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PubMed1994

Predicting the risk of abrupt vessel closure after angioplasty in an individual patient.

OBJECTIVES: We proposed to examine the relation between angiographic morphologic characteristics and abrupt closure after coronary angioplasty and to develop an empirically based risk stratification system. BACKGROUND: Certain lesion morphologic characteristics are associated with higher rates of abrupt closure after coronary angioplasty. Previous approaches have been limited by relatively small sample sizes and an inability to combine multiple characteristics to predict risk in an individual patient. METHODS: Lesion morphology was determined for 779 lesions in 658 patients undergoing an elective first angioplasty. Abrupt closure occurred in 63 lesions (8.1%). Variables associated with abrupt closure were identified by univariate and stepwise multiple logistic regression analysis, and internal validity was assessed by use of bootstrapping. An empirically based scoring system was developed by assigning different weights to each predictive characteristic and was then validated. RESULTS: Almost all lesion characteristics previously labeled "adverse" were associated with an increased risk of abrupt closure, but only total occlusion, location at a branch point, increasing lesion length, evidence for thrombus and right coronary artery location were statistically significant independent predictors. Despite the large sample size, the study was underpowered to detect even a 50% increase in risk with many characteristics. Using a scoring system, we assigned each lesion a specific risk of abrupt closure. The distribution of risk was broad, with 20% of patients having < or = 2.5% risk and 25% having > 10% risk. Internal validation techniques revealed that when 10% of patients were randomly eliminated from the sample in multiple iterations, the risk estimates varied, again pointing to the need for a larger sample. CONCLUSIONS: Empirically based weighting of lesion characteristics could quantify the risk of abrupt closure for individual patients, but a very large sample will be required to understand the interplay of complex lesion characteristics in altering expected outcomes.

Aged↗
PubMed2003

Preoperative prediction of severe postoperative pain.

We developed and validated a prediction rule for the occurrence of early postoperative severe pain in surgical inpatients, using predictors that can be easily documented in a preoperative setting. A cohort of surgical inpatients (n=1416) undergoing various procedures except cardiac surgery and intracranial neurosurgery in a University Hospital were studied. Preoperatively the following predictors were collected: age, gender, type of scheduled surgery, expected incision size, blood pressure, heart rate, Quetelet index, the presence and severity of preoperative pain, health-related quality of life the (SF-36), Spielberger's State-Trait Anxiety Inventory (STAI) and the Amsterdam Preoperative Anxiety and Information Scale (APAIS). The outcome was the presence of severe postoperative pain (defined as Numeric Rating Scale > or =8) within the first hour postoperatively. Multivariate logistic regression in combination with bootstrapping techniques (as a method for internal validation) was used to derive a stable prediction model. Independent predictors of severe postoperative pain were younger age, female gender, level of preoperative pain, incision size and type of surgery. The area under the receiver operator characteristic (ROC) curve was 0.71 (95% CI: 0.68-0.74). Adding APAIS scores (measures of preoperative anxiety and need for information), but not STAI, provided a slightly better model (ROC area 0.73). The reliability of this extended model was good (Hosmer and Lemeshow test p-value 0.78). We have demonstrated that severe postoperative pain early after awakening from general anesthesia can be predicted with a scoring rule, using a small set of variables that can be easily obtained from all patients at the preoperative visit. Before this internally validated preoperative prediction rule can be applied in clinical practice to support anticipatory pain management, external validation in other clinical settings is necessary.

Adolescent↗
PubMed2002

Systematic review of psychological therapies for cancer patients: overview and recommendations for future research.

Many cancer patients use psychological therapies because they expect them to cure their cancer or to improve their recovery. Despite these high expectations, both patients and oncologists report being moderately to very satisfied with the results of psychological therapies. Previous reviews of the literature have concluded that psychological therapies may help cancer patients in various ways, ranging from reducing the side effects of cancer treatments to improving patients' immune function and longevity. However, because those reviews lacked methodologic rigor, we critically and systematically reviewed all identifiable publications about psychological therapies used by cancer patients to provide an objective and scientific evaluation of nontraditional therapies. We identified 627 relevant papers that reported on 329 intervention trials by searching MEDLINE, Healthplan, Psychlit, and Allied and Complementary Medicine databases and in the bibliographies of the papers identified. Despite increased use of randomized, controlled trial designs over time, the methodologic quality of the intervention trials, on 10 internal validity indicators, was generally suboptimal, with only one trial achieving a quality rating of "good" for its methodology. Using effectiveness results from 34 trials with psychosocial outcomes, 28 trials with side effect outcomes, 10 trials with conditioned side-effect outcomes, and 10 trials with survival or immune outcomes, we make only tentative recommendations about the effectiveness of psychological therapies for improving cancer patients' outcomes. Nevertheless, by exploring the relative effectiveness of the different intervention strategies for each outcome and follow-up period, we suggest the specific therapies that should be considered for further investigation. In addition, we suggest how future trials can maximize their internal validity by describing the minimal reporting standards that should be required in this field.

