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PubMed1999

Evidence for effective suppression of recombination in the chromosome 17q21 segment spanning RNU2-BRCA1.

Characterization of associations between polymorphic sites located throughout the approximately 200-400-kb variable-length region spanning RNU2-BRCA1 reveals nearly complete linkage disequilibrium. This segment spans the RNU2 array, which includes 6-30 tandem copies of the U2 snRNA gene, and an adjacent region containing NBR1, the LBRCA1 pseudogene, NBR2, and BRCA1 in a tandemly duplicated structure. A series of biallelic polymorphisms define two common haplotypes that do not vary significantly, in structure or frequency, between populations of primarily European (n=275) or Asian (n=34) ancestry. Lower-frequency variants occurring at distantly located sites within this region also show very strong associations. The rarer haplotype classes appear to be distinguished by mutational alteration and are not recombination products of the two major classes. The two major haplotypes also exhibit significantly different allele-length distributions for local simple tandem-repeat markers. The conservation of extensive distinct chromosomal haplotypes during a long period of human population expansion and divergence indicates that selective forces or specific chromosomal mechanisms result in effective recombination suppression. The extreme degree of long-range linkage disequilibrium at this locus may be exceeded only by that reported for the human MHC locus, where allele-specific functional interactions are believed to be significant. These findings have implications for the estimation of the time of origin of BRCA1 mutations having a founder effect, the interpretation of the significance of rare allelic variants, and the study of the origins of modern populations.

Alleles↗

PubMed2005

Displaced fracture through the anterior atlantal synchondrosis.

In the acute setting, accurate radiological interpretation of paediatric cervical spine trauma can be difficult due to a combination of normal variants and presence of multiple synchondroses. We present a rare case of a fracture through the anterior atlantal synchondrosis in a paediatric spine. A five-year-old boy, who fell backwards onto the top of his head while swinging across on a monkey bar frame, presented with neck pain, cervical muscle spasm and decreased right lateral rotation and extension of his neck. Computed tomography showed a displaced diastatic fracture through right anterior atlantal synchondrosis. There are only 12 cases of paediatric C1 fractures reported in the world literature. The importance of considering this diagnosis in the appropriate clinical setting, and the normal variants in the paediatric atlas that can cause diagnostic dilemma to the interpreting radiologist, are discussed in this case report.

Cartilage, Articular↗

PubMed1985

Heterochromatic chromosome variation and reproductive failure.

The literature on the association of heterochromatic chromosome variants and reproductive failure, manifesting as infertility or recurrent spontaneous abortion, is critically reviewed. Many methodological problems confound attempts to interpret the data. The weight of evidence is against autosomal variants having any significant effect. Although conflicting, reports on the effect of Y heterochromatin variants on both infertility (Yq-) and recurrent abortion (Yq+) are mainly positive, and further data are required in both these areas.

Abortion, Habitual↗

PubMedDate not supplied

Tubes, lines, catheters, and other interesting devices.

Medical devices (tubes, catheters, lines, prostheses, etc.) are a common finding on radiologic studies. Sometimes they may be misdiagnosed as a pathologic process, or an important observation concerning a medical device may be overlooked because of lack of familiarity with a particular device. This review discusses a variety of tubes, lines, catheters, and other interesting and important medical devices found on everyday radiologic studies. Whenever an unusual radiologic finding is encountered, the first question to be asked is, "Is the finding a film artifact or an artifact of the imaging modality itself (computed radiography, computed tomography [CT], ultrasound, magnetic resonance imaging [MRI], nuclear medicine)? If not, does it represent a medical device or foreign material in or on the patient?" All those who interpret radiologic studies should develop the good habits of obtaining and reviewing the patient's prior studies and should, in addition, read the prior radiology reports. Good reading habits, combined with a knowledge of imaging artifacts, medical devices, foreign bodies, and normal anatomic variants, provide a solid starting point for the interpretation of radiologic studies. One very important factor often not appreciated by radiologists and referring physicians is that, in many instances, the radiologic visibility of a medical device has been given no thought, and the device has been designed with no input from the radiologic community. To compound this problem further, devices are often purchased by a hospital or medical center for the lowest price. Those purchasing devices frequently fail to seek advice from radiologists and other physicians concerning the radiologic detectability of the devices they purchase. Medical devices are manufactured from a variety of substances known as biomaterials. These include various types of metals, polymers, rubbers, ceramics, and composites. Biomaterials are substances brought into contact with living tissue for the purpose of treating a medical or dental problem. They must be compatible with human tissues chemically, mechanically, and pharmacologically. There are many ways to classify biomaterials, such as synthetic versus "natural," permanent versus transient, liquid versus solid, hard versus soft, and so forth. Although most life-support devices are within the patient's heart, blood vessels, lungs, or pleura, miscellaneous tubing, clamps, syringes, electrocardiograph (ECG) leads, and other apparatus often lie on or under the patient and appear on radiographs, especially chest studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Biocompatible Materials↗

PubMed1985

A new variant of the anion transport protein in human erythrocytes.

