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PubMed2002

[Intraepithelial capillary hemangioma?].

INTRODUCTION: Histological examination of a biopsy of a lesion of the glans penis revealed blood capillaries within the malpighian epithelium. CASE REPORT: A 66 year-old man exhibited two circumscribed red plaques of the glans penis following posthectomy. Their histological examination revealed blood capillaries within the epithelium without basal membrane and pericytes between the endothelial cells and keratinocytes. Further evolution was towards lichen planus of the genital mucous membranes. In spite of a verrucous carcinoma which had been surgically removed, the evolution within a follow-up time of 6 years was favorable. DISCUSSION: Blood capillaries ascending in the epithelium of the genital mucous membranes have been observed in a special variant of Zoon's balanitis, the lichenoid, telangiectatic and purpuric balanitis described by Jonquières in 1971. In our patient exhibiting a lichen planus of the glans penis, the occurrence of blood vessels in the malpighian layer of the epithelium may be interpreted as the consequence of an unusual epithelial and vascular regeneration of an erosive lichenoid lesion. It may also be interpreted as an original neoplasia, and could therefore be considered as a genital intraepithelial capillary hemangioma.

Aged↗
PubMedDate not supplied

[Angiopathy caused by vibration and CREST syndrome: beware of hidden pathologies!].

The etiologic definition of an occupational disease should be achieved via an accurate differential diagnosis. A careful assessment of any clinical features that are atypical or unusual for the disease in question can sometimes lead to the identification of other morbid states that are either hidden or show few symptoms, and may or may not interfere with the occupational picture. The case described is of a man who, after working for 10 years with vibrating tools, developed a vibration disease with typical circulatory alterations in the hands and osteoarticular and neurological alterations. However, the appearance of a necrotic ischaemic lesion at the tip of the second finger of the right hand and signs of sclerodactylia in the second finger of both hands led us to suspect the presence of another concomitant disease. The finding of anticentromere antibodies suggested the presence of a CREST syndrome, which is a serologic variant of diffuse scleroderma. More in-depth investigations and examination of the state of other organs and apparatuses confirmed the diagnostic suspicion, with evidence of impairment also of the cardio-pulmonary system. The presence of the CREST syndrome was interpreted as a state of hypersusceptibility to the traumatic action of vibrating tools on the vascular system.

Arm↗
PubMed1989

[The pulmodiaphragmal ligament. An often misinterpreted normal variant].

In some cases the pulmonary ligament extends caudally to the diaphragm, where it blends with the parietal pleura. This anatomical variant is named the pulmodiafragmal ligament. In chest X-ray it gives rise to spikes and unsharp areas in the central part of the diaphragm in the lateral view. The article describes the pulmodiafragmal ligament and its significance by the interpretation of chest X-ray in normal and pathologic states.

Diaphragm↗
PubMed2005

Atypical fibroxanthoma: a clinicopathological study of 89 cases.

Atypical fibroxanthoma is a controversial entity with a disputed histogenesis. It has recently been suggested that most atypical fibroxanthoma are actually variants of squamous cell carcinoma. We reviewed 100 purported cases of atypical fibroxanthoma received over 4 years to perform clinical follow up and immunohistochemical markers. In particular, we focused on the detection of any recurrence or metastasis. Ten cases were subsequently excluded on the basis of either incorrect coding, or insufficient or absent paraffin blocks on file. A further case was interpreted as a malignant fibrous histiocytoma. Additional new markers, such as CD10 and CD99, were employed in a proportion of cases. Our cases were typical of the usual clinical presentation of atypical fibroxanthoma on the skin of the sun-damaged elderly. We found no cases of recurrent or metastatic atypical fibroxanthoma. Two patients developed a second primary atypical fibroxanthoma. CD10 proved to be a useful marker for atypical fibroxanthoma when used on 20 cases in the present study, as was CD99 in seven cases. The only case demonstrating positive staining for keratin also stained for CD10. It had dual features of atypical fibroxanthoma and squamous cell carcinoma. However, as the majority of atypical fibroxanthoma had no adjacent solar keratosis, our data suggest it is unlikely that atypical fibroxanthoma is a variant of squamous cell carcinoma.

Adult↗
PubMed2025

SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study.

BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold &#x2264;30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0&#xb7;0001) and individuals older than 60 years (p=0&#xb7;0027). The median within-host genome-wide evolutionary rate was 7&#xb7;9&#x2009;&#xd7;&#x2009;10-4 substitutions per site per year (IQR 7&#xb7;0-9&#xb7;0&#x2009;&#xd7;&#x2009;10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.

Humans↗
PubMed1992

Methods for quality adjustment of life years.

