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PubMed1994

Modular arrangement of proteins as inferred from analysis of homology.

The structure of many proteins consists of a combination of discrete modules that have been shuffled during evolution. Such modules can frequently be recognized from the analysis of homology. Here we present a systematic analysis of the modular organization of all sequenced proteins. To achieve this we have developed an automatic method to identify protein domains from sequence comparisons. Homologous domains can then be clustered into consistent families. The method was applied to all 21,098 nonfragment protein sequences in SWISS-PROT 21.0, which was automatically reorganized into a comprehensive protein domain database, ProDom. We have constructed multiple sequence alignments for each domain family in ProDom, from which consensus sequences were generated. These nonreduntant domain consensuses are useful for fast homology searches. Domain organization in ProDom is exemplified for proteins of the phosphoenolpyruvate:sugar phosphotransferase system (PEP:PTS) and for bacterial 2-component regulators. We provide 2 examples of previously unrecognized domain arrangements discovered with the help of ProDom.

Amino Acid Sequence↗

PubMed2026

Educational interventions to improve medical students' bad news communication skills: A systematic review and meta-analysis.

OBJECTIVES: This systematic review aimed to both determine whether educational interventions improve medical students' ability and/or confidence in Bad News Communication (BNC), as well as assess the relative efficacy of instructional formats. METHODS: Performed according to the PRISMA guidelines, four databases were searched for articles describing education-based interventions to improve medical student's BNC ability and/or confidence, published in English between 2001 and 2024. Data on students' self-reported or observer-assessed level of competence/ability in BNC (primary outcome), and students' self-assessed confidence in BNC skills (secondary outcomes), were analysed. Meta regression explained the influence of several categorical moderators on heterogeneity in relation to intervention effects on competence/ability. RESULTS: 27 studies met the criteria for inclusion in the systematic review and 17 studies for the meta-analysis. Interventions described in controlled studies were associated with a moderate and significant increase in BNC ability (13 data sets; standardized mean difference [SMD] = 1.09, 95% CI = 0.52 - 1.66). Interventions detailed in pre-post design studies were associated with a significant increase in BNC ability (20 data sets; SMD = 0.92, 95% CI = 0.52 - 1.32), and student confidence/comfort in their BNC skills (12 data sets; SMD = 1.16, 95% CI = 0.57 - 1.75). Subgroup analysis demonstrated better skills/competence outcomes in studies that included simulation-based training (SBT). CONCLUSIONS: Educational interventions improve the BNC ability and confidence of medical students. Interventions should include an SBT element as this leads to greater improvements in BNC ability. Further research is needed to determine to what extent these interventions translate to positive patient outcomes. PRACTICE IMPLICATIONS: Diverse educational programme, especially those including simulation-based training, are effective in improving BNC skills, although the longetivity of these improvements is at present unclear. Therefore, we recommend that refresher courses or practice opportunities should be scheduled throughout students' medical education to ensure retention of BNC skills.

Humans↗

PubMed2001

Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis.

Nowadays, most of the neonatal screening programs for cystic fibrosis (CF) combine the assay of immunoreactive trypsinogen (IRT) with the analysis of the most common mutations of the CFTR gene. The efficiency of this strategy is now well established, but the identification of heterozygotes among neonates with increased IRT is perceived as a drawback. We proposed to assess the heterozygosity frequency among the children with hypertrypsinaemia detected through the CF screening program implemented in Brittany (France) 10 years ago, to describe the CFTR mutations detected in them and to determine the frequency of the IVS8-5T variant. The molecular analysis relies, in our protocol, on the systematic analysis of three exons of the gene (7-10-11). A total of 160,019 babies were screened for CF in western Brittany between 1992 and 1998. Of the 1964 newborns with increased IRT (1.2%), 60 were CF and 213 were carriers. Heterozygosity frequency was 12.8%), i.e. 3 times greater than in the general population (3.9%; p < 10(-6)), Variability of mutations detected in carriers was greater than in CF children (21 mutations versus 10) and a high proportion of mild mutations or variants (A349V, R297Q, R347H, V317A, G544S, R553G, etc) was observed in carriers. The allelic frequency of the 5T (5.6%) was not significantly increased in this cohort. This study is consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinaemia. The strategy of screening used here allows to highlight the variability of mutations detected in heterozygotes and to show that severe mutations, as well as mild mutations, have been observed in neonates with hypertrypsinaemia. If there is no doubt that neonatal hypertrypsinaemia is associated with an elevated frequency of carriers, the underlying mechanisms remain obscure.

