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PubMed2003

Modelized analysis of pressure-flow studies of patients with lower urinary tract symptoms due to benign prostatic enlargement.

AIMS: To gain insight from an adaptable computer model of micturition into the pathophysiological phenomena occurring during voiding in men with lower urinary tract symptoms due to benign prostatic enlargement (BPE). METHODS: By using the Valentini-Besson-Nelson (VBN) micturition model, we proceeded with an in-depth and systematic analysis of the pressure-flow studies of 71 patients (119 tracings) provided by three different institutions. RESULTS: The modelized analysis identified and quantified several pathophysiological phenomena during voiding: compressive obstruction, variations in detrusor contraction force (enhanced or reduced), progressive relaxation of the prostatic fossa, occasional detrusor-bladder neck coupling, and sphincteric control dysfunctions. Once these phenomena were taken into account by using a set of new parameters, the computed flow rate and detrusor pressure curves became very similar to the recorded ones. CONCLUSIONS: The accuracy of this sophisticated analysis allows us to separate and to study during each voiding the phenomena belonging to the urethra, the detrusor, the bladder neck, the prostate, and their neurologic coordination in BPE patients.

Aged↗
PubMed2006

Analysis of preexistent vertebral rotation in the normal spine.

STUDY DESIGN: A newly developed CT measurement method was used to investigate axial rotation from T2 to L5 in the normal, nonscoliotic spine. OBJECTIVES: To identify a preexistent rotational pattern in the normal, nonscoliotic spine. SUMMARY OF BACKGROUND DATA: The data available on axial rotation measurements in the normal spine are scant and limited to only a few vertebrae. Systematic analysis of the thoracic and lumbar vertebrae of the normal spine, based on computed tomography has, to our knowledge, not been performed. METHODS: CT scans of the thorax and abdomen of 50 persons without clinical or radiologic evidence of scoliosis were used to measure vertebral axial rotation from T2 to L5 with a newly developed semiautomatic computerized method. RESULTS: The results of the present study showed a predominant rotation to the left of the high thoracic vertebrae, and to the right of the mid and lower thoracic vertebrae in the normal, nonscoliotic spine, which differed significantly from an equal right-left distribution. This rotational pattern is present in both males and females. CONCLUSION: The normal, nonscoliotic spine demonstrates a preexistent pattern of vertebral rotation that corresponds to what is seen in the most prevalent types of thoracic idiopathic scoliosis.

Adolescent↗
PubMed2005

Ambiguity resolution analysis in incremental parsing of natural language.

Incremental parsing gains its importance in natural language processing and psycholinguistics because of its cognitive plausibility. Modeling the associated cognitive data structures, and their dynamics, can lead to a better understanding of the human parser. In earlier work, we have introduced a recursive neural network (RNN) capable of performing syntactic ambiguity resolution in incremental parsing. In this paper, we report a systematic analysis of the behavior of the network that allows us to gain important insights about the kind of information that is exploited to resolve different forms of ambiguity. In attachment ambiguities, in which a new phrase can be attached at more than one point in the syntactic left context, we found that learning from examples allows us to predict the location of the attachment point with high accuracy, while the discrimination amongst alternative syntactic structures with the same attachment point is slightly better than making a decision purely based on frequencies. We also introduce several new ideas to enhance the architectural design, obtaining significant improvements of prediction accuracy, up to 25% error reduction on the same dataset used in previous work. Finally, we report large scale experiments on the entire Wall Street Journal section of the Penn Treebank. The best prediction accuracy of the model on this large dataset is 87.6%, a relative error reduction larger than 50% compared to previous results.

Algorithms↗
PubMed2005

Proteome analysis of the rice etioplast: metabolic and regulatory networks and novel protein functions.