Adolescent↗
PubMed2004

Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer.

PURPOSE: We developed a model to predict the side specific probability of extracapsular extension (ECE) in radical prostatectomy (RP) specimens based on the clinical features of the cancer. MATERIALS AND METHODS: We studied 763 patients with clinical stage T1c-T3 prostate cancer who were diagnosed by systematic needle biopsy and subsequently treated with RP. Candidate predictor variables associated with ECE were clinical T stage, the highest Gleason sum in any core, percent positive cores, percent cancer in the cores from each side and serum prostate specific antigen (PSA). Receiver operating characteristic (ROC) analyses were performed to assess the predictive value of each variable alone and in combination. We constructed and internally validated nomograms to predict the side specific probability of ECE based on logistic regression analysis. RESULTS: Overall 30% of the patients and 17% of 1,526 prostate lobes (left or right) had ECE. The areas under the ROC curves (AUC) of the standard features in predicting side specific probability of ECE were 0.627 for PSA, 0.695 for clinical T stage on each side and 0.727 for Gleason sum on each side. When these features were combined predictive accuracy increased to 0.788. The highest value (0.806) was achieved by adding the percent positive cores and the percent cancer in the biopsy specimen to the standard features. The resulting nomograms were internally validated and had excellent calibration and discrimination accuracy. CONCLUSIONS: Standard clinical features of prostate cancer in each lobe-PSA, palpable induration and biopsy Gleason sum-can be used to predict the side specific probability of ECE in RP specimens. The predictive accuracy is increased by adding information from systematic biopsy results. The predictive nomograms are sufficiently accurate for use in clinical practice in decisions such as wide versus close dissection of the cavernous nerves from the prostate.

Adult↗
PubMed2026

A weakly supervised deep learning-based recurrence prediction and risk stratification of lung adenocarcinoma from pathology whole-slide images.

BACKGROUND: Accurate prediction of postoperative recurrence in lung adenocarcinoma (LUAD) is essential for guiding clinical decision-making and improving patient outcomes. Although various predictive models have been developed, most rely on complex genomic analyses and high-dimensional clinical data. The complexity of these approaches substantially limits their feasibility for routine clinical use. To address this clinical challenge, this study aims to predict postoperative recurrence using routinely available hematoxylin and eosin (H&E)-stained images and characterize the associated biological features. METHODS: A total of 329 patients who underwent curative resection at the First Affiliated Hospital of Wenzhou Medical University (FHWMU) were retrospectively enrolled and randomly assigned to training and internal validation cohorts in a 7:3 ratio. An independent external validation cohort comprising 70 patients from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was included. Three patch-level feature extractors (Inception_V3, ResNet18, and DenseNet121) were evaluated within a weakly supervised multiple-instance learning (MIL) framework incorporating automated region-of-interest (ROI) detection on segmented whole-slide images (WSIs). Model performance was assessed using the area under the receiver operating characteristic curve (AUC), Kaplan-Meier (KM) survival analysis, and multivariable Cox proportional hazards regression. Transcriptomic profiling and gene set enrichment analysis (GSEA) were conducted to investigate biological differences between risk groups. RESULTS: The model achieved AUCs of 0.923 in the training cohort, 0.891 in the internal validation cohort, and 0.847 in the external validation cohort. The model effectively stratified patients into high- and low-risk groups with significantly different recurrence-free survival (RFS) across all cohorts (all P&#x2009;<&#x2009;0.001) and retained prognostic value within AJCC stages I-III. Transcriptomic analyses revealed consistent enrichment of cell cycle-related pathways and neutrophil extracellular trap (NET) formation in high-risk patients across both institutional and CPTAC cohorts, aligning with distinct biological profiles of the model-derived risk stratification. CONCLUSIONS: This weakly supervised deep learning framework enables accurate and externally validated prediction of postoperative recurrence in LUAD using routinely available histopathological images, and integration of histopathological features with molecular analyses enhances biological interpretability. This work provides a clinically accessible and cost-effective tool for postoperative risk assessment in LUAD patients.

