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Prion diseases in humans show considerable clinical and pathological heterogeneity. The identification of a new variant of Creutzfeldt-Jakob disease, and its interpretation as evidence of transmission of mad cow disease to man, rely critically on our understanding of the epidemiology of prion diseases.
Functional and anatomic evaluation of penile arterial blood flow is essential in the work up of erectile dysfunction. Duplex ultrasonography is an ideal screening modality with cavernosal mean peak systolic blood flow velocity being the most sensitive predictor of arterial disease. Arterial variability of the penis may affect sonographic evaluation leading to frequent misinterpretation and therefore pudendal arteriography remains the current gold standard for penile arterial evaluation. Appreciation of the type and frequency of anatomic variants and potential collateral routes is important in interpreting penile arteriograms and in evaluating the hemodynamic significance of suspected arterial disease.
This study aims to identify genetically diverged clone mates in apomictic dandelions. Clone mates are defined as individuals that may have diverged as a result of mutation accumulation and that have undergone only clonal reproduction since their most recent common ancestor. Based on distinctive morphology and an aberrant and rare chloroplast haplotype, northwest European individuals of Taraxacum section Naevosa are well suited for the detection of clonal lineages in which mutation has occurred. In the case of strictly clonal reproduction, nuclear genetic variability was expected to be hierarchically organized. Nucleotide polymorphisms in internal transcribed spacer (ITS) sequences, however, were incompatible with a clonal structure of the Norwegian individuals, probably due to persistent ancestral polymorphisms that pre-date the origin of the Naevosa clone. This interpretation is supported by the presence of ITS variants in section Naevosa that were also found in distantly related dandelions. In contrast to the ITS sequence data, amplified fragment length polymorphisms (AFLPs), isozymes and microsatellites strongly supported the contention of prolonged clonal reproduction and mutation accumulation in Norwegian Naevosa. Because these markers are generally considered to be more variable and more rapidly evolving than ITS sequences, mutations in these markers probably evolved after the origin of the clone. Within the Norwegian clone, a surprising number of markers distinguished the clone mates. As a consequence, incorporation of mutation in the detection of clone mates is anticipated to have a big impact on estimates of size, geographical range and age of clones as well as on experimental designs of studies of clonal plants.
This article describes the present status and future directions of magnetic resonance arthrography (MRA) of the elbow and the wrist. The indications are evolving and not yet clearly defined. MRA of the elbow is useful for evaluation of collateral ligaments, the articular surfaces, and suspected loose bodies. MRA of the wrist currently is typically reserved for difficult cases. A description and a comparison of direct and indirect MRA techniques is provided. Direct MRA produces reliable joint enhancement with capsular distension. Indirect MRA does not require a radiologist experienced with arthrography but if it is improperly performed, results in suboptimal delineation of intra-articular structures. A review of pertinent normal anatomy and common variants is included as well as a discussion of pathology that is suitably demonstrated by MRA technique. Typical examples of normal variants, abnormalities, and pitfalls are illustrated to reduce interpretive error for radiologists using MRA of the elbow and the wrist.
Protein WIS is a human gamma3 heavy (H) chain disease immunoglobulin variant whose amino acid sequence is most readily interpreted by postulating that three residues of the amino terminus are followed by a deletion of most of the variable (VH) domain, which ends at the variable-constant (VC) joining region. Then there is a stretch of eight residues, three of which are unusual, while the other five have striking homology to the VC junction sequence. This is followed by a second deletion, which ends at the beginning of the quadruplicated hinge region. These findings are consistent with mutations resulting in deletions of most of the gene coding for the V region and CH1 domain followed by splicing at the VC joining region and at the hinge. These structural features fit well the notion of genetic discontinuity between V and C genes and also suggest similar mechanisms of excision and splicing in the interdomain regions of the C gene of the heavy chain.
