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PubMed2006

The CATH domain structure database: new protocols and classification levels give a more comprehensive resource for exploring evolution.

We report the latest release (version 3.0) of the CATH protein domain database (http://www.cathdb.info). There has been a 20% increase in the number of structural domains classified in CATH, up to 86 151 domains. Release 3.0 comprises 1110 fold groups and 2147 homologous superfamilies. To cope with the increases in diverse structural homologues being determined by the structural genomics initiatives, more sensitive methods have been developed for identifying boundaries in multi-domain proteins and for recognising homologues. The CATH classification update is now being driven by an integrated pipeline that links these automated procedures with validation steps, that have been made easier by the provision of information rich web pages summarising comparison scores and relevant links to external sites for each domain being classified. An analysis of the population of domains in the CATH hierarchy and several domain characteristics are presented for version 3.0. We also report an update of the CATH Dictionary of homologous structures (CATH-DHS) which now contains multiple structural alignments, consensus information and functional annotations for 1459 well populated superfamilies in CATH. CATH is directly linked to the Gene3D database which is a projection of CATH structural data onto approximately 2 million sequences in completed genomes and UniProt.

Classification↗

PubMed2004

Histopathological aspects of transitional cell carcinoma of the bladder: analysis of 20 years experience.

BACKGROUND: In this study we used histopathological examinations performed over a 20-year period to describe the characteristics of newly diagnosed transitional cell carcinoma (TCC) of the bladder in relation to patient age, and to verify changes in the TCC over different periods of observation or in relation to patient age. METHODS: We reviewed all histopathological examinations performed from January 1979 to December 1998 in patients undergoing surgery who were newly diagnosed with TCC of the bladder. All examinations were performed by the same pathologist and reviewed by two pathologists. In each case analyzed, we evaluated T classification of the tumor, histological grade, size, localization, growth type, multiplicity and carcinoma in situ (CIS). RESULTS: The study population included 3113 men and 620 women. The mean patient age was 66.31 +/- 10.84 years. A high percentage of Ta (52.2%) and T1 (27.7%) tumors were found. The number of cases observed and, in particular, the percentage of Ta tumors increased significantly and progressively from the first (1979-1983 = 376 cases; Ta = 37.8%) to the last (1994-1998 = 1732 cases; Ta = 56.3%) period of observation (P < 0.001). A significant difference in the distribution of histological grade and T classification in the different age decades was apparent (P < 0.001); in particular, for G1 and Ta tumors there was a trend to decrease, whereas for G3, T1 and T2 tumors there was a tendency to increase with age decades. CONCLUSION: In our analysis, age of patient and the period of examination significantly influenced different pathological characteristics of newly diagnosed TCC of the bladder.

Aged↗

PubMed1997

Dynamic MR imaging of invasive breast cancer: correlation with tumour grade and other histological factors.

The purpose of this study was to explore the association between dynamic MR enhancement characteristics and histopathological prognostic factors of invasive breast cancer. 53 women with primary invasive breast cancer underwent dynamic contrast enhanced breast MRI. Region of interest (ROI) analysis was performed on synthetic images obtained by kinetic modelling of the dynamic data. Operator-defined, large ROIs and computer-defined, 9-pixel ROIs were selected for each tumour. The relative increase in mean ROI pixel intensity was expressed in the form of enhancement ratios. Univariate and multivariate analyses were performed to explore the association of these ratios with standard histological factors, including tumour size, histopathological classification, histological grade, the presence of extensive in situ component and lymphovascular invasion, multifocal disease, and axillary lymph node status. All enhancement ratios showed significant differences between node-positive and node-negative tumours (max. p = 0.002). However, automated ROI ratios showed less overlap between node-positive and node-negative carcinomas than did large ROI ratios. A strongly significant association was observed between all automated ROI enhancement ratios and histological tumour grade (max. p = 0.001). Based on stepwise multiple regression analysis, node status and histological grade were the only histopathological factors with a significant independent effect on the enhancement characteristics. In summary, there is a strong association between dynamic MR characteristics and two important prognostic markers of invasive breast cancer, namely axillary node status and histological grade. This may allow MRI to be used in pre-operative predictions of tumour behaviour and biological activity.

Adult↗

PubMed2003

Molecular classification of familial non-BRCA1/BRCA2 breast cancer.

In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.

Adult↗

PubMed2004

High-resolution serum proteomic features for ovarian cancer detection.