Humans↗
PubMed1994

[Changes in interpersonal values in student nurses: a longitudinal study].

Our cross-sectional studies of interpersonal values in female student nurses showed that (1) third graders attached more importance to the values of Support and Independence and less to those of Benevolence and Leadership than did first graders, and (2) the discrepancy between the ratings of what they were and those of what their ideal nurses were was greater in the third than in the first graders. We interpreted these differences between the two graders as indicating a developmental change brought about during the three years. This study examined the internal validity of this interpretation through the use of a longitudinal method. The KG-SIV (Kikuchi-Gordon Survey of Interpersonal Values) was administered twice to 85 female student nurses: immediately after entering their nursing schools and immediately before finishing them, with a testing interval of approximately three years. For each testing, subjects were asked to rate what they were and then what their ideal nurses were. Analyses produced almost the same results as obtained in cross-sectional studies: perceived values of Benevolence and Leadership decrease while those of Support and Independence increase over the three years, with the discrepancy increasing from the first to the second testing. Findings thus support the internal validity of our prior interpretation. The changes in interpersonal values found for the student nurses suggest a socialization process they undertake in nurse training and imply an increase of stress they experience in that process.

Cross-Sectional Studies↗
PubMed2002

Physiologically based model of acute ischemic stroke.

In the treatment of acute ischemic stroke most of the clinical trials have failed, contrasting with promising results in the preclinical stages. This continuing discrepancy suggests some misconceptions in the understanding of acute ischemic stroke. One possible method for identifying the shortcomings of present-day approaches is to integrate all the available knowledge into a single mathematical model and to subject that model to challenges via simulations with available experimental data. As a first stage, then, the authors developed a simplified model, defining the structure and the different parameters that represent the phenomena that occur during the hyperacute phase of ischemic stroke. First, the different critical points of the evolution of ischemic stroke, based on the available evidence on the pathophysiology of stroke, were identified. Those key steps were then related to the quantitative data obtained by magnetic resonance imaging and positron emission tomography scan. These two techniques allow the measurement of diverse key markers of cerebral metabolism: cerebral blood flow (CBF), oxygen extraction factor, cerebral metabolism rate of oxygen, and the apparent diffusion coefficient of water, among others. Those markers were organized together through mathematical equations, and changed over time in order to describe the evolution of an acute ischemic stroke. At each time during the evolution of stroke those parameters are summarized in a parameter called survival delay. This parameter made possible the definition of three different states for tissues-functional, infarcted, salvageable-as end point. Once the model was designed, simulations were performed to explore its internal validity. Simulation results were consistent with the reality of acute ischemic stroke and did not reveal any major drawbacks in the use of the model. The more rapid the decrease in CBF, the larger is the final infarcted area. The model also allowed for the characterization of two types of tissue in the penumbra: tissues with an initial metabolic impairment and tissues altered owing to the closeness of the ischemic area. The results of this experiment were consistent with what is known of acute ischemic stroke. The model integrated different markers of acute ischemic stroke into a single entity in order to mimic acute ischemic stroke, and has been shown to have a reasonable degree of internal validity.

Animals↗
PubMed2026

Development of a PCR-based technique for genotyping UGT1A1 gene and distribution of rs3064744 alleles in the Russian population.