We report an extensive proteome analysis of rice etioplasts, which were highly purified from dark-grown leaves by a novel protocol using Nycodenz density gradient centrifugation. Comparative protein profiling of different cell compartments from leaf tissue demonstrated the purity of the etioplast preparation by the absence of diagnostic marker proteins of other cell compartments. Systematic analysis of the etioplast proteome identified 240 unique proteins that provide new insights into heterotrophic plant metabolism and control of gene expression. They include several new proteins that were not previously known to localize to plastids. The etioplast proteins were compared with proteomes from Arabidopsis chloroplasts and plastid from tobacco Bright Yellow 2 cells. Together with computational structure analyses of proteins without functional annotations, this comparative proteome analysis revealed novel etioplast-specific proteins. These include components of the plastid gene expression machinery such as two RNA helicases, an RNase II-like hydrolytic exonuclease, and a site 2 protease-like metalloprotease all of which were not known previously to localize to the plastid and are indicative for so far unknown regulatory mechanisms of plastid gene expression. All etioplast protein identifications and related data were integrated into a data base that is freely available upon request.

Amino Acid Sequence↗
PubMed1989

P-glycoprotein expression in plasma-cell myeloma is associated with resistance to VAD.

Tumor cell-associated expression of multidrug resistance (MDR) was quantitated in 22 patients with DNA-aneuploid myeloma using 2-parameter flow cytometry with monoclonal antibody (MoAb) C-219 for the detection of cytoplasmic p-170 and propidium iodide for nuclear DNA content. The proportion of cells expressing p-170 and the intensity of p-170-related fluorescence were determined for each patient. Among the 14 patients treated with vincristine-adriamycin-dexamethasone (VAD), the proportion of p-170-positive cells distinguished sensitive from resistant disease (P less than .01). Among a subgroup of seven patients with MDR analysis available prior to VAD therapy, two subsequent nonresponders had high proportions of C-219-reactive cells. The presence de novo of high proportions of p-170-expressing cells in another still untreated patient and in a further individual with resistance to dexamethasone and interferon (not associated with MDR) warrants systematic analysis of p-170 expression prior to therapy to determine its clinical implications for response to MDR-associated drugs as combined in the VAD regimen. Concurrent MDR expression by aneuploid tumor cells and cells in the diploid subcompartment may represent involvement of diploid cells in the myeloma disease process.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

[Alzheimer's disease followed in a single case].

Descriptions of Alzheimer's disease are usually based on the observation of populations of patients. Their advantage is the systematic analysis of signs and symptoms according to a logical approach enumerating the involvement of neurological, neuropsychological, affective and behavioral fields. Their disadvantage is to neglect the natural evolutive way and the subtle gearing of these diverse aspects of the disease. This paper aspires to bring a complement to the necessary systematic knowledge, by the description of a patient who has been followed regularly every 3 months for 4 and a half years. It describes the evolution as it is lived by the patient and his spouse, and as it is observed by the clinician. Three main facts are inferred. The first is the precocious involvement of two functions particularly affected later: language and the ability of identifying others. The second is with the evolution of the disease the identification, in the neuropsychological domain, of some tests which show no or little alteration, of some others altered from the outset, the majority deteriorating progressively. The third is the observation of a brisk and definitive worsening following a transient ischemic attack, demonstrating the vulnerability of these patients when the disease has reached an advanced stage.

Activities of Daily Living↗
PubMed2005

Tumor risk in Beckwith-Wiedemann syndrome: A review and meta-analysis.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with macroglossia, abdominal wall defects, ear anomalies, and an increased risk for embryonic tumors. Reported tumor risk estimates vary between 4% and 21%. It has been hypothesized that tumor predisposition in BWS is related to the imprinting status of the H19 and LIT1 genes on chromosome 11p15. A loss of imprinting (LOI) of H19 implies a higher tumor risk. However, a systematic analysis of available data is lacking. Therefore, we performed a review and meta-analysis of reported associations between the imprinting status of the LIT1 and H19 genes and the risk for tumor development in BWS. Five publications suitable for meta-analysis were identified by electronic database searches. Sufficient data were available for 402 out of 520 patients. Patients were divided into four groups based on the imprinting status of H19 and LIT1: group I with LOI of LIT1 (45%); group II with LOI of H19 (9%); group III with LOI of LIT1 and LOI of H19 (21%); and group IV with normal imprinting patterns (26%). Differences in tumor risk between groups were studied with random effects meta-analysis. Tumors occurred in 55 patients. The odds of tumor development was significantly lower in group I when compared to group II (OR=0.06; 95% CI: 0.02-0.21) and group III (OR=0.12; 95% CI: 0.04-0.37). Tumor risk did not differ significantly between groups II and III (OR=1.40; 95% CI: 0.56-3.50). Compared to group IV, tumor risk was significantly lower in group I (OR=0.33; 95% CI: 0.12-0.87) and higher in groups II (OR=4.0; 95% CI: 1.5-10.4) and III (OR=2.6; 95% CI: 1.2-5.7). Tumor incidence rate for group IV was 10.6% (95% CI: 3.6-17.7). Calculated absolute risks were 3% for group I, 43% for group II, and 28% for group III, respectively. No Wilms tumor was seen in group I. In total, other tumors were seen with comparable frequencies in groups I-III. The results show a strong association between a LOI of H19 and especially Wilms tumor development in BWS.