Serum proteomic pattern diagnostics is an emerging paradigm employing low-resolution mass spectrometry (MS) to generate a set of biomarker classifiers. In the present study, we utilized a well-controlled ovarian cancer serum study set to compare the sensitivity and specificity of serum proteomic diagnostic patterns acquired using a high-resolution versus a low-resolution MS platform. In blinded testing sets, the high-resolution mass spectral data contained multiple diagnostic signatures that were superior to the low-resolution spectra in terms of sensitivity and specificity (P<0.00001) throughout the range of modeling conditions. Four mass spectral feature set patterns acquired from data obtained exclusively with the high-resolution mass spectrometer were 100% specific and sensitive in their diagnosis of serum samples as being acquired from either unaffected patients or those suffering from ovarian cancer. Important to the future of proteomic pattern diagnostics is the ability to recognize inferior spectra statistically, so that those resulting from a specific process error are recognized prior to their potentially incorrect (and damaging) diagnosis. To meet this need, we have developed a series of quality-assurance and in-process control procedures to (a) globally evaluate sources of sample variability, (b) identify outlying mass spectra, and (c) develop quality-control release specifications. From these quality-assurance and control (QA/QC) specifications, we identified 32 mass spectra out of the total 248 that showed statistically significant differences from the norm. Hence, 216 of the initial 248 high-resolution mass spectra were determined to be of high quality and were remodeled by pattern-recognition analysis. Again, we obtained four mass spectral feature set patterns that also exhibited 100% sensitivity and specificity in blinded validation tests (68/68 cancer: including 18/18 stage I, and 43/43 healthy). We conclude that (a) the use of high-resolution MS yields superior classification patterns as compared with those obtained with lower resolution instrumentation; (b) although the process error that we discovered did not have a deleterious impact on the present results obtained from proteomic pattern analysis, the major source of spectral variability emanated from mass spectral acquisition, and not bias at the clinical collection site; (c) this variability can be reduced and monitored through the use of QA/QC statistical procedures; (d) multiple and distinct proteomic patterns, comprising low molecular weight biomarkers, detected by high-resolution MS achieve accuracies surpassing individual biomarkers, warranting validation in a large clinical study.

Biomarkers, Tumor↗

PubMedDate not supplied

Clustering of lifestyle behaviors: the relationship between cigarette smoking, alcohol consumption, and dietary intake.

PURPOSE: To examine relationships between cigarette smoking, alcohol use, and dietary intake. DESIGN: Respondents to the U.S. Department of Agriculture's Continuing Survey of Food Intakes by Individuals, a nationwide probability sample conducted from January 1994 through January 1997 (n = 23,602; response rate = 80%), were selected. Adults ages 19 years and older were grouped according to their smoking and drinking habits. Selected demographic variables, food group servings, food energy, and densities of selected nutrients were compared. SETTING: In-home interviews were conducted in the 50 states and the District of Columbia. SUBJECTS: The selected sample (n = 6745) included 3229 nonsmokers, 1701 former smokers, and 1808 current smokers, and 2284 abstainers, 2713 occasional drinkers, 1000 moderate drinkers, and 748 liberal drinkers. MEASURES: Responses to standard questionnaires were examined by Student's t-test, chi 2, one-way analysis of variance, and univariate and multivariate analyses of covariance. RESULTS: Men were more likely than women to be current smokers and liberal drinkers (64% vs. 40% and 62% vs. 38%). For both, the use of cigarettes and alcohol was closely related. An additive relationship was observed between smoking/drinking classification and lower food group servings and nutrient intakes. Although cigarette and alcohol use may have been underreported, these findings support previous ones showing poor food choices along with lower nutrient intakes as smoking and drinking increase. CONCLUSIONS: Smoking and drinking habits may alter individuals' food selections and nutrient intakes. Future interventions for health promotion may achieve greater success by targeting multiple risk factors simultaneously or sequentially.

Adult↗

PubMed1993

A multivariate approach to the description of patient populations. An example of the analysis of the hormone profiles of patients with advanced prostate cancer.