BACKGROUND: Accurate determination of tandem thymine-adenine (TA) repeat numbers in the UGT1A1 promoter region (rs3064744) is essential for diagnosing Gilbert's syndrome and personalizing therapy with toxic agents like irinotecan and atazanavir. However, traditional polymerase chain reaction (PCR) assays face severe limitations due to the AT-rich sequence and overlapping melting temperatures (Tm) of the highly homologous 7TA and 8TA alleles. In this context, melting curve analysis (MCA) employing fluorophore-quencher systems has emerged as a promising alternative. The purpose of this study was to develop a novel genotyping approach combining optimized aPCR-MCA analysis with an automated classifier to overcome the limitations posed by the differentiation of highly homologous alleles and to demonstrate its practical application, providing the distribution of rs3064744 genotypes across four regional cohorts of the Russian population. METHODS: A specialized Dual Head 1D-convolutional neural network (1D-CNN) ensemble with Test-Time Augmentation (TTA) was developed. The model was trained and internally validated on 1,620 engineered plasmid samples, and independently evaluated on an external clinical test set of 440 unique patient genomic DNA specimens. Real-time PCR was performed on CFX96 and DTprime platforms. Additionally, population-wide screening was conducted on 997 archival clinical samples from Moscow, Sakha (Yakutia), Dagestan, and Rostov regions. RESULTS: While 5TA and 6TA alleles were easily separated, absolute Tm distributions of 7TA and 8TA alleles overlapped significantly, and non-uniform Tm shifts of 0.8&#xa0;&#xb0;C-1.4&#xa0;&#xb0;C occurred across platforms. Conventional absolute Tm thresholding was therefore inadequate. By assessing relative morphological curve divergence against co-amplified 7TA/7TA and 7TA/8TA reference anchors, the 1D-CNN ensemble neutralized instrument noise. It achieved 100% accuracy on internal validation and 100% concordance (440/440) with clinical reference pyrosequencing. Population screening revealed that Dagestan, Yakutia, and Rostov cohorts closely align with the European population. Rare 5TA and 8TA alleles were detected at low frequencies in Yakutia and Moscow. CONCLUSION: Combining LNA-modified aPCR-MCA with a comparative 1D-CNN model successfully circumvents thermodynamic limitations and eliminates human operator bias. This integrated system offers an accessible, high-throughput, and clinically valid solution for routine UGT1A1 pharmacogenetic testing.

1D-CNN↗
PubMed2026

Machine Learning-Driven Prediction of Coronary Artery Disease Risk Based on UK Biobank Plasma Proteomics.

BACKGROUND: Coronary artery disease (CAD) is a leading global cause of mortality, yet the predictive accuracy of conventional risk models is limited. Here, we integrate conventional risk factors, polygenic risk scores, and large-scale proteomics to develop a unified model for enhanced CAD risk prediction. METHODS: Using data from UK Biobank, participants with plasma proteomics and genetic risk data were included after excluding prevalent CAD. Participants from England were split into training (n=32&#x2009;330) and internal validation (n=13&#x2009;857) sets, and Scotland/Wales participants formed an external validation set (n=5775). Incident CAD was ascertained from linked health records. A 202-protein proteomic risk score was derived by least absolute shrinkage and selection operator Cox regression, and CatBoost models were trained using conventional risk factors alone and with incremental addition of polygenic risk scores and protein proteomic risk scores; Shapley Additive Explanations-guided forward selection identified a compact protein panel. RESULTS: Across cohorts, the median age was 58&#x2009;years and &#x223c;45% were men. Protein proteomic risk score was dose-dependently associated with CAD risk. Compared with conventional risk factors alone, integrating polygenic risk scores and protein proteomic risk scores improved discrimination, with the area under the curve increasing from 0.750 (95% CI, 0.732-0.767) to 0.789 (95% CI, 0.772-0.805) in internal validation and from 0.717 (95% CI, 0.683-0.750) to 0.762 (95% CI, 0.732-0.791) in external validation. A 9-protein panel (GDF15 [growth differentiation factor 15], MMP12 [matrix metalloproteinase 12], NPPB [natriuretic peptide B], PGF [placental growth factor], REN [renin], ADGRG2 [adhesion G-protein coupled receptor], ACE2 [angiotensin-converting enzyme 2], CDCP1 [CUB domain-containing protein 1], CXCL17 [C-X-C motif chemokine ligand 17)]) captured most proteomic predictive information. CONCLUSIONS: Our findings demonstrate that integrating conventional risk factors, polygenic risk scores, and proteomic data improves CAD risk prediction. This study highlights the utility of proteomics in precision cardiovascular medicine and simplified risk stratification tools.

Humans↗
PubMed1999

Quality of life in nasal polyposis.