Beckwith-Wiedemann Syndrome↗
PubMed1994

Reduction of escapee formation in flow cytometric analysis of lymphocyte subsets.

Most experienced flow cytometrists performing immunophenotyping of lymphocyte subsets are aware of the escape phenomenon, in which some positive cells are found outside a lymphocyte gate based on forward and right angle scatter. However, little information is available on the levels of escapees formed with different antibodies, the roles of fluorochromes and lysing agents, the mechanism explaining the phenomenon, or methods to reduce it. We thus performed a systematic analysis of the escapee phenomenon to clarify these issues. A panel of monoclonal antibodies, including a phycoerythrin (PE) conjugate and a fluorescein isothiocyanate (FITC) conjugate of the same antibody from one manufacturer, was used to treat whole blood specimens, after which red cells were lysed using 0.15 M ammonium chloride (AmChl). The percentages of gated lymphocytes expressing CD3, CD8, CD19, and HLA-DR, but not CD2, CD4, CD16, and CD25, were significantly lower in FITC-stained versus PE-stained preparations. Correlated analysis of green fluorescence and forward scatter showed that, on average, 18% of CD3+ events, 24% of CD8+ events, and 25% of CD19+ events were escapees when using the FITC conjugate. In dual color analysis, CD3+ escapees were positive for CD62-P, CD13, and CD14, indicating that the escapee events consisted of FITC-anti-CD3-coated lymphocytes complexed with platelet-coated myeloid cells. In studies of the role of lysing agent, essentially no escapees were found in specimens treated with FACS lysing solution, which contains formaldehyde. We therefore included a similar denaturing agent, paraformaldehyde (0.1%), in the AmChl lysing agent, and found that the occurrence of escapees was markedly reduced. These findings show that the escapee phenomenon occurs when using some FITC-conjugated monoclonal antibodies in conjunction with AmChl lysing agent, and can be reduced by inclusion of paraformaldehyde in the lysing agent.

Ammonium Chloride↗
PubMed1986

An analysis of the costs of infertility treatment.

For 597 couples receiving care at an infertility clinic in Nova Scotia, the average cost of diagnosis and treatment per successful pregnancy is $10,700. This is compared to the costs of alternatives to infertility treatment. Adoption costs generally range from $3,000 to $10,000, and surrogate mother arrangements are much higher (around $20,000). This study demonstrates the feasibility and value of a systematic analysis of the costs of infertility.

Adoption↗
PubMed2004

STAT6 transcription factor binding sites with mismatches within the canonical 5'-TTC...GAA-3' motif involved in regulation of delta- and mu-opioid receptors.

