state intravenous heparin requirements.

BACKGROUND: There is a significant direct relationship between steady-state intravenous heparin dose requirements and total body weight. Less is known about whether sex, age, clinical diagnosis, and the thromboplastin used to measure the activated partial thromboplastin time (aPTT) affect heparin dose requirements. METHODS: Four cohorts of patients treated with intravenous heparin were gathered from 3 hospitals: 2 cohorts with deep vein thrombosis (DVT) and 2 cohorts with coronary artery disease (CAD). For each clinical diagnosis, half the patients were monitored using one aPTT reagent and the remainder were monitored using a second reagent. Heparin doses and aPTT measurements were recorded, and the dose necessary to achieve an aPTT ratio of 2.0 was calculated using a computer software program. RESULTS: We analyzed the records of 340 patients: 165 with DVT and 175 with CAD. Using analysis of variance, there was a significant difference in the steady-state heparin requirements among patients with DVT compared with patients with CAD (P < .001). For each clinical diagnosis, the use of a different thromboplastin reagent did not affect heparin dose requirements (P > .42). Linear regression modeling disclosed that the steady-state heparin dose for patients with DVT was a function of weight plus an effect modifier involving weight and age, whereas for patients with CAD there was only a weak relationship with weight. CONCLUSIONS: Steady-state heparin dose requirements were significantly different in patients with DVT compared with patients with CAD, suggesting that different dosing nomograms are needed for each condition. For patients with DVT, the accuracy of the initial heparin dose estimate may be improved by considering the patient's age and weight.

Aged↗
PubMed2005

Complementary roles of simple variables, NYHA and N-BNP, in indicating aerobic capacity and severity of heart failure.

AIMS: The extent of exercise intolerance in patients with chronic heart failure (CHF) is dependent on and representative of the severity of heart failure. However, few primary care physicians have direct access to facilities for formal exercise testing. We have therefore explored whether information readily obtainable in the community can reliably predict the functional capacity of patients. METHODS AND RESULTS: Ninety-six subjects with a wide range of cardiac function (10 healthy controls and 86 CHF patients with NYHA classes I-IV, LVEF 36.9+/-15.2%) were recruited into the study and had resting plasma N-BNP and cardiopulmonary exercise testing to measure peak oxygen consumption (VO2). Significantly higher N-BNP levels were found in the CHF group (299.3 [704.8] fmol/ml, median [IQR]) compared with the healthy control group (7.2 [51.2] fmol/ml), p<0.0001. There were significant correlations between peak VO2 and N-BNP levels (R=0.64, P<0.001), peak VO2 and NYHA class (R=0.76, P=0.001), but no significant correlation was seen between peak VO2 and LVEF (R=0.0788, P=0.33). Multivariate analysis identified plasma N-BNP (P<0.0001) and NYHA class (P<0.0001) as significant independent predictors of peak VO2. Logistic modelling with NYHA class and log N-BNP to predict peak VO2<20 ml/kg/min showed that the area under the curve of receiver-operating-characteristic (ROC) curve was 0.906 (95% CI 0.844-0.968). A nomogram based on the data has been constructed to allow clinicians to estimate the likelihood of peak VO2 to be <20 ml/kg/min for given values of plasma N-BNP and NYHA class. CONCLUSIONS: By combining information from a simple objective blood test (N-BNP) and a simple scoring of functional status (NYHA), a clinician can deduce the aerobic exercise capacity and indirectly the extent of cardiac dysfunction of patients with CHF.

Adult↗
PubMed1978

Monitoring digoxin therapy: III. How useful are the nomograms?

1. A previously described set of guidelines for digoxin therapy has been evaluated in twenty-four patients. 2. Six different published methods (nomograms and equations) for predicting digoxin requirements have been studied to determine their clinical usefulness in the context of the twenty-four patients. 3. The limitations of the nomograms and equations are discussed.

Adult↗
PubMed1985

[Clinical studies of intravenous drip infusion of micronomicin. 1. Pharmacokinetics (Part 2). Intravenous Micronomicin Research Group].

Following the previous report on pharmacokinetics of micronomicin (MCR) in healthy volunteers, pharmacokinetic studies were made again in patients with different degree of renal impairment, and a nomogram was obtained. MCR at a dose of 60 mg/time was given by 1-hour drip infusion to 14 inpatients who consented to receive MCR (age: 35 to 84 years, Ccr: 17.96 to 104.35 ml/min). The blood collection was performed in accordance with the schedule made upon the degree of renal impairment, and the serum concentration was determined by HPLC method. The results were analyzed by MULT program using two- or one-compartment open model. The serum concentration (Cmax) just after administration of MCR was 5.8 +/- 0.9 microgram/ml (mean +/- S.D.). The biological half-life was 1.81 to 12.35 hours. Taking the above results into consideration together with the previous ones of healthy males, the following correlation was obtained between the elimination constant (Kel or beta) and Ccr calculated from S-Cr.: Kel or beta = 0.0038 X Ccr - 0.0097. Further, no side effect was observed in these studies. Elimination of MCR from blood was dependent on renal function like other aminoglycosides, and so it was possible to estimate the elimination constant from Ccr. From these results, a nomogram for the optimum dosage regimen of MCR was obtained.