The major plasma membrane protein of human erythrocytes is the anion transport protein, termed protein 3. We previously reported a variant form of protein 3 that is elongated on the amino-terminal end of the molecule, which is exposed on the cytoplasmic side of the membrane, but otherwise its features are identical with those of the normal molecule. We have termed this molecule protein 3 variant 1. We now report a new variant form, protein 3 variant 2. The erythrocyte donor was a double heterozygote whose red cells possess a normal protein 3 and a protein 3 variant which is elongated and possesses a second variation at the 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) reactive site. Variant 2 reacts with 4,4'-diisothiocyano-1,2-diphenylethane-2,2'-disulfonic acid (H2DIDS) more readily than does the normal molecule. At high pH values, H2DIDS acts as a bifunctional cross-linking agent; it cross-links the proteolytic products generated by Pronase (or chymotrypsin) treatment of variant 2 less efficiently than noted for normal protein 3 or the first variant. Thus, the newly identified molecule has an alteration at the DIDS reactive site, which is near the outer surface of the membrane. The results can be interpreted as indicating that the DIDS binding site of variant 2 is more exposed than the normal molecule, but further removed from the site on the carboxyl-terminal fragment involved in cross-linking. Although there is a difference in the reactivity of the two protein 3 chains in variant 2, the reaction of variants 1 and 2 and normal cells with varying concentrations of [3H]H2DIDS results in the same amount of incorporation in all cells. Since protein 3 exists as a dimer or higher aggregate in the membrane, these results may indicate an interaction between monomers.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1985

Aliphatic semisynthetic variants of the amino-terminal residue of sperm whale myoglobin: enrichment with 13C and determination and interpretation of terminal pK values.

The synthesis of a series of myoglobins substituted in the amino-terminal residue to provide variation in the aliphatic nature of the side chain and enrichment in 13C was accomplished by semisynthetic methods. The replacements for valine, the native first residue, included 13C-enriched glycine, alanine, valine, leucine, and isoleucine. The products were extensively characterized and found to be virtually indistinguishable by most physical methods. 13C NMR spectroscopy showed significant differences in the amino-terminal pK value, ranging from 7.72 for [Gly1]myoglobin to 7.15 for [Leu1]myoglobin. Consideration of the electrostatic effects of the charge matrix indicated a balance of interactions at this site not significantly altered by these variations in the side chain. By examination of the crystal structure, consideration of earlier work regarding the interactions of the side chain of Leu-2, and data regarding the motions of the terminal residue, it was concluded that the interaction of the side chain of the first residue with the hydrophobic cluster formed primarily by close contact of invariant residues Leu-2 and Leu-137 was the primary cause for the reduction in terminal pK values seen for the larger aliphatics. By restricting the freedom of the residue, this interaction limits the available hydration volume and consequently favors the unprotonated form of the amine. The concurrent observation of both functional elements in the series of alpha-amino-terminal residues brings out the interrelated consequences for the two categories of solvent interactions controlling structural and functional properties in a graded way.

Amino Acid Sequence↗

PubMed2026

Human IL-34 Deficiency Primes Microglia Toward Alzheimer's Disease-Associated States.