The "aperture problem" refers to the inherent ambiguity of the motion generated by an untextured contour moving within an aperture. The limited spatial extent of the receptive fields of neurons in cortical areas like V1 and MT render them susceptible to this problem. Most psychophysical experiments have probed how the visual system overcomes the aperture problem by presenting moving contours behind one or more simulated apertures. The assumption has been that the computational ambiguities that arise in resolving these displays are equivalent to the computational problems created by receptive fields that sample a small region of visual space. Evidence is presented here that challenges this view. We demonstrate that a fundamental computational difference in the interpretation of contour terminators arises in these two variants of the aperture problem. When the aperture is a receptive field, and a moving contour extends beyond its boundaries, the contour "terminators" delimit the boundaries of the receptive field, not the ends of the contour. In contrast, when a moving contour is viewed through a simulated aperture, the contour terminators are generated by the occluding edges of the aperture. In a series of experiments, we show that reciprocal interactions arise between computations of occlusion and those of motion direction and integration. Our results demonstrate that the visual system solves the aperture problem by decomposing moving contours into moving segments, and unpaired terminators that arise from the accretion and deletion of contours behind occluding edges, generating both coherent motion and illusory occluding surfaces.
To address the role of dimerization in the function of the monocyte chemoattractant protein-1, MCP-1, we mutated residues that comprise the core of the dimerization interface and characterized the ability of these mutants to dimerize and to bind and activate the MCP-1 receptor, CCR2b. One mutant, P8A*, does not dimerize. However, it has wild type binding affinity, stimulates chemotaxis, inhibits adenylate cyclase, and stimulates calcium influx with wild type potency and efficacy. These data suggest that MCP-1 binds and activates its receptor as a monomer. In contrast, Y13A*, another monomeric mutant, has a 100-fold weaker binding affinity, is a much less potent inhibitor of adenylate cyclase and stimulator of calcium influx, and is unable to stimulate chemotaxis. Thus Tyr13 may make important contacts with the receptor that are required for high affinity binding and signal transduction. We also explored whether a mutant, [1+9-76]MCP-1 (MCP-1 lacking residues 2-8), antagonizes wild type MCP-1 by competitive inhibition, or by a dominant negative mechanism wherein heterodimers of MCP-1 and [1+9-76]MCP-1 bind to the receptor but are signaling incompetent. Consistent with the finding that MCP-1 can bind and activate the receptor as a monomer, we demonstrate that binding of MCP-1 in the presence of [1+9-76]MCP-1 over a range of concentrations of both ligands fits well to a simple model in which monomeric [1+9-76]MCP-1 functions as a competitive inhibitor of monomeric MCP-1. These results are crucial for elucidating the molecular details of receptor binding and activation, for interpreting mutagenesis data, for understanding how antagonistic chemokine variants function, and for the design of receptor antagonists.
Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAP(ICE)) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same approximately 300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAP(ICE) association results in about 4,500 subjects is consistent with a small (odds ratio approximately 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP(ICE) is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus.
We describe two histologically unusual cases of ependymoma of the filum terminale. Both tumors occurred in 14-year-old boys. An intradural encapsulated mass attached to the filum terminale was demonstrated radiologically in both cases and totally resected at surgery. In case 1 the neoplasm was uniformly composed of pleomorphic giant cells and was without perivascular pseudorosettes or myxopapillary changes. Case 2 was a myxopapillary ependymoma with multiple foci of pleomorphic giant cells. Neither tumor had prominent mitotic activity, necrosis, or endothelial proliferation. Both tumors were immunopositive for cytokeratin and glial fibrillary acidic protein. Ultrastructural features included basal laminae, interdigitating cell processes, microvilli, cilia, intercellular junctions, and cytoplasmic intermediate filaments. Cytogenetic analysis in case 1 showed a hypodiploid karyotype with monosomy of chromosomes 1, 10, 14, 16, 20, and 22. We interpret both tumors as most consistent with a variant of ependymoma. Because of the unique gigantocellular light microscopic appearance of the entire tumor in case 1, we propose classifying this tumor as a new morphologic subtype: giant cell ependymoma of the filum terminale. The combination of gigantocellular and myxopapillary features in case 2 supports a histogenetic relationship between giant cell ependymoma and myxopapillary ependymoma.