In view of the multifactorial nature of the endocrine dysfunctions that may develop during prostate cancer and the unsuitability of the most widely used statistical methods to study such dysfunction, we have in the present study examined the relationships among 17 biological variables in 26 patients with advanced prostate cancer by two complementary multivariate methods, correspondence factorial analysis (CFA) and a hierarchical automatic classification procedure. The 17 variables included 14 hormones, their precursors or metabolites [LH, FSH, estradiol (E2), testosterone, dihydrotestosterone (DHT), androstenedione (A), androstenediol (Ediol), dehydroepiandrosterone (DHA), DHA-sulphate (DS), cortisol (CORT), 17 alpha-hydroxyprogesterone (17-OH-PROG), pregnenolone (PREG), 17 alpha-hydroxypregnenolone (17-OH-PREG), and androstanediol glucuronide (ADG)], one plasma binding protein, namely, sex-hormone-binding protein (SHBG) and two tumour markers, prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA). The originality of these multivariate methods is that they do not preselect a dependent variable nor perform two-by-two correlations as in stepwise multiple regression analysis but describe the patient population by extracting layers of correlations (from strong to weak) from amid confounding variables. Compared to principal component analysis which is based on covariance, CFA, based on the chi 2-metric, enables the licit representation of both tests and patients on the same factorial maps. From an examination of proximity among variables, it is possible to deduce which tests are related, which groups of patients have similar hormone profiles, and which tests vary most in which patients. The most discriminant factors in this particular population of patients were PSA and PAP levels, which were, however, not strongly correlated and were apparently selectively associated with certain hormones. PAP seemed the more pathological marker; PSA was somewhat anticorrelated to the adrenal androgen (DHA and DS) and PREG levels. The hormones with the lowest variance were A, Ediol and CORT reflecting their key roles in metabolism. A number of patients were hypogonadic. SHBG levels were not closely related to total T levels but anticorrelated with ADG suggesting that, in the patients concerned, SHBG decreases the bioavailable T fraction. There was no correlation between ADG and precursor hormones (PREG, DHA, DS) but a slight anticorrelation between these precursors and DHT. Therefore the source of ADG in these patients does not seem to be increased levels of precursor hormones nor of DHT but increased peripheral tissue metabolism of androgens. In future, descriptive multivariate analyses of large patient cohorts should help to define subpopulations with distinctive hormone profiles for prospective clinical studies.

Hormones↗

PubMed1997

Morphology of acute promyelocytic leukemia with cytogenetic or molecular evidence for the diagnosis: characterization of additional microgranular variants.

Early diagnosis of t(15;17) acute promyelocytic leukemia (APL) is essential because of the associated disseminated intravascular coagulation and the unique response of the disease to all-trans retinoic acid (ATRA) therapy. Early diagnosis depends primarily on morphological recognition. The French-American-British (FAB) classification, however, does not describe all morphological variations that occur in APL. In 25 cases with evidence of APL confirmed by cytogenetic and/or molecular analysis, we found a heterogeneous morphological group. The most common form of APL was heterogeneous and consisted of various combinations of cells in which hypergranular cells and some cells with multiple Auer rods were obvious. In some cases, one cell predominated. This led to the description of five subcategories. These included the classical FAB M3 with hypergranular cells and multiple Auer rods; the FAB variant with hypogranular bilobed cells; the basophilic cell type of McKenna et al. [Br. J. Haematol 50:201, 1982]; and two additional subtypes, one consisting of differentiated promyelocytes and a few blast cells (M2-like), and the other consisting largely of blast cells and a few early promyelocytes (M1-like). Immunophenotyping revealed a pattern of CD33 and/or CD13 positivity, and CD14 and HLA-DR negativity in 96% of cases. CD2 was positive in the FAB variant and in the subtype with basophilic cells, but negative with other subtypes. Three out of five cases with basophilic cell predominance [McKenna et al.: Br J Haematol 50:201, 1982], and one out of two M2-like cases, responded to ATRA therapy. Awareness of the heterogeneity and the atypical morphologic subtypes found in t(15;17) APL will contribute to improved recognition and early institution of ATRA therapy.

Adolescent↗

PubMed1992

Stereologic, histopathologic, flow cytometric, and clinical parameters in the prognostic evaluation of 74 patients with intraoral squamous cell carcinomas.