Opioid receptors are expressed in neuronal and immune cells and regulated in response to immunological processes. Herein, we demonstrate up-regulation of the delta-opioid receptor gene by interleukin-4 in immune cells (primary T and polymorphonuclear leukocytes, Jurkat E6 T cells), and in NG 108-15 neuronal cells. We identified an interleukin-4-responsive element at nt -671 on the murine gene promoter, to which the transcription factor STAT6 binds, as shown by reporter gene analysis and STAT6/DNA interaction studies in living cells with transcription factor decoy oligonucleotides. STAT6 normally binds to palindromic DNA motifs with a 5'-TTC...GAA-3' core. Notably, the delta-opioid receptor STAT6 site (5'-TTC...GGA-3') is an imperfect palindrome with a mismatch within this core sequence. A systematic analysis of possible mismatch 5'-TTC...GAA-3' motifs revealed that STAT6 also binds to the sequence 5'-TTA...GAA-3'. This motif occurs as a polymorphism in the human mu-opioid receptor gene (Kraus et al. 2001 J. Biol. Chem 276, 43901-43908). We show that this mutated element has a significantly reduced STAT6 binding activity which correlates to its reduced interleukin (IL)-4 inducibility. In contrast, the non-canonical STAT6 site of the delta-opioid receptor binds STAT6 with similar high activity as a perfectly palindromic STAT6 site and is strongly inducible by IL-4.

Amino Acid Motifs↗
PubMed2026

Long-Read Haplotype Phasing Resolves Allelic Configuration as a Missing Layer of Precision Oncology.

Conventional short-read sequencing cannot determine whether co-occurring variants within a cancer gene reside on the same allele (cis) or on opposing alleles (trans), a distinction with direct biological and therapeutic consequences. Trans configurations confirm biallelic tumor suppressor inactivation and inform therapy selection, while cis configurations generate compound oncogenic alleles with enhanced activity. We analyzed 768 patients with prostate, breast, or ovarian cancers in the PROBLEM cohort, using mutational signatures to nominate cryptic genomic instability cases where the causative biallelic event was not apparent from short-read sequencing. Long-read nanopore sequencing resolved 32 of 46 cryptic cases (69.6%), leveraging its unique advantages in direct methylation detection, long insertion resolution, and complex structural variant characterization, confirming trans biallelic inactivation in all resolved tumor suppressor cases. Systematic analysis of 4,496 MiOncoSeq samples identified 17,519 multi-hit gene pairs, of which 78.7% exceeded the 500 bp short-read phasing limit. Long-read phasing further revealed recurrent compound cis oncogenic alleles in NOTCH1, PIK3CA, PDGFRB, and KIT with functionally synergistic activity. Haplotype phasing resolves a systematically overlooked gap in cancer variant interpretation and warrants broader integration into precision oncology workflows.

Journal Article↗
PubMed1997

[An analysis of the information in the Medicom International Vade Mecum with respect to drugs with vitamin A].

OBJECTIVE: Determination of whether rational drug use is facilitated by the quality of the information provided by the Medicom International Vademecum on drugs containing vitamin A as active component. DESIGN: Descriptive study. SETTING: Primary, specialized and hospital health care within the national context. SUBJECTS: Total drugs containing vitamin A, included in the 1995 Medicom International Vademecum. MEASUREMENTS: Systematic analysis of the information contained in the technical note on drugs containing vitamin A included in the Medicom International Vademecum, with respect to several parameters. RESULTS: The Medicom International Vademecum lists a total of 37 drugs containing vitamin A (35 in combination). A total of 112 different indications are given; 74 are not accepted in the literature, and 29 are related to the active components present in combination with vitamin A. CONCLUSIONS: The analysis of the technical information provided by the Medicom International Vademecum on medications containing vitamin A reveals major deficiencies in the parameters investigated.

Contraindications↗
PubMed2006

The prediction of bereavement outcome: development of an integrative risk factor framework.

We propose an integrative risk factor framework to enhance understanding of individual differences in adjustment to bereavement and to encourage more systematic analysis of factors contributing to bereavement outcome (e.g., examination of interactions between variables and establishing pathways in the adaptation process). The examination of individual differences in adaptation to bereavement is essential for practical (e.g. targeting high risk individuals for intervention) and theoretical (e.g. testing the validity of theoretical claims about sources of differences) purposes. And yet, existing theoretical approaches have not led to systematic empirical examination and empirical studies in the current literature are fraught with shortcomings. Derived from Cognitive Stress Theory [Lazarus, R. S. & Folkman, S. (1984). Stress, appraisal, and coping. New York: Springer] and the stressor-specific Dual Process Model of Coping with Bereavement [Stroebe, M. S., & Schut, H. A. W. (1999). The dual process model of coping with bereavement: Rationale and description. Death Studies, 23, 197-224], the framework incorporates an analysis of stressors, intra/interpersonal risk/protective factors, and appraisal and coping processes that are postulated to impact on outcome. Advantages of using the approach are outlined. Challenges in undertaking such research are addressed.