BACKGROUND: Genome-wide association studies (GWAS), with independent replication in large European consortia, have identified a common nonsense variant in IL-34 (Y213X) as a genetic risk factor for late-onset Alzheimer's disease (AD). However, the biological consequences of this IL-34 mutation in humans, its prevalence in the population, and the mechanisms by which IL-34-Y213X alters microglial homeostasis, cerebrospinal fluid (CSF) proteomic networks, and amyloid pathology remain poorly understood. METHODS: We combined human genetics, cerebrospinal fluid (CSF) and serum proteomics, transcriptomics, large-scale phenome-wide association analyses, and preclinical experimental models to define the impact of human IL-34 deficiency. IL-34 concentrations were first quantified in CSF and serum from deeply phenotyped AD cohorts stratified by the common IL-34-Y213X nonsense variant. IL-34 levels and IL-34-Y213X status were then integrated with unbiased CSF proteomic networks and AD biomarkers. Transcriptomic profiling of purified microglia from IL-34 knockout mice was performed to assess disease-associated microglial programs. Using APP/PS1 mice lacking IL-34, we examined the effects of IL-34 deficiency on microglial survival, tiling, and plaque encapsulation. Finally, we performed postmortem analyses of temporal cortex from AD patients carrying IL-34-Y213X to assess microglial density, spatial organization, and plaque-associated responses. FINDINGS: IL-34-Y213X was a strong, dose-dependent loss-of-function (LOF) allele that reduced IL-34 levels by up to 2.5 standard deviations in CSF and serum and was common in multiple populations. IL-34 deficiency reshaped CSF proteomic networks, downregulating axon guidance and microglial support modules while upregulating inflammatory and extracellular matrix signatures, and showed pleiotropic associations with neurological, inflammatory, and metabolic traits. Transcriptomic analysis of sorted microglia from healthy 9-month-old IL-34KO compare to wild-type mice revealed a profound pro-inflammatory and disease-associated microglial transcriptional program enriched for disease-associated microglia (DAM) signatures, inflammatory pathways, and AD risk genes including APOE, CLU, and CASS4. In APP/PS1 mice, genetic IL-34 deletion selectively depleted homeostatic gray-matter microglia, disrupted microglial tiling, and impaired plaque encapsulation, resulting in altered amyloid structure and enhancing neuritic injury. Concordantly, AD patients homozygous for IL-34-Y213X displayed markedly reduced cortical microglial density and increased microglial spatial dispersion, indicating a breakdown of the microglial network organization in the human brain. INTERPRETATION: A common human IL-34 LOF variant creates a naturally occurring model of IL-34 deficiency that links microglial survival, CSF network signatures, and amyloid pathology in both mice and humans. Importantly, IL-34 deficiency alone is sufficient to induce inflammatory, AD-associated microglial states beyond simply reducing microglial number. These findings identify IL-34/CSF1R signaling as a critical determinant of microglial resilience and a potential upstream pathway linking human genetic variation to AD susceptibility, highlighting IL-34-dependent pathways as promising targets for disease modification. FUNDING: This work was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades/FEDER/UE (PID2024-157400OB-I00) and FORTALECE program (FORT23/00008; Instituto de Salud Carlos III, Spain) to RRL and JLV, ISCIII of Spain co-financed by FEDER funds (European Union) through grants PI24/00308 (JV) and CIBERNED collaborative grant 2022/01 to JV, PID2023-147125OB-I00 and CEX2023-001386-S (Severo Ochoa Programme) to SMTBC. A.R. is supported by STAR Award. University of Texas System. Tx, United States, The South Texas ADRC. National Institute of Aging. National Institutes of Health. USA. (P30AG066546), the Keith M. Orme and Pat Vigeon Orme Endowed Chair in Alzheimer's and Neurodegenerative Diseases (2024-2025) and Patricia Ruth Frederick Distinguished Chair for Precision Therapeutics in Alzheimer's and Neurodegenerative Diseases (2025-2028). AR is also supported by the Agency for Innovation and Entrepreneurship (VLAIO) grant N° PR067/21 for the HARPONE project and the ADAPTED project the EU/EFPIA Innovative Medicines Initiative Joint Undertaking Grant N° 115975 and CIBERNED (ISCIII).

Journal Article↗

PubMed1985

QTc and R-R intervals in victims of the sudden infant death syndrome.

Electrocardiograms obtained during sleep within the first and/or fourth week postnatally were available on eight infants who subsequently died of the sudden infant death syndrome (SIDS). The corrected QT (QTc) and R-R intervals were compared with controls for the purpose of evaluating their relevance for SIDS. The QTc interval in controls increased with age and tended to be longer during sleep without rapid eye movements. The R-R interval decreased with age. None of the SIDS victims was found to have a prolonged QTc interval. However, the R-R interval during rapid eye movement epochs was significantly shorter in future SIDS victims compared with controls. These data were interpreted as being inconsistent with the congenital variants of the long-QT hypothesis but compatible with the growing conviction that infants who die of SIDS have a chronic underlying abnormality that has subtle manifestations within the immediate postnatal period.

Electrocardiography↗

PubMed2005

PROTICdb: a web-based application to store, track, query, and compare plant proteome data.