BACKGROUND AND METHODS: A consecutive series of all 78 incident cases of intraoral squamous cell carcinoma occurring during a 2-year period in a population of 1.4 million inhabitants were evaluated by histologic score (the modified classification of Jacobsson et al.), flow cytometry, stereology, tumor size, and the TNM classification. RESULTS: The investigation showed a significant difference between the volume-weighted mean nuclear volume (nuclear vv) of oral leukoplakia (n = 29) and oral squamous cell carcinomas (P = 0.001). The value of the parameters as prognostic indicators of survival and recurrence was tested with Kaplan-Meier plots and Cox multiple hazard regression analysis. Tumor size, T-stage, stereologically estimated nuclear vv, and mean nuclear profile area were all of significant prognostic value in single factor analysis with reference to both survival and recurrence. The histologic parameters of mitotic activity, morphologic nuclear dedifferentiation, and histologic mean malignancy score and the DNA ploidy level had no prognostic value. A prognostic index based on the results of the Cox analysis that included T-stage and nuclear vv was correlated highly with survival (P = 0.00001) and recurrence (P = 0.002). CONCLUSION: These findings may contribute to optimal and individualized therapy.

Adult↗

PubMed2002

Eye-head coordination during postural perturbation as a predictor of falls in community-dwelling elderly women.

OBJECTIVES: To assess the functional significance of eye-head coordination during postural perturbations and to determine the contribution of angular vestibulo-ocular reflex (AVOR) suppression to the prediction of 1-year fall history in community-dwelling elderly women. DESIGN: Descriptive analysis of factors correlated with falls. SETTING: Community-based independent and senior assisted living facilities. PARTICIPANTS: Volunteer sample of 38 older women (mean age +/- standard deviation, 81.6+/-3.9y; range, 74-92y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Multiple and logistic regression variables (slope coefficients, partial R2, percent-correct fall history classifications) and fall prediction equations generated by using minimal sets of predictor variables. RESULTS: Instantaneous AVOR gain and sedative use were predictors of 1-year history of falls in all minimal sets of predictor variables. R2 for the prediction models varied from.47 to.62 and indicated substantial shared variance with the 1-year history of falling. Elderly women who failed to suppress the AVOR gain were 18 times more likely to have experienced a fall in the past year compared with elderly women who showed AVOR suppression (odds ratio=18; 95% confidence interval, 1.63-198.42). CONCLUSIONS: When controlling for all other variables in the model, instantaneous AVOR gain accounted for nearly 30% of the variance of fall history. The strong association between 1-year fall history, the use of sedatives, and changes in the AVOR gain supports a functional link between AVOR suppression and effective balance in elderly women.

Accidental Falls↗

PubMed2002

A major susceptibility locus for specific language impairment is located on 13q21.

Children who fail to develop language normally-in the absence of explanatory factors such as neurological disorders, hearing impairment, or lack of adequate opportunity-are clinically described as having specific language impairment (SLI). SLI has a prevalence of approximately 7% in children entering school and is associated with later difficulties in learning to read. Research indicates that genetic factors are important in the etiology of SLI. Studies have consistently demonstrated that SLI aggregates in families. Increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of the familial clustering. We have collected five pedigrees of Celtic ancestry that segregate SLI, and we have conducted genomewide categorical linkage analysis, using model-based LOD score techniques. Analysis was conducted under both dominant and recessive models by use of three phenotypic classifications: clinical diagnosis, language impairment (spoken language quotient <85) and reading discrepancy (nonverbal IQ minus non-word reading >15). Chromosome 13 yielded a maximum multipoint LOD score of 3.92 under the recessive reading discrepancy model. Simulation to correct for multiple models and multiple phenotypes indicated that the genomewide empirical P value is <.01. As an alternative measure, we also computed the posterior probability of linkage (PPL), obtaining a PPL of 53% in the same region. One other genomic region yielded suggestive results on chromosome 2 (multipoint LOD score 2.86, genomic P value <.06 under the recessive language impairment model). Our findings underscore the utility of traditional LOD-score-based methods in finding genes for complex diseases, specifically, SLI.

Autistic Disorder↗

PubMed1998

Factors associated with inappropriate hospitalization days in internal medicine wards in Israel: a cross-national survey.