Adaptation, Physiological↗
PubMed2006

Predictors for malignant middle cerebral artery infarctions: a postmortem analysis.

BACKGROUND: Early detection of malignant infarction of the middle cerebral artery (MI-MCA) is important because of possible treatment by hemicraniectomy. OBJECTIVE: To investigate the anatomic and vascular predictors of MI-MCA. METHOD: The authors evaluated 192 consecutive autopsies of patients with nonlacunar cerebral infarction affecting the MCA territory. MI-MCA was defined by an infarct with temporal or central brain herniation and brain swelling. The autopsy protocol included a systematic analysis of intracranial arteries (including the bony segments of carotid and vertebral arteries and the circle of Willis), extracranial arteries, the aortic arch, and the heart. RESULTS: A total of 45 patients with MI-MCA were identified. Their median (range) survival time was 6 (0 to 20) days as compared with 18 (0 to 2,040) days for non-MI-MCA patients. Compared with non-MI-MCA, MI-MCA cases more frequently involved the superficial and deep MCA territory and were more frequently associated with anterior cerebral and anterior choroidal artery territory infarcts. Hemorrhagic transformation, Duret hemorrhages, carotid occlusion, and ipsilateral abnormalities of the circle of Willis were also more frequent (p < 0.05). Multivariable analysis showed that younger age, female sex, absence of stroke history, higher heart weight, carotid artery occlusion, and abnormal circle of Willis ipsilaterally were all independently associated with MI-MCA (p < 0.03). CONCLUSIONS: Typical pathologic pattern for development of malignant infarction of the middle cerebral artery is a carotid occlusion with abnormal ipsilateral circle of Willis in a young patient who had a first-ever large hemispheric stroke including the superficial territory with possibly a slight predominance of female sex.

Aged↗
PubMed2006

Vaginal vault smears after hysterectomy for reasons other than malignancy: a systematic review of the literature.

BACKGROUND: Vaginal vault smears are used to detect persisting neoplasia of the lower genital tract after hysterectomy. Recent data suggest both widespread use and uncertain evidence of their effectiveness. OBJECTIVES: To identify and synthesise evidence on the use and effectiveness of vaginal vault smears and to assess the quality. SEARCH STRATEGY 'vault smear' OR 'vaginal vault smear' OR 'cervical vault smear' OR ('Hysterectomy') AND ('Follow up' OR 'Smear'). SELECTION CRITERIA Primary research, women who had a hysterectomy and were followed up by vault cytology. DATA COLLECTION AND ANALYSIS: Systematic search (eight electronic databases), supplemented by contact with experts and review of bibliographies. Two independent reviewers determined eligibility/validity and extracted data concerning test performance characteristics. Quality was assessed according to the established criteria. RESULTS: Of 441 unique references, only 19 were suitable. Quality of studies varied considerably and few were of 'high' methodological quality. Studies were geographically diverse, and were published over more than 40 years in 16 journals. From the higher scoring papers, there were 11 659 hysterectomies [6546, benign; 76, cervical intraepithelial neoplasia (CIN) I/CIN II; 5037, CIN III]. Proportions of abnormal vault smears and abnormal biopsies during follow up increased with worsening histology at hysterectomy (P < 0.0001 and P = 0.0001). There was only one report of vaginal cancer subsequent to hysterectomy for CIN and insufficient data to allow for reliable meta-analysis. CONCLUSIONS: Vault smears cause anxiety, consume resources and their value is largely unproven. Inconsistency of study design and limited methodological quality means that the value of vault smears could not be established. High-quality research is required to ensure that the guidelines are evidence based.

Female↗
PubMed1996

Relationships between bacterial drug resistance pumps and other transport proteins.