Alleles↗

PubMed2026

Diagnostic Performance of Machine Learning for Systemic Lupus Erythematosus: Systematic Review and Meta-Analysis.

BACKGROUND: Early and accurate diagnosis of systemic lupus erythematosus (SLE) and its organ involvement is essential. Previous reviews of machine learning (ML) in SLE combined heterogeneous tasks and validation strategies and may have overinterpreted model performance. OBJECTIVE: This study evaluated the diagnostic performance of ML and deep learning (DL) models for 3 clinically distinct SLE-related tasks: SLE classification or diagnosis, lupus nephritis (LN) diagnosis, and neuropsychiatric systemic lupus erythematosus (NPSLE) discrimination. We also assessed methodological quality and certainty of evidence. METHODS: PubMed, Embase, Cochrane Library, Web of Science, and IEEE Xplore were searched from January 2014 to April 2026. Eligible peer-reviewed diagnostic accuracy studies developed or validated ML or DL models for 1 of the 3 prespecified tasks, used an accepted reference standard, and provided data for a 2×2 contingency table. Bivariate random-effects meta-analyses with the Hartung-Knapp-Sidik-Jonkman adjustment were used to pool sensitivity and specificity. We reported 95% prediction intervals (PIs), assessed risk of bias using the Quality Assessment of Diagnostic Accuracy Studies for Artificial Intelligence tool (QUADAS-AI; Viknesh Sounderajah [Imperial College London]), and evaluated certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework for diagnostic test accuracy. RESULTS: Twenty-nine studies were included: 17 for SLE classification, 5 for LN diagnosis, and 7 for NPSLE discrimination. In the primary task-stratified analysis, pooled sensitivity was 0.91 (95% CI 0.86-0.94; 95% PI 0.56-0.99), and pooled specificity was 0.94 (95% CI 0.91-0.96; 95% PI 0.69-0.99), with low heterogeneity (I²=23.9% and 22.9%, respectively). DL models showed a sensitivity of 0.93 and specificity of 0.95, compared with 0.88 and 0.94 for traditional ML models. Certainty of evidence was high for most analyses but low for LN diagnosis because of inconsistency and imprecision. All studies were retrospective, and only 9 of 29 (31%) performed independent external validation. Overall risk of bias was high or unclear in 22 of 29 (75.9%) studies. No study reported model calibration, decision-curve analysis, or net clinical benefit. CONCLUSIONS: ML models showed promising diagnostic accuracy across 3 distinct SLE-related tasks, but wide PIs, limited external validation, and pervasive risk of bias restrict conclusions about real-world generalizability. Prospective multicenter studies with standardized tasks and reference standards, independent external validation, and formal assessment of calibration and clinical utility are required before clinical implementation.

Humans↗

PubMed2000

Effect of postmenopausal hormone replacement therapy on dental outcomes: systematic review of the literature and pharmacoeconomic analysis.

A systematic review and economic analysis of clinical trials evaluating the effect of hormone replacement therapy (HRT) on dental outcomes in postmenopausal women were conducted. Twenty published studies involving more than 13,735 postmenopausal women were summarized and analyzed. In prospective studies, the effect of HRT on osteoporosis (OP) has been well documented. The effect of OP on mandibular bone density has also been examined in some observational studies. Few studies, however, have examined the effect of HRT directly on mandibular bone density or on dental outcomes. From these studies, the effect of HRT on costs of dental treatment and prophylaxis was estimated directly and indirectly. It was determined that HRT use was associated with reduction in adverse dental outcomes and the associated costs of dental care. Annualized excess cost in a cohort of 1,000 untreated women averaged $100,000. From this analysis, it is clear that postmenopausal women with OP who do not receive HRT have a greater incidence of adverse dental outcomes and higher dental care costs than those who do.