BACKGROUND: Nasal polyposis (NP) is a frequent inflammatory chronic disease of the upper respiratory tract, which may impair quality of life (QOL). The NP impact, which is frequently associated with lower respiratory disorders, has never before been studied. OBJECTIVE: We initiated this prospective study to establish internal validity and reliability of the generic SF-36 questionnaire in NP and to determine to what level daily functioning becomes impaired as a result of NP. METHODS: Forty-nine consecutive patients with NP were included. They were assessed for the severity of nasal symptoms and underwent pulmonary function tests. The QOL profiles in patients with NP were compared with those of patients with perennial rhinitis (n = 111) and healthy subjects (n = 116). RESULTS: Cronbach's coefficient alpha demonstrated the high reliability and validity of the SF-36 questionnaire for patients with NP (alpha =.89). NP impaired QOL more than perennial allergic rhinitis (P <.05). The impairment of QOL was greater when NP was associated with asthma (P <.05). SF-36 scores appeared highly correlated to pulmonary function (FEV1, maximal midexpiratory flow, forced vital capacity), suggesting relationships between QOL in NP and associated bronchial obstruction. Severity of nasal symptoms were not related to QOL scales. In addition, sequential evaluations of QOL, nasal symptoms, and pulmonary function were performed 10 months after the first evaluation in 28 patients with NP. These evaluations demonstrated that NP treatment either with nasal steroids or endonasal ethmoidectomy significantly improved both nasal symptoms and QOL without significant change of pulmonary function. CONCLUSION: Our study clearly demonstrated that the SF-36 questionnaire presented a high internal validity and reliability in patients with NP. NP impaired QOL to a greater degree than perennial allergic rhinitis. QOL improvement after NP treatment is related to nasal symptoms improvement.

Adult↗
PubMed1999

[The evaluation of the quality of clinical trials: the rationale, usefulness and drawbacks].

The quality of a randomised controlled trial should be understood as its internal validity, that is, the extent in which the study conclusions show correctly what actually happened in the design and conduct phases. This validity may be compromised by multiple biases coming from the allocation of subjects to study groups, treatment administration, observation of outcome variables, patient follow-up and statistical analysis. The presence of bias is assessed through three kinds of measurements: individual components, checklists and numerical scales. In systematic reviews some kind of quality assessment is necessary, which evaluates the quality of individual trials by means of several methods: a) a threshold that sets the minimal level of quality required; b) the relationship between quality and variability in trial results; c) sensitivity analysis, and d) quality scores as weights of trials. However, there exists considerable discrepancy among the published scales whereas their usefulness to assess the quality of trials to be included in the systematic review is a matter of controversy. We hope that the Consolidated Standards of Reporting Trials (CONSORT) initiative to standardize the report of randomized controlled trials and other proposals will contribute to obtain a more realistic view for each trial and to improve their internal validity.

Humans↗
PubMed1986

A quality assessment of randomized control trials of primary treatment of breast cancer.

The methodology of randomized control trials (RCTs) of the primary treatment of early breast cancer has been reviewed using a quantitative method. Sixty-three RCTs comparing various treatment modalities tested on over 34,000 patients and reported in 119 papers were evaluated according to a standardized scoring system. A percentage score was developed to assess the internal validity of a study (referring to the quality of its design and execution) and its external validity (referring to presentation of information required to determine its generalizability). An overall score was also calculated as the combination of the two. The mean overall score for the 63 RCTs was 50% (95% confidence interval [CI] = 46% to 54%) with small and nonstatistically significant differences between types of trial. The most common methodologic deficiencies encountered in these studies were related to the randomization process (only 27 of the 63 RCTs adopted a truly blinded procedure), the handling of withdrawals (only 26 RCTs included all patients in the analyses), the description of the follow-up schedule (only 12 RCTs reported adequately), the report of side effects (adequate information given in 33 RCTs), and the description of the patient population (satisfactory in 29 RCTs). Telephone calls to the principal investigators improved the quality scores by seven points on a scale of 100, indicating that some of the deficiencies lay in reporting rather than performance. There was evidence that quality has improved over time and that the increasing tendency of involving a biostatistician in the research team was positively associated with the improvement of the internal validity but not with the external.

Breast Neoplasms↗
PubMed2002

Postoperative nomogram for 12-year sarcoma-specific death.