PROTICdb is a web-based application, mainly designed to store and analyze plant proteome data obtained by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and mass spectrometry (MS). The purposes of PROTICdb are (i) to store, track, and query information related to proteomic experiments, i.e., from tissue sampling to protein identification and quantitative measurements, and (ii) to integrate information from the user's own expertise and other sources into a knowledge base, used to support data interpretation (e.g., for the determination of allelic variants or products of post-translational modifications). Data insertion into the relational database of PROTICdb is achieved either by uploading outputs of image analysis and MS identification software, or by filling web forms. 2-D PAGE annotated maps can be displayed, queried, and compared through a graphical interface. Links to external databases are also available. Quantitative data can be easily exported in a tabulated format for statistical analyses. PROTICdb is based on the Oracle or the PostgreSQL Database Management System and is freely available upon request at the following URL: http://moulon.inra.fr/ bioinfo/PROTICdb.

Computer Graphics↗

PubMedDate not supplied

Emergency radiology of the pediatric chest.

This monograph will present an overview of pediatric emergency room chest radiology. Technique, interpretative approach, normal radiologic appearances, common normal variants, and unique features of the pediatric lung are discussed. The radiologic features of common pediatric chest emergencies (infection, airway foreign body, asthma, hydrocarbon aspiration, near-drowning pneumothorax, trauma, hemosiderosis and upper airway obstruction) are described and illustrated.

Child↗

PubMed2006

Estimating vaccine effectiveness against laboratory-confirmed influenza using a sentinel physician network: results from the 2005-2006 season of dual A and B vaccine mismatch in Canada.

INTRODUCTION: We report a case-control design using a sentinel physician network to estimate vaccine effectiveness (VE) against laboratory-confirmed, medically attended influenza (LC-MAI) and provide results for the 2005-2006 season of dual A and B vaccine mismatch in Canada. METHODS: Participants were patients >or=5 years of age presenting with influenza-like illness (ILI) to a sentinel physician in British Columbia, Canada between November 1, 2005 and April 30, 2006. Cases were participants in whom influenza was identified; controls tested negative for influenza A and B by PCR, R-mix and culture. Isolates were characterized by gene-sequencing and hemagglutination-inhibition (HI) assays. Odds ratios (OR) for LC-MAI in vaccinated versus non-vaccinated persons were derived with adjustment for age and chronic conditions. VE was estimated as [1-OR (vaccinated/unvaccinated)]. RESULTS: The sample included 442 patient visits: median age was 26 years, 10% were >or=65 years, 15% had a chronic condition and 22% received the 2005-2006 trivalent inactivated influenza vaccine >or=2 weeks before ILI onset. Two hundred and six participants were positive for influenza; 107 (52%) had influenza A/H3N2 and 99 (48%) had influenza B/Victoria lineage. Gene sequencing identified mutations away from the vaccine strain at key antigenic binding sites of the hemagglutinin (HA) protein of H3N2 isolates; the neuraminidase (NA) protein was conserved. Based on HI assays, three-quarters of influenza A and all B isolates were mismatched to the 2005-2006 vaccine. Point estimates for VE against LC-MAI were in the range of 50 to 70% for both types of influenza. CONCLUSION: 2005-2006 was the third consecutive season of vaccine mismatch based on varying HA for the A/H3N2 component and the third also for the B component since 2001. Vaccine mismatch resulted in diminished VE but substantial cross-protection. More timely detection of drift variants through gene sequencing of isolates facilitates interpretation of VE results. Since it may be more antigenically conserved, the vaccine content and contribution of NA to overall VE should be further evaluated for both A and B components. Infrastructure for real-time epidemiologic assessment of vaccine performance is important annually and in preparation for a pandemic.

Adolescent↗

PubMed2004

Long-range (17.7 kb) allele-specific polymerase chain reaction method for direct haplotyping of R117H and IVS-8 mutations of the cystic fibrosis transmembrane regulator gene.