Aged↗

PubMed1999

Detection of mutations in the COL4A5 gene in over 90% of male patients with X-linked Alport's syndrome by RT-PCR and direct sequencing.

X-linked Alport's syndrome is caused by mutations in the COL4A5 gene encoding the type IV collagen alpha5 chain (alpha5[IV]). Polymerase chain reaction-single-str and conformation polymorphism (PCR-SSCP) on genomic DNA has previously been used to screen for mutations in the COL4A5 gene, but this method was relatively insensitive, with mutations detected in less than 50% of patients. Here, we report a systematic analysis of the entire coding region of the COL4A5 gene, using nested reverse-transcription-polymerase chain reaction (RT-PCR) and the direct sequence method using leukocytes. This study examines twenty-two unrelated Japanese patients with X-linked Alport's syndrome showing abnormal expression of alpha5(IV) in the glomerular or epidermal basement membranes. Mutations that were predicted to be pathogenic were identified in 12 of the 13 male patients (92%) and five of the nine female patients (56%). Six patients had missense mutations, four had out-of-frame deletion mutations, three had nonsense mutations, and three had mutations causing exon loss of the transcript. The current study shows that nested RT-PCR and the direct sequence method using leukocytes are highly sensitive and offer a useful approach for systematic gene analysis in patients with X-linked Alport's syndrome.

Adolescent↗

PubMed2005

Sorption mechanisms of zinc on hydroxyapatite: systematic uptake studies and EXAFS spectroscopy analysis.

The systematics and mechanisms of Zn uptake by hydroxyapatite (HAP) in preequilibrated suspensions open to PCO2 were characterized using a combination of batch sorption experiments, X-ray diffraction (XRD), and extended X-ray absorption fine structure spectroscopy (EXAFS) over a wide range of pH and Zn concentrations. Sorption isotherms of Zn(II) on HAP at pH 5.0 and 7.3 show an initial steep slope at low Zn(II) concentrations, followed by a plateau up to [Zn] < approximately 750 microM, suggesting Langmuir-type behavior. At [Zn] > 750 microM, a sharp rise in the pH 5.0 isotherm suggests precipitation, whereas slight continued uptake in the pH 7.3 isotherm is suggestive of an additional uptake mechanism. The sorption isotherm at pH 9.0 shows a steep uptake step at [Zn] < or = 0.8 microM, followed by an increasing linear trend up to [Zn] = 5 microM, without any indication of a maximum, suggesting that precipitation is an important uptake process at this pH. Zn K edge EXAFS results show a first oxygen shell at 1.96-1.98 +/- 0.02 A in sorption samples with [Zn]tot < or = 250 microM at pH 5.0, 7.3, and 9.0, consistent with tetrahedral coordination. EXAFS results reveal additional P and Ca neighbors that support formation of an inner-sphere Zn surface complex where the Zn is coordinated to surface P04 tetrahedra in a corner-sharing bidentate fashion, bridging a Ca atom. In contrast, EXAFS and XRD data indicate that precipitation of Zn3(PO4)2-4H2O (hopeite) dominates the mode of Zn uptake at [Zn]tot > or = 3 mM at pH 5.0. Principal component analysis and linear combination fits of EXAFS data reveal a mixture of inner-sphere Zn surface complexation and precipitation of Zn5(OH)6(CO3)2 (hydrozincite) in sorption samples for [Zn]tot = 5 mM at pH 7.3 and for [Zn]tot = 1 mM at pH 9.0.

Adsorption↗

PubMed2001

[Critical analysis of a systematic review of the literature and a meta-analysis on exercise therapy and chronic low back pain].