We have used three reference sequences representative of bacterial drug resistance pumps and sugar transport proteins to collect the 91 most closely related sequences from a composite, nonredundant protein sequence database. Having eliminated certain very close relatives, the remainder were subjected to analysis and alignment by using two different similarity matrices: one of these was a matrix based on structural conservation of amino acid residues in proteins of known conformation and the other was based on the more familiar mutational matrix. Unrooted similarity trees for these proteins were constructed for each matrix and compared. A systematic analysis of the differences between these trees was undertaken and the sequences were analyzed for the presence or absence of certain sequence motifs. The results show that the clades created by the two methods are broadly comparable but that there are some clusters of sequences that are significantly different. Further analysis confirmed that (1) the sequences collected by this objective method are all known or putative 12-helix (in some cases reported as 14-helix) transmembrane proteins, (2) there is evidence for few cases of an origin based on gene duplication, (3) the bacterial drug resistance pumps are distributed in more than one clade and cannot be regarded as a definitive subset of these proteins, and that (4) the diversity is such that there is no evidence of a single ancestral protein. The possible extension of the methods to other cases of divergent protein sequences is discussed.

Amino Acid Sequence↗
PubMed2002

An antibody-calmodulin fusion protein reveals a functional dependence between macromolecular isoelectric point and tumor targeting performance.

PURPOSE: Human monoclonal antibodies are promising agents for the development of improved anticancer therapeutics, because, unlike low-molecular-weight chemotherapeutic agents, they can selectively localize to solid tumors. In particular, the scFv(L19) antibody fragment, specific for the EDB domain of fibronectin, a marker of angiogenesis, has demonstrated an impressive tumor targeting performance in a variety of tumor-bearing animals and in patients with cancer. The purpose of this study was to develop a tumor pretargeting strategy, based on a novel anti-EDB fusion protein. METHODS AND MATERIALS: We have fused the scFv(L19) to calmodulin, a small acidic protein for which specific binding peptides with a dissociation constant in the picomolar range are available. The resulting fusion protein has been expressed in mammalian cells and purified to homogeneity, before being characterized by quantitative biodistribution analysis in mice bearing the F9 murine teratocarcinoma. RESULTS: Surprisingly, we have found that the fusion of scFv(L19) to calmodulin completely abrogated the tumor targeting ability of the antibody in vivo, although both scFv(L19) and calmodulin moieties within the fusion protein retained unaltered binding affinities toward their respective ligand. Furthermore, a systematic analysis of 13 derivatives of scFv(L19) recently produced in our laboratories showed that the 10 derivatives that retain the tumor targeting ability of the parental antibody have isoelectric points (pI) between 5.0 and 9.0, whereas scFv(L19)-calmodulin (pI = 4.49) and two other derivatives of scFv(L19) with pI >9.0 were unable to target tumors in vivo. CONCLUSIONS: Because the EDB domain of fibronectin is a component of the modified extracellular matrix, predominantly located at the abluminal side of tumor blood vessels, our data suggest that extreme pI values of antibody-based pharmaceuticals may inhibit protein extravasation, perhaps by virtue of electrostatic interactions with endothelial cells and/or components of the extracellular matrix.

Animals↗
PubMed2001

Congenital skeletal abnormalities: an introduction to the radiological semiology.

Despite the recent advances in the molecular diagnosis of congenital abnormalities, the initial identification and the decision to refer a patient for further molecular analysis and expensive genetic tests still relies frequently on clinical and radiological criteria. The radiological identification of syndromes, dwarfs and dysplasias is a difficult task, because there are so many findings to consider and so many syndromes to remember that the problem is overwhelming. There is a definite need for an easy and systematic analysis system, in order to try to categorize a skeletal dysplasia in a certain group. In this brief review, we suggest an approach to the evaluation of skeletal syndromes, based on the analysis of cardinal criteria, from which the most useful information is derived, and additional criteria, making further differentiation possible. Generally, cardinal information is derived from analysis of the long bones, hands, pelvis and the spine, whereas the analysis of other skeletal elements, like the skull, feet, and other flat bones is of additional value.

Bone Diseases, Developmental↗