Several valuation techniques are in use for quality adjusting life years in cost utility analysis. The paper gives an overview of the variability in results. A close inspection of a number of instruments with respect to their theme, instructions, decision framing and the phrasing of questions make many of the observed differences in results understandable. When judging the validity of the different techniques, three points should be kept in mind. One is that statements about validity should be made with respect to concrete versions rather than broad categories like 'the rating scale', 'time trade-off' etc. Another point is that a valuation technique that is valid in clinical decision analysis may not be valid in health program evaluation, and vice versa. The third point is that quality weights for life years are empirically more meaningful, in the sense that they are more amenable to empirical testing, if they are interpreted simply as preference weights rather than measures of amounts of well life in the utilitarian tradition. Time trade-off with a moderate time horizon is recommended in clinical decision analysis, while a combination of time trade-off and a variant of person trade-off is recommended in health program evaluation.

Attitude to Health↗
PubMed1999

Hypertrophic discoid lupus erythematosus of the conjunctiva.

PURPOSE: To report the ophthalmic manifestations of hypertrophic discoid lupus erythematosus of the conjunctiva. METHOD: Case report and review of biopsy results. RESULTS: A 58-year-old woman with a history of chronic blepharoconjunctivitis presented with an unusual raised conjunctival lesion. Previous biopsy slides were reviewed and interpreted as diagnostic of discoid lupus erythematosus, hypertrophic or verrucous type. Both blepharoconjunctivitis and the raised conjunctival lesion resolved with hydroxychloroquine therapy. CONCLUSIONS: A raised conjunctival mass in the context of refractory blepharoconjunctivitis should elicit suspicion for discoid lupus erythematosus. The hypertrophic variant of this disease can affect the conjunctiva.

Biopsy↗
PubMed2001

A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population.

We have previously reported that there is a high incidence of microsatellite instability (MSI) and germline mismatch repair gene mutation in colorectal cancer arising from young Hong Kong Chinese. Most of the germline mutations involve hMSH2, which is different from the mutation spectrum in the Western population. It is well known that alternative splicing is common in hMLH1, which complicates RNA based mutation detection methods. In contrast, large deletions in hMLH1, commonly observed in some ethnic groups, tend to escape detection by exon-by-exon direct DNA sequencing. Here we report the detection of a novel germline 1.8 kb deletion involving exon 11 of hMLH1 in a local hereditary non-polyposis colorectal cancer family. This mutation generates a mRNA transcript with deletion of exons 10-11, which is indistinguishable from one of the most common and predominant hMLH1 splice variants. A diagnostic test based on PCR of the breakpoint region led to the identification of an additional young colorectal cancer patient with this mutation. Haplotype analysis suggests that they may share a common ancestral mutation. Our results caution investigators in the interpretation of alternative splicing and have important implications for the design of hMLH1 mutation detection strategy in the Chinese population.

Adaptor Proteins, Signal Transducing↗
PubMed2005

The hydrophobic hinge region of rat DNA polymerase beta is critical for substrate binding pocket geometry.

The hydrophobic hinge of DNA polymerase beta facilitates closing and stabilization of the enzyme once the nucleotide substrate has bound. Alteration of the hydrophobic nature of the hinge by the introduction of a hydrophilic glutamine residue in place of isoleucine 260 results in an inaccurate polymerase. The kinetic basis of infidelity is lack of discrimination during the binding of substrate. The I260Q polymerase beta variant has lower affinity than wild type enzyme for the correct substrate and much higher affinity for the incorrect substrate. Our results demonstrate that the hinge is important for formation of the substrate binding pocket. Our results are also consistent with the interpretation that DNA polymerase beta discriminates the correct from incorrect substrate during the binding step.

Amino Acid Substitution↗
PubMed1984

"Chronic pain as a variant of depressive disease". A critical reappraisal.

This paper critically examines the hypothesis that chronic pain is the physical manifestation of an underlying depressive disorder, as proposed by Blumer and Heilbronn in 1982 ( Blumer , D., and Heilbronn , M. Chronic pain as a variant of depressive disease. The pain-prone disorder. J. Nerv . Ment . Dis., 170: 381-406, 1982). The logic of this argument and the empirical evidence provided by Blumer and Heilbronn to support their hypothesis are discussed and their validity challenged. Alternative interpretations for the results as well as for the relationship between pain and depression are noted. Although it may be plausible to view a small subset of chronic pain patients as manifesting a " muted depressive state," the burden of proof still lies with those theorists who adhere to this formulation.

Arthritis, Rheumatoid↗
PubMed2002

The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal.