OBJECTIVES: To determine wether the type of quality assessment scale used for evaluating the role of the physical training in chronic low back pain affects the conclusions of meta-analytic studies. DESIGN AND SETTING: Analysis of 20 trials assessing exercise therapy in chronic low back pain using 16 different scales to identify high-quality trials. Correlations between the scale scores were assessed using the Spearmans rank correlation coefficient. Inter-reader reliability was assessed with the intraclass correlation coefficient (ICC) and with the Bland and Altman technique. For the quality assessment scales allowing the classification in high quality or low quality trials, the degree of agreement between the two readers was calculated using the kappa coefficient. RESULTS: The range of the Spearman rank correlation coefficients between the different quality scales was wide (from 0.94 to 0.49). The quality scales inter-reader reliability were heterogeneous, ICC ranging from 0.86 to 0.39. The Bland and Altman analysis showed that with two scales the differences were not centered and that with 3 scales there was a systematic effect (r=0.32, 0.41, and 0.50). Finally, inter-reader agreement was low most of the time, the K coefficient being less than or equal to 0.60 for 8 of the 12 quality scales tested. CONCLUSIONS: Our data suggest that the use of summary scores to identify trials of high quality is problematic. Relevant methodological aspects should be assessed more specifically based on treatment strategies than on the own disease. A large reflexion on the elaboration and validation of specific quality scales is needed.

Humans↗

PubMed2006

Clinical features and gene analysis in Korean patients with early-onset Parkinson disease.

BACKGROUND: Systematic analysis of clinical features and gene mutations has not been performed in Korean patients with early-onset Parkinson disease (PD). OBJECTIVE: To investigate the clinical characteristics and genetic background of Korean patients with early-onset PD. DESIGN: Clinical and genetic study. SETTING: University hospital. PATIENTS: Ninety-four patients with early-onset PD (mean +/- SD age at onset, 39.8 +/- 7.3 years) of 1100 patients with PD. INTERVENTIONS: Analysis of clinical characteristics and mutation analysis of the parkin and PTEN-induced kinase (PINK1) genes by direct sequencing and gene-dosage analysis using the multiplex ligation-dependent probe amplification technique. MAIN OUTCOME MEASURES: The correlation between age at onset and clinical characteristics and the clinical features of patients with onset before age 30 years vs patients with onset after age 30 years. RESULTS: Because age at onset was younger, levodopa-induced dyskinesia and off-dystonia were more frequently observed (P=.008). Patients affected before age 30 years showed more frequent levodopa-induced dyskinesia and off-dystonia (P=.002). We identified 3 patients (5%) with parkin gene mutations but none with the PINK1 mutation. CONCLUSIONS: Earlier onset of levodopa-induced dyskinesia and off-dystonia were characteristic features of early-onset PD, especially before an onset age of 30 years. However, parkin gene mutations were less frequent in these patients than in Japanese groups reported elsewhere.

Adult↗

PubMed1992

Collagens in human atherosclerosis. Immunohistochemical analysis using collagen type-specific antibodies.

This study represents a systematic analysis of the distribution of collagen types in human atherosclerotic lesions. Formalin-fixed, paraffin-embedded aortic tissues of 40 lesions from 16 different individuals ranging in age from 1 month to 84 years were examined immunohistochemically using antibodies to type I, III, IV, V, and VI collagens. Preembedding immunoelectron microscopy was used to simultaneously localize type V and VI collagens within the lesions. Localization of type III collagen was very similar to that of type I, and type VI collagen appeared together with these two types of collagen in the thickened intimas of all stages of the lesion. Type V collagen was not detected in either fatty streaks or the mild intimal thickening of the aortas of children. With advancing age and lesion progression, the immunoreactivity with anti-type V collagen antibody became more intense. Type IV collagen was detected in the basement membrane region of intimal cells. In advanced lesions thick deposits of type IV collagen were found around the elongated smooth muscle cells. Using immunoelectron microscopy, type V collagen was found to be localized to cross-banded collagen fibers, and type VI collagen was found to be localized to beaded filaments present throughout the interstitium of the thickened intima. These findings suggest that collagens preserve the pathophysiological and functional integrity of the vascular wall by providing mechanical support as well as assuring the proper interaction of cells during the formation of atherosclerotic lesions.