PURPOSE: Few published studies have analyzed risk factors for sarcoma-specific death. We developed and internally validated a nomogram that combines the factors to predict the probability of 12-year sarcoma-specific death using a database of 2,136 prospectively followed adult patients treated at a single institution. PATIENTS AND METHODS: Nomogram predictor variables included age at diagnosis, tumor size (< or = 5, 5 to 10, or > 10 cm), histologic grade (high or low), histologic subtype (fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve tumor, synovial, or other), depth (superficial or deep), and site (upper extremity, lower extremity, visceral, thoracic or trunk, retrointraabdominal, or head or neck). Death from sarcoma or treatment complication was the predicted end point. Three prediction methods were compared, Kaplan-Meier analysis of all possible subsets, recursive partitioning, and Cox proportional hazards regression analysis. The concordance index was used as an accuracy measure with bootstrapping to correct for optimistic bias. RESULTS: Sarcoma-specific death at 12 years was 36% (95% confidence interval, 33% to 39%). The bootstrap-corrected concordance indices were as follows: Kaplan-Meier, 0.69; recursive partitioning, 0.74; and Cox regression, 0.77. A nomogram was drawn on the basis of the Cox regression model. This nomogram was internally validated using bootstrapping and shown to have excellent calibration. CONCLUSION: A nomogram has been developed to predict 12-year sarcoma-specific death. This tool may be useful for patient counseling, follow-up scheduling, and clinical trial eligibility determination.

Age Factors↗
PubMed2003

Counseling in the clinical setting to prevent unintended pregnancy: an evidence-based research agenda.

Unintended pregnancies account for about half of all pregnancies in the United States and, in 1995, numbered nearly 3 million pregnancies. They pose appreciable medical, emotional, social and financial costs on women, their families and society. The US is not attaining national goals to decrease unintended pregnancies, and little is known about effective means for reducing unintended pregnancy rates in adults or adolescents.To examine the evidence about the effectiveness, benefits and harms of counseling in a clinical setting to prevent unintended pregnancy in adults and adolescents and to use the evidence to propose a research agenda.We identified English-language articles from comprehensive searches of the MEDLINE, CINAHL, PsychLit and other databases from 1985 through May 2000; the main clinical search terms included pregnancy (mistimed, unintended, unplanned, unwanted), family planning, contraceptive behavior, counseling, sex counseling, and knowledge, attitudes and behavior. We also used published systematic reviews, hand searching of relevant articles, the second Guide to Clinical Preventive Services and extensive peer review to identify important articles not otherwise found and to assure completeness. Of 673 abstracts examined, we retained 354 for full article review; of these, we used 74 for the systematic evidence review and abstracted data from 13 articles for evidence tables. Four studies addressed the effectiveness of counseling in a clinical setting in changing knowledge, skills and attitudes about contraception and pregnancy; all had poor internal validity and generalizability and collectively did not provide definitive guidance about effective counseling strategies. Nine studies (three in teenage populations) addressed the relationship of knowledge on contraceptive use and adherence. Knowledge of correct contraceptive methods may be positively associated with appropriate use, but reservations about the method itself, partner support of the method, and women's beliefs about their own fertility are important determinants of method adherence that may attenuate the knowledge effect. Many factors influence contraceptive use and adherence; among them are age, marital status, ambivalence about becoming pregnant, attitudes of partner, side effects, satisfaction with provider and costs; however, the impact of such factors may not be consistent across populations defined by cultural, age or other factors. The studies themselves differed materially in outcome variables, populations and methodologies and did not yield a body of work that can reliably identify specific influences on contraceptive use and adherence. No literature reports on harms of counseling or on the costs or cost-effectiveness of different approaches to counseling about unintended conceptions in the primary care setting. Virtually no experimental or observational literature reliably answers questions about the effectiveness of counseling in the clinical setting to reduce rates of unintended (unwanted, mistimed) pregnancies in this country. Existing studies suffer from appreciable threats to internal validity and loss to follow-up and are extremely heterogeneous in terms of populations studied and outcomes measured. The quality of the existing research does not provide strong guidance for recommendations about clinical practice but does suggest directions for future investigations. Numerous issues warrant rigorous investigation.

Adolescent↗
PubMed2004

Single muscle fiber gene expression in human skeletal muscle: validation of internal control with exercise.