Adult↗
PubMed2002

Prevention of complicated ulcer disease among chronic users of nonsteroidal anti-inflammatory drugs: the use of a nomogram in cost-effectiveness analysis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of clinical upper gastrointestinal tract (UGI) events, namely, symptomatic ulcer, perforation, bleeding, and obstruction. Our objective in this study was to compare the cost-effectiveness of several strategies aimed at reducing the risk of clinical UGI events in NSAID users. METHODS: A decision tree model was used for patients requiring long-term treatment with NSAIDs to compare conventional NSAID therapy alone with 7 other treatment strategies to reduce the risk of NSAID-related clinical UGI events (cotherapy with proton-pump inhibitor, cotherapy with misoprostol, cyclooxygenase [COX]-2-selective NSAID therapy, or Helicobacter pylori treatment followed by each of the previous strategies, including conventional NSAID treatment, respectively). The outcome measure is the incremental cost per clinical UGI event prevented compared with conventional NSAID treatment over 1 year. RESULTS: The use of a COX-2-selective NSAID and cotherapy with proton-pump inhibitors were the 2 most cost-effective strategies. However, the incremental cost associated with these strategies was high (>$35 000) in persons with a low risk of clinical UGI event with conventional NSAIDs (eg, 2.5% per year). If the baseline risk of clinical UGI events is moderately high (eg, 6.5%), using a COX-2-selective NSAID becomes the most effective and least costly (dominant) treatment strategy, followed closely by cotherapy with a daily proton-pump inhibitor. Because small changes in costs or assumed efficacy of these drugs could change the conclusions, the incremental cost-effectiveness ratios between any 2 strategies were presented in a nomogram that allows the flexible use of a wide range of values for costs and rates of clinical UGI events. CONCLUSIONS: The risk of clinical UGI events in NSAID users depends on their baseline risk, the added risk associated with the individual NSAID, and the protection conferred by cotherapy. A nomogram can be used to incorporate these factors and derive estimates regarding cost-effectiveness of competing strategies aimed at reducing the risk of clinical UGI events.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Strain imaging of corneal tissue with an ultrasound elasticity microscope.

PURPOSE: We hypothesize that high-resolution elasticity measurements can guide corrective refractive surgery of the cornea. Elasticity measurements would improve surgical outcomes by adding biomechanical information not used in existing clinical nomograms. As an initial investigation, we determined the usefulness and evaluated the ability of our ultrasound elasticity microscope by measuring strain ex vivo in an intact porcine eye globe. METHODS: Strain was predicted with a finite element model guided by direct mechanical measurements of corneal elasticity. Next, a porcine cornea was deformed with a slitted plate while being imaged with ultrasound. For high spatial resolution, the ultrasound elasticity microscope uses a 50 MHz transducer with a 1.4 f/number. It produces high-quality conventional ultrasonic B-scans over large thicknesses by confocal processing. Strain was calculated from tracking speckle in these images after deformation. This technique is compatible with in vivo measurements. RESULTS: Compressional and expansional deformations were the same order of magnitude from -3.5% to as great as +3.5%. Strain imaging indicated the stroma expanded into the slit of the deformation plate while Bowman's layer compressed. This bipolar variation within a specimen is unusual. Within the stroma, a variation of strain with depth was measured suggesting a distribution of elasticity. Results compared favorably with the finite element model. CONCLUSION: An ultrasound elasticity microscope can produce high-resolution strain images throughout the corneal depth. Various layers with different elastic properties appeared as different strains in the images.

Animals↗
PubMed1995

Nomogram for estimating plasma unbound disopyramide concentrations in patients with varying plasma alpha 1-acid glycoprotein concentrations.

Since plasma protein binding of disopyramide (DP)--a class IA antiarrhythmic widely used in the prevention and treatment of various types of cardiac arrhythmias--is not only saturable within the therapeutic range but also altered under various pathophysiological conditions, the interpretation of total DP concentrations, Ctotal, measured during routine therapeutic drug monitoring (TDM) is often complicated. To circumvent this problem, we attempted to establish a comprehensive nomogram that allows estimation of unbound DP concentrations (Cu) based upon Ctotal of the drug and plasma concentration of alpha 1-acid glycoprotein (AAG), a major DP-binding protein. The nomogram was formulated with use of the in vitro binding data retrieved from 103 subjects categorized into 10 different groups each with a different mean concentration of AAG (range: 0.14-1.54 g/L). Data analysis, using a binding model assuming one specific binding site and nonspecific binding(s), revealed that alterations in plasma DP binding are attributable mainly to those in the capacity, Bmax, rather than affinity, ka, constant of the specific binding site. In addition, plasma AAG concentration correlated significantly (r = 0.90, p < 0.001) with the Bmax value over the range 0.09-2.28 g/L. For this reason, we substituted Bmax calculated by the regression equation as a function of AAG and the overall mean ka and nonspecific binding parameter values for the respective individual variables of the binding model, so that Cu of each plasma sample was estimated from the corresponding data on Ctotal and plasma AAG levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMedDate not supplied

The Conneulor: unbiased estimation of connectivity using physical disectors under projection.

The Euler number and the connectivity of an arbitrary object is defined, and it is illustrated why the connectivity of an n-dimensional object cannot be estimated in an (n-1)-dimensional section. The disector--principle for 3-D counting of the Euler--events is illustrated in cancellous bone. The correct handling for unbiased counting of events at artificial edges is outlined. A nomogram for predicting the precision of an estimate is provided.

Bone and Bones↗