Adult↗

PubMed1999

[Analysis of blue ballpoint ink components by FT-IR microspectrometry].

Systematical analysis on the 108 kinds of blue ballpoint writing inks with FT-IR microspectrometry is presented in this paper. The results show that the differences of the ink compounds keep some regular. These blue ballpoint writing inks can be classified by the transmittance spectra. The method is rapid, accurate, highly sensitive and nondestructive.

English Abstract↗

PubMedDate not supplied

[Inhibitory analysis of DNA polymerases from human viruses using modified substrates].

A systematic analysis of DNA polymerase of human herpes simplex type 1 virus, cytomegalovirus, and human type 2 adenovirus with the help of a broad set of modified substrates of these enzymes has been carried out. It revealed compounds capable of inhibiting the DNA synthesis catalyzed both by all three enzymes and DNA polymerase alpha from human placenta. Compounds have been found which effectively and specifically inhibit the DNA synthesis catalyzed by some of the abovementioned enzymes. It has been shown that the molecular mechanism of inhibition consists either in the termination of DNA elongation or in inhibition without incorporation into the growing DNA chain.

Adenoviruses, Human↗

PubMed1992

Activity labeling patterns in the medulla of Drosophila melanogaster caused by motion stimuli.

We quantitatively describe 2-deoxyglucose (2-DG) neuronal activity labeling patterns in the first and second visual neuropil regions of the Drosophila brain, the lamina and the medulla. Careful evaluation of activity patterns resulting from large-field motion stimulation shows that the stimulus-specific bands in the medulla correspond well to the layers found in a quantitative analysis of Golgi-impregnated columnar neurons. A systematic analysis of autoradiograms of different intensities reveals a hierarchy of labeling in the medulla. Under certain conditions, only neurons of the lamina are labeled. Their characteristic terminals in the medulla are used to differentiate among the involved lamina monopolar cell types. The 2-DG banding pattern in the medulla marks layers M1 and M5, the input layers of pathway p1 (the L1 pathway). Therefore, activity labeling of L1 by motion stimuli is very likely. More heavily labeled autoradiograms display activated cells also in layers M2, M9, and M10. The circuitry involved in the processing of motion information thus concentrates on pathways p1 and p2. Layers M4 and M6 of the distal medulla hardly display any label under the stimulus conditions used. The functional significance of selective activity in the medulla is discussed.

Animals↗

PubMed1996

Detection of epitopes on follicle-stimulating hormone and FSH-antiserum-induced suppression of bioactivity of follicle-stimulating hormone and luteinizing hormone.

There are currently two major approaches to hormonal male contraception. One relies on testosterone (analogs) either alone or in combination with gonadotropin releasing hormone (GnRH) (analogs or immunizations), the other on immunizations against follicle-stimulating hormone (FSH). Theoretically, the latter method will suppress spermatogenesis whilst not interfering with libido. An absolute requirement is, however, that an anti-FSH vaccine does not include anti-luteinizing hormone (LH) antibodies (LH being responsible for the induction of testosterone which is necessary to maintain libido). In this report we show that when whole FSH is used for vaccination, in most cases in addition to biological activity against FSH, anti-LH activity is also induced. By systematic analysis of the antisera raised with FSH using systematic epitope scanning (PEPSCAN) we found differences between the FSH-specific and FSH-nonspecific sera. Only the FSH-specific antiserum contained antibodies that recognized amino acid sequence 37-55 on the beta-subunit in a linear manner. Because antibodies against this epitope have not been found in the cross-reactive sera this epitope forms a prime candidate for an anti-FSH contraceptive vaccine.

Amino Acid Sequence↗

PubMedDate not supplied

The sensitivity of cardiac markers: an evidence-based approach.