BACKGROUND: Angiotensin converting enzyme (ACE) perhaps plays roles in regulating coronary vasomotor tone by producing angiotensin II and degrading bradykinin. OBJECTIVES: We sought to investigate the role of ACE gene polymorphism in the pathogenesis of variant angina and to compare it with that of other clinical risk factors for male patients with variant angina and age-matched and sex-matched control subjects. METHODS: We studied 78 male patients with variant angina who exhibited spontaneous or provoked coronary spasms during coronary angiography and compared prevalences of ACE gene genotype (deletion D and insertion I) and other risk factors between this group of patients with variant angina and age-matched and sex-matched control subjects whose angiograms were normal and in whom the ergonovine test did not cause spasms (n = 80). RESULTS: Smokers were more prevalent in the group of patients with variant angina (P < 0.05). Genotype and allele prevalences of the group of patients with variant angina (0.14, 0.53 and 0.33 for DD, DI and II and 0.41 and 0.59 for D and I, respectively) were no different from those of the control group (0.16, 0.49 and 0.35 for DD, DI and II and 0.40 and 0.60 for D and I). Multiple logistic regression analysis showed that smoking was a significant risk factor for variant angina (odds ratio 2.61, 95% confidence interval 1.03-6.66) whereas ACE genotype was not. CONCLUSIONS: Variant angina is associated with an environmental factor, such as smoking, rather than a genetic factor, such as ACE gene polymorphism.
Our review is concerned with the relationship of the five-factor model of personality to psychopathology, focusing in particular on Axis II personality disorders and depression. The five factors provide a particularly compelling model for interpreting the Axis II personality disorders as maladaptive variants of normal personality traits. However, we also discuss methodological and conceptual limitations of this application. There has been little research on the relationship of Openness, Agreeableness, and Conscientiousness to Axis I mental disorders, but considerable attention has been given to Neuroticism and Extraversion. We focus in particular on the difficulty in distinguishing between the various ways in which personality can relate to depression, either as a predisposition to, a complication of, a pathoplastic effect upon, or a spectrum variant of the mental disorder. We conclude with recommendations for future research.
BACKGROUND: Several entities or variants within focal segmental glomerulosclerosis (FSGS) have been described, but their changes with time and interrelationships are undetermined. METHODS: Changes with time were studied in two series of segmental sclerosing lesions in the nephrotic syndrome, one of 22 specimens from ten patients in a trial, the other of 176 specimens from 121 consecutive patients. RESULTS: The earliest lesions were probably all at the tubular origin, equivalent to the tip variant of FSGS. In some patients, lesions remained at this site, but progression to renal failure was accompanied by morphologic progression, with development of lesions at various sites, equivalent to FSGS, not otherwise specified (NOS). Progression was more likely if there were large lesions, abnormal mesangium, and extensive acute tubular damage. Patients with lesions at the tubular origin at presentation had a shorter duration of symptoms and less chronic renal damage than those with multiple lesions, were more likely to have a complete response of the nephrotic syndrome, and were less likely to progress to renal failure. Recurrent nephrotic syndrome occurred in 12 of 14 allografts at risk, and was usually accompanied by lesions at the tubular origin, then multiple lesions. CONCLUSION: At least some patients with FSGS (NOS) have evolved from the tip variant. The tip variant has been considered a distinct entity. Another interpretation is that it includes two conditions, one an early form of classic FSGS, and the other closely related to minimal change nephropathy (MCN), equivalent to the glomerular tip lesion as originally defined.
We report on 9 patients with pilomatricomas that showed unusual histopathologic features. Our patients were mainly elderly individuals (age range 42 to 88 years; mean age 70.1 years) who presented solitary cutaneous nodules situated on the head and neck (7 neoplasms), upper arm (1 neoplasm), and back (1 neoplasm). All the lesions were treated by simple excision. Follow-up data available in 7 of the 9 patients (mean follow-up, 17 months) revealed local recurrences in 1 patient whose lesion recurred 3 times. No lymph node involvement or distant metastases were recorded in any of our cases. Histopathologically, most neoplasms were characterized by a relatively large lesion in the dermis that in some cases showed extension to the subcutis. Each lesion was predominantly composed of a lobular proliferation of basaloid cells in association with adjacent focal areas containing eosinophilic, cornified material with shadow cells. In some cases, relatively large areas of shadow cells were present, whereas, in others only small foci of shadows cells were observed. Cytomorphologically, the basaloid cells showed features of matrical and supramatrical cells of a normal hair follicle and exhibited variable nuclear atypia and mitotic figures. The overall architectural pattern of the neoplasms was different from that of large fully developed stereotypical pilomatricomas that maintain a cystic character with basaloid cells predominantly aligned at the periphery. Based on the histopathologic findings, namely the presence of a large, lobular proliferation of basaloid cells in association with small to large foci of shadow cells, we interpreted these neoplasms to be a distinctive proliferative variant of pilomatricoma and propose the designation "proliferating pilomatricoma." Proliferating pilomatricomas should be differentiated from the recently described matricoma, basal-cell carcinoma with matrical differentiation, and matrical carcinoma (pilomatrical carcinoma).
