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PubMed2006

Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis.

OBJECTIVE: Our objective was to investigate a role of the intracellular tyrosine phosphatase PTPN22*R620W variant in autoimmune myasthenia gravis (MG), considering disease heterogeneity. METHODS: We used a case-control design, comparing 470 patients and 296 controls, all French whites. Patients were categorized depending on the presence of a thymoma and serum anti-titin antibodies. RESULTS: The 620W risk allele was increased in 293 nonthymoma patients without anti-titin antibodies (odds ratio, 1.97; 95% confidence interval, 1.32-2.97, p = 0.00059) but not in nonthymoma patients with anti-titin antibodies or in thymoma patients. INTERPRETATION: Our genetic findings strengthen the concept that these groups of patients correspond to etiologically distinct disease entities.

Adult↗
PubMed2003

Different binding pattern of antibodies to prion protein on lymphocytes from patients with sporadic Creutzfeldt-Jakob disease.

In Creutzfeldt-Jakob disease (CJD), progressive neuronal cell death probably occurs as a result of a change in conformation of the physiological prion protein (PrP(C)). There is evidence of participation of the lymphatic system and in particular of lymphocytes in the intracorporeal transportation of the pathological prion protein (PrP(Sc)) in new variant CJD and scrapie. Using fluorescence cytometry, we investigated a possible alteration of PrP(C) on lymphocytes of patients with sporadic CJD. We demonstrated a significantly lower binding pattern of antibodies (3F4) against physiological prion protein to lymphocytes of patients with sporadic CJD (n=16) compared with control patients. In contrast this difference was not found on platelets (n=23). For the first time we were able to present a measurable difference of antibody binding on lymphocytes of patients with CJD. One interpretation of this finding is that lymphocytes patrolling the brain bind and transport PrP(Sc) which has a lower binding affinity for the antibodies directed against physiological PrP.

Adult↗
PubMed2002

Children use whole-part juxtaposition as a pragmatic cue to word meaning.

When parents label novel parts of familiar objects, they typically provide familiar whole-object terms before offering novel part terms (e.g., "See this cup? This is the rim."). Such whole-part juxtaposition might help children to accurately interpret the meaning of novel part terms, but it can do so only if they recognize the conjunction as a potential cue to part meaning. Two studies examined (a) whether 3- to 4-year-olds use whole-part juxtaposition to accurately interpret novel part terms and (b) how they might do so. Study 1 confirmed that children indeed use juxtaposition to guide learning of novel part terms. Furthermore, 2 control conditions clarified that children's use of juxtaposition was not simply due to memory effects, such as the facilitation of lexical access, nor to recognition of the grammatical frame that typically accompanies juxtaposition. Study 2 revealed that children readily use juxtaposition in a novel, gestural format. Such flexibility in recognizing and utilizing novel variants of juxtaposition strongly suggests that pragmatic understanding lies at the heart of children's sensitivity to whole-part juxtaposition.

Association Learning↗
PubMed2003

Association studies for asthma and atopic diseases: a comprehensive review of the literature.

Hundreds of genetic association studies on asthma-related phenotypes have been conducted in different populations. To date, variants in 64 genes have been reported to be associated with asthma or related traits in at least one study. Of these, 33 associations were replicated in a second study, 9 associations were not replicated either in a second study or a second sample in the same study, and 22 associations were reported in just a single published study. These results suggest the potential for a great amount of heterogeneity underlying asthma. However, many of these studies are methodologically limited and their interpretation hampered by small sample sizes.

Asthma↗
PubMed2000

Prevalence of detectable abnormal prion protein in persons incubating vCJD: plausible incubation periods and cautious inference.

BACKGROUND: Both small and large variant Creutzfeldt Jakob disease (vCJD) epidemics are consistent with the current observed incidence. Uncertainty in vCJD projections could potentially be reduced by incorporating information on the prevalence of the infectious agent in persons incubating vCJD. The prospect of vCJD prevalence studies has been raised by detection of abnormal prion protein, thought to be the infectious agent, in appendices and tonsils removed from vCJD patients. Although unlinked anonymous testing of stored operative tissues for abnormal prion protein is very appealing, the design and interpretation of such prevalence studies is complicated by the lack of information on how early in the incubation period of vCJD the abnormal prion protein becomes detectable. METHODS: We simulate a range of vCJD epidemics, consistent with the limited available information on the incidence of vCJD, to illustrate some of the potential problems encountered when interpreting the results from prevalence studies of detectable abnormal prion protein. We assume plausible incubation period distributions and dietary exposure patterns. RESULTS: We demonstrate, in the context of our simulated epidemics, that prevalence studies of detectable abnormal prion protein would require the testing of tens of thousands of operative specimens and, even then, that unlinked anonymous testing positives would be unexpected.