The aim of this study was to determine whether, using an evidence-based approach, the results of the papers found in the literature are valid and sufficiently scientifically rigorous to be used to definitely address the problem of cardiac marker sensitivity in detection of acute myocardial infarction. In particular, the diagnostic sensitivities of myoglobin, creatine kinase (CK)-MB isoenzyme, determined as mass concentration, CK-MB isoforms, and of the two cardiac troponins, troponin I and troponin T, were reviewed using a priori formulated inclusion/exclusion criteria for judging the eligibility of studies to be included in the analysis. A clear final message derived from this systematic analysis is the unacceptably poor diagnostic sensitivity of all evaluated markers at patient admission, with substantial failure rate to rule out myocardial infarction at this time. Myoglobin is at present the most sensitive of the markers studied for excluding early AMI with an optimum timing of sampling at patient presentation and approximately 4 h later. However, this marker cannot be used by itself as a proportion of patients admitted to the hospital with a late infarction could be missed. The early rate of rise of CK-MB mass and troponin T is similar. Maximum sensitivity of these two parameters is achieved by the analysis of a second sample 6 to 12 h after admission. Additional larger studies are needed to address the question which troponin shows earlier release after myocardial damage, and to clarify the role of CK-MB isoforms as a possible early marker of myocardial infarction.

Biomarkers↗

PubMed1987

Determinants of resistance to antifolates: biochemical phenotypes, their frequency of occurrence and circumvention.

Biochemical alterations associated with acquired resistance of tumor cells to antifolates are diverse and multiple in number. These most often have included both quantitative and qualitative alterations at the level of membrane transport and of the primary intracellular target, dihydrofolate reductase (DHFR). More recent studies suggest determining biochemical alterations at the level of thymidylate synthase activity and 4-aminofolate polyglutamylation. Approaches to the circumvention of acquired antifolate resistance at the level of new drug design are described which incorporate a kinetic analysis of the various biochemical phenotypes and a systematic analysis of their structure-activity relationships. A consideration of the relative frequency of occurrence of individual phenotypes during therapy is also included. This introduces the notion of population genetics in an evaluation of resistance phenomenon and of clinically significant approaches for its circumvention.

Biological Transport↗

PubMed2002

Fractal analysis of sampled profiles: systematic study.

A quantitative evaluation of the influence of sampling on the numerical fractal analysis of experimental profiles is of critical importance. Although this aspect has been widely recognized, a systematic analysis of the sampling influence is still lacking. Here we present the results of a systematic analysis of synthetic self-affine profiles in order to clarify the consequences of the application of a poor sampling (up to 1000 points) typical of scanning probe microscopy for the characterization of real interfaces and surfaces. We interpret our results in terms of a deviation and a dispersion of the measured exponent with respect to the "true" one. Both the deviation and the dispersion have always been disregarded in the experimental literature, and this can be very misleading if results obtained from poorly sampled images are presented. We provide reasonable arguments to assess the universality of these effects and propose an empirical method to take them into account. We show that it is possible to correct the deviation of the measured Hurst exponent from the "true" one and give a reasonable estimate of the dispersion error. The last estimate is particularly important in the experimental results since it is an intrinsic error that depends only on the number of sampling points and can easily overwhelm the statistical error. Finally, we test our empirical method calculating the Hurst exponent for the well-known 1+1 dimensional directed percolation profiles, with a 512-point sampling.

Journal Article↗

PubMed2000

Ultradian clocks in eukaryotic microbes: from behavioural observation to functional genomics.

Period homeostasis is the defining characteristic of a biological clock. Strict period homeostasis is found for the ultradian clocks of eukaryotic microbes. In addition to being temperature-compensated, the period of these rhythms is unaffected by differences in nutrient composition or changes in other environmental variables. The best-studied examples of ultradian clocks are those of the ciliates Paramecium tetraurelia and Tetrahymena sp. and of the fission yeast, Schizosaccharomyces pombe. In these single cell eukaryotes, up to seven different parameters display ultradian rhythmicity with the same, species- and strain-specific period. In fission yeast, the molecular genetic analysis of ultradian clock mechanisms has begun with the systematic analysis of mutants in identified candidate genes. More than 40 "clock mutants" have already been identified, most of them affected in components of major regulatory and signalling pathways. These results indicate a high degree of complexity for a eukaryotic clock mechanism. BioEssays 22:16-22, 2000.

Activity Cycles↗