Virion capture assays, in which immobilized antibodies (Abs) capture virus particles, have been used to suggest that nonneutralizing Abs bind effectively to human immunodeficiency virus type 1 (HIV-1) primary viruses. Here, we show that virion capture assays, under conditions commonly reported in the literature, give a poor indication of epitope expression on the surface of infectious primary HIV-1. First, estimation of primary HIV-1 capture by p24 measurements shows a very poor correlation with an estimation based on infectivity measurements. Second, virion capture appears to require relatively low Ab affinity for the virion, as shown by the ability of a monoclonal Ab to capture a wild-type and a neutralization escape variant virus equally well. Nevertheless, in a more interpretable competition format, it is shown that nonneutralizing anti-CD4 binding site (CD4bs) Abs compete with a neutralizing anti-CD4bs Ab (b12) for virus capture, suggesting that the nonneutralizing anti-CD4bs Abs are able to bind to the envelope species that is involved in virion capture in these experiments. However, the nonneutralizing anti-CD4bs Abs do not inhibit neutralization by b12 even at considerable excess. This suggests that the nonneutralizing Abs are unable to bind effectively to the envelope species required for virus infectivity. The results were obtained for three different primary virus envelopes. The explanation that we favor is that infectious HIV-1 primary virions can express two forms of gp120, an accessible nonfunctional form and a functional form with limited access. Binding to the nonfunctional form, which needs only to be present at relatively low density on the virion, permits capture but does not lead to neutralization. The expression of a nonfunctional but accessible form of gp120 on virions may contribute to the general failure of HIV-1 infection to elicit cross-neutralizing Abs and may represent a significant problem for vaccines based on viruses or virus-like particles.
OBJECTIVE: This article evaluates the feasibility of single-dose gadobenate dimeglumine-enhanced MRI as both an angiographic and biliary contrast medium for making a preoperative evaluation of the donor candidates for a living-donor-related liver transplantation. SUBJECTS AND METHODS: Eleven right hepatic lobe donors underwent MRI examinations using T1- and T2-weighted imaging and T2-weighted MR cholangiography (MRC). The MR angiography (MRA) and contrast-enhanced (CE) T1-weighted MRC images then were obtained after injecting a single dose of gadobenate dimeglumine. One radiologist and one surgeon prospectively reviewed all the MRI examinations for hepatic vascular and biliary abnormalities and compared them with the surgical findings and intraoperative cholangiograms. In addition, two blinded reviewers evaluated the two sets of MRC (T2-weighted MRC set and T2-weighted MRC plus CE-T1-weighted MRC set) retrospectively and recorded the anatomic types of the hilar biliary branching pattern along with their confidence in the interpretation. RESULTS: Prospective analysis detected the following vascular variants: hepatic arterial variation in two patients, portal venous variation in one, and a significantly large accessory hepatic vein (> 5 mm) in one. Biliary variants also were identified in two patients. All the MRI findings on the vascular and biliary anatomy were corroborated intraoperatively. Retrospective analysis showed that the mean diagnostic confidence in the combined set was significantly higher than that of the T2-weighted MRC alone by both reviewers (p < 0.05). CONCLUSION: Obtaining both MRA and CE-T1-weighted MRC is feasible using a single dose of gadobenate dimeglumine. Therefore, gadobenate dimeglumine-enhanced MRI might play a role as a preoperative imaging technique for the vascular and biliary evaluation of potential living donors.