BACKGROUND: The high costs of health care mandate a quality control system that ensures efficient utilization of hospitalization days. OBJECTIVES: To obtain a national estimate of the rate of inappropriate hospitalization days in medical wards and to identify the variables associated with inappropriateness. DESIGN: A 1-day cross-national survey. SETTING: A sample of internal medicine wards in all public hospitals in Israel. SURVEY POPULATION: The survey population included all patients hospitalized in the ward for at least 24 hours on the survey day. INSTRUMENTS: We used an adapted version of the appropriateness evaluation protocol (AEP) (Gertman and Restuccia). Reviewers were final year medical students trained to work with the AEP. Final classification of inappropriate days was done by one of the senior investigators. OUTCOME MEASURE: Utilization of hospitalization days according to the AEP. RESULTS: A total of 1003 hospitalization days in 33 medical wards in 24 hospitals was surveyed. Of this, 182 (18.1%) of the days were found to be inappropriate. In multiple logistic regression analysis, variables significantly associated with inappropriate days were government versus other hospital ownership (OR, 1.51; CI, 1.15-1.96), diagnosis on admission of acute cardiac event versus other diagnosis (OR, 0.46; CI, 0.27-0.77), and period (first, second or final third) of the stay (OR, 1.61; CI, 1.29-2.03). In 62.6% of the 'inappropriate days', continuation of hospitalization was justified (72% were patients awaiting tests or consultation). In 6.7% of the total days surveyed, no justification for continuation of hospitalization was found. CONCLUSION: The percentage of inappropriate days found in this study is similar to the means found in studies that were conducted in other countries. Awaiting procedures and consultation is a major cause of inappropriate days and may be an important target for intervention.

Aged↗

PubMed2025

Genomics insight on passion fruit viral disease complexity.

Passion fruit viral diseases pose a significant threat to Kenya's passion fruit industry. To unravel the complexity of these diseases, comprehensive virus surveys were conducted across major passion fruit-growing counties. Passion fruit woodiness disease symptoms, like fruit hardening, chlorotic mottling, and leaf distortion, were prevalent. The study unveiled the first 23 complete genomes of Ugandan passiflora virus (UPV) and two East Asian passiflora distortion virus (EAPDV) in Kenya. UPV showed 99% nucleotide (nt) match to a UPV genome from Uganda and 66% nt identity match to EAPDV. In addition, UPV variants and two partial passion fruit green spot virus sequences and partial (passiflora emaravirus) segment RNA1-5 (novel allexivirus and an emaravirus, respectively) were detected. Phylogenetic analysis revealed distinct lineages (I-III), indicating potential multiple introductions into Kenya. Recombination analysis detected no significant breakpoints. However, the study proposed the renaming of EAPDV to passiflora distortion virus (PDV) and UPV to passiflora virus (PV) for neutral nomenclature, without geographical association. Additionally, the study highlighted the role of coinfections in symptom expression, suggesting a potential synergistic relationship between PV, PDV, and other viruses. The results recommend stringent management strategies and enhanced surveillance to mitigate the economic impact of these viruses on the Kenyan passion fruit industry. The findings from this study underscore the need to strengthen nursery certification programs and pest diagnostic protocols in Kenya. Additionally, enhanced pest surveillance and import regulations are critical to preventing the introduction and spread of emerging plant viral diseases, thereby safeguarding the country's horticultural productivity and biosecurity. To our knowledge, this is the first comprehensive study of viral diseases of passion fruit in Kenya.IMPORTANCEThis study presents the first comprehensive survey of viral pathogens affecting passion fruit in Kenya, identifying Ugandan passiflora virus (UPV) and East Asian passiflora distortion virus (EAPDV) as major contributors. Through genomic sequencing, 23 complete genomes of UPV and two of EAPDV were characterized, revealing a 99% nucleotide (nt) similarity between UPV strains from Uganda and Kenya, and 66% nt match with EAPDV. Phylogenetic analysis identified distinct lineages, suggesting possible multiple viral introductions in Kenya. The study also highlights potential synergistic coinfections between UPV, EAPDV, and other viruses, leading to more severe disease symptoms. In light of these findings, the study proposes renaming EAPDV as passiflora distortion virus and UPV as passiflora virus for a more neutral name classification. The research underscores the urgent need for enhanced surveillance, stringent phytosanitary measures, and improved management strategies to mitigate the threat of viral diseases, to safeguard the Kenyan passion fruit industry, and elsewhere.

Plant Diseases↗

PubMed1996

Speaker identification using time-delay HMEs.

In this paper, we extend the Hierarchical Mixture of Experts (HME) to temporal processing and explore it for a substantial problem, that of text-dependent speaker identification. For a specific multiway classification, we propose a generalized Bernoulli density instead of the multinomial logit density to avoid the instability during training. Time-delay technique is applied for spatio-temporal processing in the HME and a combining scheme is presented for combining multiple time-delay HMEs in order to complete a multi-scale analysis for the temporal data. Using the time-delay HME along with the EM algorithm as well as the combination of multiple time-delay HMEs, the speaker identification system has a good performance and yields significantly fast training. We have also addressed some issues about the time-delay techniques in the HME.