Animals↗
PubMed1987

[Kaposi disease in an LAV/HTLV-III antibody negative patient at risk for AIDS].

We report on a disseminated variant of Kaposi's sarcoma (M.K.) with a moderate course in a homosexual patient negative for LAV/HTLV-III antibodies. The disease had started at the age of 44 years. Clinical examination proved the patient's good condition. Serological findings revealed numerous former infections. Control investigations for 5 years have not shown any signs of immune deficiency, so far. Morphological investigation (applicable to all forms of M.K.) indicated a reversed differentiation of the vascular connective tissue with ensuing misdifferentiation. Thus, the tumor should be interpreted as an abnormal product of the primary vascular mesenchyme. It is characterized by a synchymal/spongiochymal structure. This view corresponds with older ideas. Recent histochemical and electron microscopical findings do not contradict this conception in any way, but do rather confirm it.

Acquired Immunodeficiency Syndrome↗
PubMed1986

The anatomy of the greater saphenous venous system.

To define surgical anatomy, a prospective study of the greater saphenous venous system in 385 instances in 331 patients was carried out with the use of prebypass phlebography (either pre- or intraoperative). The phlebographic interpretations were confirmed during the operative procedures and from the completion angiogram. These details were recorded and analyzed by a specific computer program. These data consisted of a number of superficial branches, perforators, the identification of valve leaflets, sinuses, and the size and position of the main venous trunk both in the thigh and in the calf. The study showed that a single trunk was present in the thigh in 65% of patients and in the calf in 45%. The remainder were variants of double systems. In two thirds of patients who had complete double systems, the larger system was used for in situ bypass but the rest required the use of parts of both systems. Phlebography was accurate in the depiction of the anatomic variations (93%), double systems, cross connections, and perforator branches (87%). However, the number of competent valves could not be accurately determined (accuracy, 68%). The diameter of the vein was frequently underestimated (in 80% by 1.1 +/- 0.4 mm) and hence could not be used as an index of vein adequacy. After phlebography, four patients had transient rises in serum creatinine levels and one had an iatrogenic thrombosis of a distal segment. This study suggests that the precise anatomy of the greater saphenous venous system should be determined preoperatively by phlebography since this information is valuable for proper surgical planning before vein is used as a graft or for in situ bypass in the lower extremity.

Adult↗
PubMed1999

Phylogenetic evidence for horizontal transmission of Wolbachia in host-parasitoid associations.

Endosymbiotic Wolbachia infect a number of arthropod species in which they can affect the reproductive system. While maternally transmitted, unlike mitochondria their molecular phylogeny does not parallel that of their hosts. This strongly suggests horizontal transmission among species, the mechanisms of which remain unknown. Such transfers require intimate between-species relationships, and thus host-parasite associations are outstandingly appropriate for study. Here, we demonstrate that hymenopteran parasitoids of frugivorous Drosophila species are especially susceptible to Wolbachia infection. Of the five common European species, four proved to be infected; furthermore, multiple infections are common, with one species being doubly infected and two triply infected (first report). Phylogenetic statuses of the Wolbachia infecting the different species of the community have been studied using the gene wsp, a highly variable gene recently described. This study reveals exciting similarities between the Wolbachia variants found in parasitoids and their hosts. These arguments strongly support the hypothesis of frequent natural Wolbachia transfers into other species and open a new field for genetic exchanges among species, especially in host-parasitoid associations.

Animals↗
PubMed1989

Scatter compensation in digital chest radiography using Fourier deconvolution.

The authors present a numerical deconvolution technique to compensate for image degrading effects caused by scattered photons in radiographic chest images. Fourier transform techniques are used to deconvolve a shift invariant model of the two dimensional point spread response functions of the scattered radiation. This approach uses a digitized radiograph acquired with a standard chest imaging protocol, so no specialized imaging equipment is required. While the shift variant shape of the scatter model is optimized for the lung field, effective compensation is provided when this model shape is applied to other chest regions. Preliminary evaluation suggests that this technique can provide improved image contrast over the entire chest region.

Computer Simulation↗
PubMed2006

Quantitative perfusion imaging using arterial spin labeling.