BACKGROUND: It has been suggested that patients with somatoform disorders are high utilizers of medical care, yet interpretation of studies has been difficult because of variant methods of diagnosis. The goal of this study was to compare 5 different methods of classification on the same group of subjects and to examine prevalence rates of somatoform disorders and medical utilization. METHOD: Subjects completed a demographic questionnaire in the physician's office and the somatization section of the Diagnostic Interview Schedule (DIS) by telephone. Subsequently, their medical charts were examined. Using the 5 methods of diagnosis, somatizers were compared with nonsomatizers for level of utilization of medical services. The setting was a medical school-based family practice residency training center. Participants were 119 patients waiting to see their family doctors. The main outcome measures were prevalence of somatization symptoms and chart information (utilization, number of health problems). RESULTS: One subject met the Diagnostic and Statistical Manual (DSM-IV)-based DIS criteria for somatization disorder. With the Bucholz modification for scoring the DIS, 10 subjects were diagnosed with somatization disorder. With the abridged Escobar criteria of 6 symptoms, 7 subjects met diagnostic criteria, while 28 met the criteria for multisomatoform disorder of 3 symptoms, as suggested by Kroenke. The diagnosis of undifferentiated somatoform disorder, requiring only 1 unexplained symptom, was obtained by 94 of the subjects. CONCLUSION: Findings from this study revealed widely divergent prevalence rates of somatoform disorders, depending on methods of diagnosis used. Correlation with rates of medical utilization is suggested as an external criterion for validating diagnostic methods.
Rare coding variants can have large effects on disease risk and provide direct routes from human genetics to disease mechanisms and therapeutic targets, but their discovery is constrained by sample size, particularly for low-prevalence diseases. Here we establish the Biobank Rare Variant Analysis (BRaVa) consortium, a global rare variant association resource that integrates sequencing and linked health-record data from ten biobanks and cohorts comprising over 1.2 million individuals across diverse ancestries. We performed gene-based meta-analyses of rare coding variation across 33 clinical endpoints and 11 quantitative traits. Aggregating evidence across biobanks and ancestries identified 514 gene-trait associations, including 31 not previously reported in prior studies or curated association resources following systematic literature review. Notably, 36.1% of gene-level associations were undetectable in any individual biobank, and 91 emerged only through cross-ancestry meta-analysis, demonstrating that federated integration enables discovery beyond the reach of single cohorts. Similar gains were observed at the variant level, where 25.0% of phenotype-locus associations were detectable only through meta-analysis. Effect size estimates were correlated across ancestries with concordant directions of effect, supporting the generalizability of rare variant associations. The identified signals implicate pathways involved in transcriptional and epigenetic regulation, metabolism, vascular and epithelial biology, and immune function, highlighting rare coding variation as an engine for biological discovery across medical record phenotypes. For example, damaging variation in ANKRD12 implicates inflammatory transcriptional dysregulation in asthma and chronic obstructive pulmonary disease, and ultra-rare predicted loss-of-function variants in NAA15 link protein acetylation processes to type 2 diabetes risk. BRaVa establishes a scalable framework and freely available community resource for rare variant meta-analysis across global biobanks. Public release of gene- and variant-level association summary statistics provides a reference map of rare coding variant associations to support disease gene discovery, biological interpretation, and therapeutic target prioritization as sequencing-linked health-record resources continue to expand.
Despite the recent development of diagnostic modalities such as CT and MRI, plain radiography continues to play an important role in chest radiology. Chest radiography remains the imaging modality of choice for initial examinations because it offers simplicity, low cost, and a large amount of information. It is important for radiologists to understand normal anatomy and variants simulating disease to avoid false-positive interpretations of chest radiographs and unnecessary CT examinations. It should be noted that many cases can be diagnosed correctly by chest radiographs alone. Only after careful evaluation of an abnormality on chest radiograph should CT examination be performed. We should also be aware that some serious chest diseases, including miliary tuberculosis, can present normal chest radiographs in the early stage. In such patients with respiratory symptoms, even when the chest radiograph is negative, CT examination should be performed promptly to avoid disease progression.