Algorithms↗

PubMed2000

Risk factors for death rattle in terminally ill cancer patients: a prospective exploratory study.

Death rattle is frequently observed in cancer patients whose death is impending and may contribute to the severe distress of patients and their family members. To identify risk factors for development and persistency of death rattle, a prospective study was performed on 245 hospice inpatients. One-hundred-and-seven patients (44%) developed death rattle, 71% of whom achieved satisfactory symptom palliation until death. A multiple regression analysis identified neoplasms of brain and lung as independent risk factors for development of death rattle, while refractory symptoms were significantly associated with pulmonary neoplasms and infection/oedema. In conclusion, development of death rattle was influenced by both brain and lung malignancies, while its persistency was mainly determined by pulmonary pathology. A clinical classification of death rattle based on these factors would be established by a further confirmatory study.

Aged↗

PubMed1990

A computer-derived protocol using recursive partitioning to aid in estimating prognosis of horses with abdominal pain in referral hospitals.

In order to determine which variables are useful and accurate in estimating prognosis in horses with abdominal pain, data were analyzed from 231 horses presented at a veterinary teaching hospital. Using multiple stepwise discriminant analysis in a recursive partition model, we obtained a decision protocol that identified survivors and nonsurvivors. The prevalence of survivors was 61% in this population. The sensitivity, specificity, and positive and negative predictive values of this model were 71, 83, 87 and 65%, respectively. This decision protocol was validated by Jackknife classification and also by evaluation with a referral population of 100 horses in which the prevalence of survivors was 83%. This led to sensitivity, specificity, and positive and negative predictive values of 83, 78, 94 and 50%, respectively.

Abdominal Pain↗

PubMed1995

Localization of a gene for autosomal dominant Larsen syndrome to chromosome region 3p21.1-14.1 in the proximity of, but distinct from, the COL7A1 locus.

Larsen syndrome (LS) is a skeletal dysplasia (osteochondrodysplasia) in which multiple dislocations of the large joints are the major feature. Nosology in this group of diseases, which constitutes 8% of Mendelian disorders in man, is primarily based on clinical and radiographic features. Hopes for more accurate classification grounds are currently being met by progress in elucidation of underlying genetic defects. We have performed linkage analysis in a large Swedish kindred with autosomal dominant LS and found the gene (LAR1) to be strongly linked to chromosome 3p markers (Zmax = 13.4 at (theta = .00). Recombination analysis indicates that the LAR1 locus is located in a region defined distally by D3S1581 and proximally by D3S1600, which cytogenetically maps to chromosome region 3p21.1-14.1. Linkage and recombination analysis of a COL7A1 PvuII intragenic polymorphism versus LS and chromosome 3 markers indicate that COL7A1 is located close to, but distinct from, the LAR1 locus.

Chromosome Mapping↗

PubMed1995

A new staging system for multiple myeloma based on the number of S-phase plasma cells.

In the present study, we analyzed the cell cycle distribution of bone marrow (BM) cells in 120 untreated multiple myeloma patients using a DNA/CD38 double-staining technique at flow cytometry in which plasma cells (PCs) can be clearly discriminated from residual BM cells based on their CD38 expression. This approach allows us to determine the proliferative activity of both PCs and residual normal BM cells. The percentage of S-phase cells in the myelomatous population was found to be significantly lower than that of the residual normal BM cells (P < .001). Regarding the proliferative activity of myelomatous cells, patients with a high number of S-phase PCs (> 3%) showed a significantly (P < .05) increased incidence of anemia and hypercalcemia; higher values of beta 2-microglobulin (beta 2M), urea, and creatinine; and higher numbers of peripheral blood natural killer cells, as well as a poor prognosis as assessed both by response duration and overall survival. With respect to the residual BM normal fraction, a low proliferative activity was significantly (P < .05) associated with the presence of anemia and neutropenia together with increased numbers of BM PCs, a higher incidence of Bence Jones myelomas, and DNA diploidy. Multivariate analysis showed that the number of S-phase PCs was the most important independent prognostic factor, allowing us to discriminate two subgroups of patients with different prognoses, even within the same clinical stage. Moreover, the S-phase PCs, together with beta 2M, age, and performance status, represent the best combination of disease characteristics for stratifying patients according to prognosis and allow the establishment of a simple and powerful staging system for multiple myeloma patients. In addition, this classification can be used for planning treatment in patients who are candidates for transplantation.

ADP-ribosyl Cyclase↗