Reverse transcription and real-time PCR have become the method of choice for the detection of low-abundance mRNA transcripts obtained from small human muscle biopsy samples. GAPDH, beta-actin, beta-2M, and 18S rRNA are widely employed as endogenous control genes, with the assumption that their expression is unregulated and constant for given experimental conditions. The aim of this study was to determine if mRNA transcripts could be performed on isolated human single muscle fibers and to determine reliable housekeeping genes (HKGs) using quantitative gene expression protocols at rest and in response to an acute exercise bout. Muscle biopsies were obtained from the gastrocnemius of three adult males before, immediately after, and 4 h following 30 min of treadmill running at 70% of VO2max. A total of 40 single fibers (MHC I and IIa) were examined for GAPDH, beta-actin, beta-2M, and 18S rRNA using quantitative RT-PCR and SYBR Green detection. All analyzed single fiber segments showed ribosomal RNA (28S/18S). No degradation or additional bands below ribosomal were detected (rRNA ratio 1.5-1.8). Also, no high or low-molecular weight genomic DNA contamination was observed. For each housekeeping gene the duplicate average SD was +/-0.13 with a CV of 0.58%. Stable expression of GAPDH was observed at all time points for each fiber type (MHC I and IIa). Inconsistent expression of beta-actin, beta-2M, and 18S rRNA was observed during the post-exercise time points for each fiber type. These data indicate that successful extraction of high quality RNA from human single muscle fibers along with quantification of mRNA of selected genes can be performed. Furthermore, exercise does influence the expression of certain HKGs with GAPDH being the most stable.

Adaptation, Physiological↗
PubMed2001

Biphasic versus triphasic oral contraceptives for contraception.

BACKGROUND: Side effects caused by oral contraceptives discourage compliance with and continuation of oral contraceptives. A suggested disadvantage of biphasic oral contraceptive pills as compared to triphasic oral contraceptive pills is an increase in breakthrough bleeding. We conducted this systematic review to examine this potential disadvantage. OBJECTIVES: To compare biphasic oral contraceptives with triphasic oral contraceptives in terms of efficacy, cycle control, and discontinuation due to side effects. SEARCH STRATEGY: We searched computerized databases MEDLINE, EMBASE, POPLINE and the Cochrane Controlled Trial Register. Additionally we searched the reference lists of potentially relevant articles and book chapters. We also contacted the authors of relevant studies and pharmaceutical companies in Europe and the U.S. SELECTION CRITERIA: We included randomized controlled trial comparing any biphasic oral contraceptive with any triphasic oral contraceptive when used to prevent pregnancy. DATA COLLECTION AND ANALYSIS: We examined the studies found during the various literature searches for possible inclusion and assessed their methodological quality using the Cochrane guidelines. We contacted the authors of all included studies and of possibly randomized studies for supplemental information about the study methods and outcomes. We entered the data in RevMan 3.1 and later imported them into RevMan 4.1. We calculated Peto odds ratios for incidence of incidence of discontinuation due to medical reasons, intermenstrual bleeding, absence of withdrawal bleeding, and discontinuation due to intermenstrual bleeding. MAIN RESULTS: Only two trials of limited quality met our inclusion criteria. Larranaga (1978) compared two biphasic and one triphasic pills, each containing levonorgestrel and ethinyl estradiol. No important differences emerged, and the frequency of discontinuation due to medical problems was similar with all three pills. Percival Smith (1990) compared a biphasic pill containing norethindrone (Ortho 10/11) with a triphasic pill containing levonorgestrel (Triphasil) and another triphasic pill containing norethindrone (Ortho 7/7/7). The biphasic pill had inferior cycle control compared with the levonorgestrel triphasic pill. The odds ratio of cycles with intermenstrual bleeding was 1.7 (95%CI 1.3-2.2) for the biphasic pill compared with the triphasic levonorgestrel pill. The odds ratio of cycles without withdrawal bleeding was 6.5 (95%CI 3.1-13). In contrast, cycle control with the biphasic pill was comparable to that with the triphasic pill containing the same progestin (norethindrone). REVIEWER'S CONCLUSIONS: The available evidence is limited and of poor quality; the internal validity of these trials is questionable. Given the high losses to follow-up after randomization, these reports may be better considered observational in nature. Given that caveat, the biphasic pill containing norethindrone was associated with inferior cycle control compared with the triphasic pill containing levonorgestrel. This suggests that the choice of progestin may be more important that the phasic regimen in determining bleeding patterns.

Contraception↗