Magnetic resonance imaging (MRI) has rapidly become an important tool in clinical medicine and biological research. Its functional variant (functional magnetic resonance imaging; fMRI) is currently the most widely used method for brain mapping and studying the neural basis of human cognition. While the method is widespread, there is insufficient knowledge of the physiological basis of the fMRI signal to interpret the data confidently with respect to neural activity. This paper reviews the basic principles of MRI and fMRI, and subsequently discusses in some detail the relationship between the blood-oxygen-level-dependent (BOLD) fMRI signal and the neural activity elicited during sensory stimulation. To examine this relationship, we conducted the first simultaneous intracortical recordings of neural signals and BOLD responses. Depending on the temporal characteristics of the stimulus, a moderate to strong correlation was found between the neural activity measured with microelectrodes and the BOLD signal averaged over a small area around the microelectrode tips. However, the BOLD signal had significantly higher variability than the neural activity, indicating that human fMRI combined with traditional statistical methods underestimates the reliability of the neuronal activity. To understand the relative contribution of several types of neuronal signals to the haemodynamic response, we compared local field potentials (LFPs), single- and multi-unit activity (MUA) with high spatio-temporal fMRI responses recorded simultaneously in monkey visual cortex. At recording sites characterized by transient responses, only the LFP signal was significantly correlated with the haemodynamic response. Furthermore, the LFPs had the largest magnitude signal and linear systems analysis showed that the LFPs were better than the MUAs at predicting the fMRI responses. These findings, together with an analysis of the neural signals, indicate that the BOLD signal primarily measures the input and processing of neuronal information within a region and not the output signal transmitted to other brain regions.

Animals↗
PubMed2001

Predicting splice variant from DNA chip expression data.

Alternative splicing of premessenger RNA is an important layer of regulation in eukaryotic gene expression. Splice variation of a large number of genes has been implicated in various cell growth and differentiation processes. To measure tissue-specific splicing of genes on a large scale, we collected gene expression data from 11 rat tissues using a high-density oligonucleotide array representing 1600 rat genes. Expression of each gene on the chip is measured by 20 pairs of independent oligonucleotide probes. Two algorithms have been developed to normalize and compare the chip hybridization signals among different tissues at individual oligonucleotide probe level. Oligonucleotide probes (the perfect match [PM] probe of each probe pair), detecting potential tissue-specific splice variants, were identified by the algorithms. The identified candidate splice variants have been compared to the alternatively spliced transcripts predicted by an EST clustering program. In addition, 50% of the top candidates predicted by the algorithms were confirmed by RT-PCR experiment. The study indicates that oligonucleotide probe-based DNA chip assays provide a powerful approach to detect splice variants at genome scale.

Algorithms↗
PubMed2006

Space-time image sequence analysis: object tunnels and occlusion volumes.

We address the issue of image sequence analysis jointly in space and time. While typical approaches to such an analysis consider two image frames at a time, we propose to perform this analysis jointly over multiple frames. We concentrate on spatiotemporal segmentation of image sequences and on analysis of occlusion effects therein. The segmentation process is three-dimensional (3-D); we search for a volume carved out by each moving object in the image sequence domain, or "object tunnel," a new space-time concept. We pose the problem in variational framework by using only motion information (no intensity edges). The resulting formulation can be viewed as volume competition, a 3-D generalization of region competition. We parameterize the unknown surface to be estimated, but rather than using an active-surface approach, we embed it into a higher dimensional function and apply the level-set methodology. We first develop simple models for the detection of moving objects over static background; no motion models are needed. Then, in order to improve segmentation accuracy, we incorporate motion models for objects and background. We further extend the method by including explicit models for occluded and newly exposed areas that lead to "occlusion volumes," another new space-time concept. Since, in this case, multiple volumes are sought, we apply a multiphase variant of the level-set method. We present various experimental results for synthetic and natural image sequences.

Algorithms↗
PubMed2002

Chromosomal and allelic variation in Drosophila americana: selective maintenance of a chromosomal cline.

Geographically structured genetic variation, as represented by clines and hybrid zones, offers unique opportunities to study adaptation and speciation in natural populations. A hybrid zone has been reported between Drosophila americana americana and Drosophila americana texana, two taxa that are distinguished solely by the arrangement of their X and 4th chromosomes. In this study, samples of D. americana were collected along a latitudinal transect across the inferred hybrid zone, and the frequency of the alternative chromosomal arrangements is reported. These data illustrate that the alternative chromosomal arrangements are distributed along a shallow cline over a broad geographic region, and that the frequency of the arrangements is tightly correlated with latitude. Allelic variants at 13 RFLP loci in three genes on chromosome 4 exhibit no evidence of association with the cline. Presence of a cline for the chromosomal arrangements, as well as a general absence of geographic structure for variation at these genes, is interpreted as evidence that natural selection is responsible for the maintenance of this chromosomal cline. Furthermore, these results demonstrate that taxonomic subdivision of D. americana is unwarranted, because it exists as a cohesive species that is segregating a chromosomal fusion.

Animals↗
PubMed2002

Healthy-year equivalents in major joint replacement. Can patients provide meaningful responses?