Genotyping of genetic polymorphisms is widely used in clinical molecular laboratories to confirm or predict diseases due to single locus mutations. In contrast, very few molecular methods determine the phase or haplotype of two or more mutations that are kilobases apart. In this report, we describe a new method for haplotyping based on long-range allele-specific PCR. Reaction conditions were established to circumvent the incompatibility of using allele-specific primers and a polymerase with proofreading activity. Haplotypes are determined by post-PCR analysis using different detection methods. The clinical application presented here directly determines the phase of two mutations separated by 17.7 kilobases in the cystic fibrosis transmembrane conductance regulator gene. Each mutation, the missense mutation R117H in exon 4 and the 5T polymorphism in intron 8 (IVS-8), have mild phenotypic effect unless they are present on the same chromosome (in cis). If an individual is heterozygous for both R117H and the IVS-8 5T variant, cis/trans testing is required to completely interpret results. The molecular method presented here bypasses the need to perform family studies to establish haplotypes. We propose use of this assay as a reflex clinical test for R117H- 5T-positive samples.

Alleles↗

PubMed2006

Congenital anomalies of the spleen.

Various congenital anomalies may affect the spleen, starting with common anomalies, such as an accessory spleen, up to rare conditions such as a wandering spleen and polysplenia. Most of these anatomic variants have no clinical significance; they need, however, to be recognized by the radiologist as such. Awareness of these variants is important for the radiologist to interpret the findings correctly and avoid mistaking them for a clinically significant abnormality. In this review we illustrate the spectrum of congenital anomalies of the spleen and stress pitfalls and possible complications resulting from these anomalies.

Choristoma↗

PubMed2004

Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis.

RATIONALE AND DESIGN: The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an "immunosuppression minimization protocol" between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection. RESULTS: Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7-329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22-315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV. CONCLUSIONS: Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV clearance overlap with those leading to significant rejection.

Acute Disease↗

PubMed2006

Normal adult EEG and patterns of uncertain significance.

A thorough understanding of a normal EEG is critical in defining those patterns that are abnormal. Because EEG is unique in the ability to support a clinical diagnosis of epilepsy, epileptiform patterns merit careful consideration. Certain benign patterns maybe epileptiform, yet can occur in healthy individuals without epilepsy. Understanding normal EEG and the benign variants will help to minimize over-interpretation and possibly avoid overtreatment of patients during routine clinical practice.

Brain↗

PubMed1977

Focal pregnancy-like changes in the breast.

The aetiology of focal, preganancy-like mammary changes in non-pregnant and non-lactating women is discussed on the basis of the literature and a material of 31 patients. Such changes were found in one or more glandular lobules in 3 per cent of the breast tissue specimens received in our departments. As a rule, this finding was made in women who had been pregnant and who had been or were on oestrogenic or on contraceptive medication. They occurred in fertile, menopausal, as well as in post-menopausal women. Often they were seen many years after the pregnancy and/or intake of hormones. They were observed also in women who had never been pregnant or on hormone medication, and even in men on oestrogen therapy. It is likely, therefore, that focal pregnancy-like changes in non-pregnant and non-lactating women indicate a selective susceptibility of the mammary glandular tissue to oestrogen. Accordingly, we interpret the change as a normal histological variant.

Adenofibroma↗

PubMed1993

A study of hospital admissions over time, using longitudinal latent structure analysis.

The aim was to study patterns of utilization of non-psychiatric admissions over time and factors affecting the utilization. The study cohort includes all individuals born 1934-66, living in one of two Danish municipalities and admitted to a non-psychiatric department at least once in 1977 (n = 2,686). The hospitalizations of the cohort were followed during a 5-year period by means of the Danish National Patient Register. The data were analysed using a longitudinal latent class (LC) model and a longitudinal latent Markov (LM) model. The LC model suggests that among the cases in the cohort there were 4 variants of utilization patterns. The LM model adequately described the sample in only 3 variants or classes. These classes may be interpreted as a small group of "chronically ill" individuals (1.9% of the cohort), a major group of "healthy" individuals, with no, or only a single, random re-admission during the follow-up period (74.4% of the sample), and finally an intermediate group of "high utilizers" (23.7% of the sample). This "chronicity" variable was markedly associated with mental illness, multiple discharge diagnoses from non-psychiatric departments and total utilization of hospitalizations during the follow-up period. Conversely, gender, age and days in hospital per admission were without importance. The study implies that the analysis of patterns of hospital admissions over time can yield important insight into health service utilization and that longitudinal latent structure analyses are powerful statistical tools in this aspect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2004

Lingual vascular canals of the interforaminal region of the mandible: evaluation with conventional tomography.

The presence of lingual vascular foramina and canals in the interforaminal region may increase the risk of surgical complications during implant placement, bone grafting procedures and osteodistraction. Oral and maxillofacial radiologists should recognize this anatomical variant and include a description in their interpretative report to inform the referring clinician of the potential for surgical complications.

Angiography↗