OBJECTIVES: Healthy-years equivalents (HYEs) have been proposed as an evaluative measure with advantages over quality-adjusted life-years (QALYs). The main purpose was to assess the feasibility of eliciting HYEs from patients who have undergone major joint replacement; a secondary objective was to examine relationships with postsurgical health status. METHODS: Pre- and postsurgical reports of perceived comorbidity and current arthritic burden were obtained from 194 patients, using a comorbidity checklist, summary scores from the Western Ontario/McMaster Osteoarthritis Questionnaire (WOMAC), summary scores derived from six Likert scales, and holistic utility scores for the same attributes. After surgery, HYEs for the full across-time health profile were also elicited. RESULTS: All measures of arthritic burden were sensitive to pre/postsurgical changes (p = .0001), and comorbidity scores were stable. Two HYE subgroups emerged. An HYE-invariant subgroup ascribed full HYEs to their profiles, while reporting higher Likert (t = 2.1309; p = .0344) and utility (s = 4.1504; p = .0001) scores for their postsurgical health state. An HYE-variant subgroup reported HYEs that were weakly but significantly (p < .009) correlated with Likert (r = .30), utility (rs = .25), and comorbidity (r = -.26) scores for their postsurgical state. CONCLUSIONS: Our results indicate that patients can understand the HYE assessment procedures and provide interpretable responses. However, a significant proportion reports invariant HYEs that could inflate estimates of the overall mean HYE. Further exploration of the HYEs reported by different clinical and attitudinal populations is needed before widespread adoption of this measure.

Adult↗
PubMed2006

Interferon gamma (IFNgamma) & interleukin-4 (IL-4) gene variants & cytokine levels in pulmonary tuberculosis.

BACKGROUND & OBJECTIVES: Cytokine gene polymorphisms may alter Th1/Th2 balance with major implications in tuberculosis. The aim of our study was to find out whether Interferon gamma +874A and IL-4 -590T polymorphisms were associated with susceptibility to pulmonary tuberculosis as well as the level of IFNgamma and IL-4 in south Indian population. METHODS: Interferon gamma +874A and IL-4 -590T promoter polymorphisms were studied in 129 pulmonary tuberculosis (PTB) patients and 127 normal healthy subjects (NHS) and were associated with culture filtrate and live Mycobacterium tuberculosis induced IFNgamma and IL-4 production in peripheral blood mononuclear cells (PBMCs). IL-4 gene variants were also associated with IgG antibody levels against M. tuberculosis culture filtrate antigen. RESULTS: The variant IFNgamma genotypes and IFNgamma levels between genotypes did not differ significantly in patients and controls. Significantly increased frequency of variant IL-4 'CT' genotype in PTB patients (P<0.05) and 'CC' genotype in control group (P<0.01) was observed. IL-4 levels were detectable in very few subjects and the IgG levels did not differ between the three IL-4 genotypes. INTERPRETATION & CONCLUSION: The study suggests a lack of functional association of Interferon gamma +874A polymorphism in tuberculosis in south Indian population. The higher frequency of IL-4 'CT' genotype in PTB suggests a possible association of IL-4 -590T promoter polymorphism with susceptibility to tuberculosis, and the 'CC' genotype may be associated with protection.

Adult↗
PubMed1998

Ethanol-GABAA receptor interactions: a comparison between cell lines and cerebellar Purkinje cells.

This study compared the interaction between ethanol and gamma-aminobutyric acid (GABA)-mediated current responses elicited in several immortalized cell lines and stably transfected cells, as well as in cultured and acutely dissociated rat cerebellar Purkinje cells. Only cell lines that were found previously to possess functional GABAA receptors were examined in this study. Under identical recording conditions, ethanol (10-200 mM) exerted no effect on GABA-induced currents in any of the cell lines or stably transfected cells tested in this study. However, GABA responses monitored in both primary culture and acutely dissociated Purkinje cells were significantly potentiated by ethanol (25 and 50 mM). Mouse pancreatic cells (RINm5F) were insensitive to both diazepam and ethanol suggesting the expression of a GABAA receptor isoform lacking a gamma subunit. Immortalized neuroblastoma IMR-32 cells displayed GABA responses that could be distinguished based on differential sensitivity to diazepam. However, none of the IMR-32 cells displayed GABA responses that were sensitive to modulation by ethanol. GABA responses in the stably transfected cell lines, PA3 (alpha1beta1gamma2L) and WSS-1 (alpha1beta2gamma2), were also unaffected by exposure to ethanol. In Purkinje cells acutely dissociated from the neonatal cerebellum, the ethanol-induced potentiation of GABA-induced current response could be observed before postnatal day 7, when only the gamma2S but not the gamma2L splice variant is expressed. This indicates that the gamma2L subunit is not necessary for an ethanol-induced potentiation of GABAA receptor-mediated response to become manifest. In addition, the results point to inherent differences that should be taken into account in interpreting comparative data between native and recombinant GABAA receptors.

Animals↗