MRI-based perfusion imaging techniques can be classified into those that use exogenously administered contrast agents and those that use an endogenous material that reflects blood flow. This chapter focuses on the technique of arterial spin labeling (ASL), in which endogenous water is made a freely diffusible perfusion tracer by perturbing the magnetization of blood water in arteries prior to their entry into tissue of interest. The technique is totally noninvasive and allows repeated quantitative blood flow measurements in a time scale limited only by the spin lattice relaxation time (T1). Absolute quantitation requires measurement of T1, transit time, and labeling efficiency, as well as careful control for magnetization transfer effects. Two main variants of the ASL technique are in use: continuous ASL (CASL) and pulsed ASL (PASL). This chapter describes basic theory for CASL, and experimental and computational procedures for obtaining quantitative perfusion maps of the brain. Extension of the technique for renal perfusion imaging is outlined.

Animals↗
PubMed2026

International trends in concurrent hysterectomy at risk-reducing surgery in BRCA1/2 pathogenic variant carriers: a mixed-methods study.

BACKGROUND: BRCA1/2 pathogenic variant carriers are advised to undergo a risk-reducing salpingo-oophorectomy between the ages of 35 and 45 due to their increased risk of tubo-ovarian cancer. A concurrent hysterectomy may be performed at the time of risk-reducing salpingo-oophorectomy. Currently, the international execution of hysterectomy during risk-reducing surgery and the factors guiding related decision-making are unknown. OBJECTIVE: We aimed to evaluate the international execution of concurrent hysterectomy during risk-reducing surgery for tubo-ovarian cancer and factors guiding providers' decision-making about this. STUDY DESIGN: We conducted a mixed-methods study. First, we executed a quantitative analysis with data from the Women choosIng Surgical Prevention (WISP) and TUBectomy with delayed oophorectomy as Alternative for risk-reducing salpingo-oophorectomy in high-risk Women to assess the Safety of Prevention (TUBA-WISP II) study, both prospective preferential trials assessing surgical strategies for tubo-ovarian cancer prevention. Data were collected via electronic case report forms. Concurrent hysterectomy during risk-reducing salpingo-oophorectomy was compared between Europe, North- and South America, and Australia using Kruskal-Wallis tests. We used univariable logistic regression models to estimate the association of personal and prevention-related characteristics with the execution of hysterectomy at risk-reducing salpingo-oophorectomy in women from North- and South America. Subsequently, we conducted focus group interviews with gynecologic providers from 12 countries who provide preventive care for individuals at increased risk of tubo-ovarian cancer to identify indications, barriers, and facilitators for the execution of hysterectomy with risk-reducing salpingo-oophorectomy. RESULTS: In the quantitative analysis, we included 2181 participants, of whom 1647 (75.5%) were from Europe, 498 (22.8%) from North- and South America, and 36 (1.7%) from Australia. Execution of hysterectomy at risk-reducing salpingo-oophorectomy differed substantially between continents, with an execution of 48.8% in North- and South America, 14.2% in Australia, and 2.8% in Europe (P<.001). Execution of concurrent hysterectomy at risk-reducing salpingectomy in women from North- and South America occurred more often in women with a BRCA1 pathogenic variant compared to a BRCA2 pathogenic variant (adjusted odds ratio 0.4 [95% confidence interval, 0.2-0.7]). In the qualitative analysis, we interviewed 23 healthcare providers and identified 31 barriers and 32 facilitators regarding hysterectomy execution during risk-reducing salpingo-oophorectomy. A total of 8 different indications were mentioned, but opinions varied on the validity and weight given to each indication. Providers indicated that important barriers or facilitators for concurrent hysterectomy included a lack of clear guidelines, cultural variation between countries, (lack of) consensus within departments, and different interpretation of the endometrial cancer risk. CONCLUSION: Internationally, there is a large variation in execution of hysterectomy during risk-reducing surgery with frequent utilization in North- and South America, and rare utilization in Europe. This could be explained by the interpretation of indications for hysterectomy by providers, which might be explained by cultural variation, the absence of clear guidelines, and limited scientific evidence.

Humans↗
PubMed2006

GFP-based FRET analysis in live cells.

Fluorescence resonance energy transfer (FRET) is a widely utilized optical technique for measuring small distances of 1-10 nm in live cells. In recent years, its application has been greatly popularized by the discovery of green fluorescent protein (GFP) and many improved variants which make good donor-acceptor fluorophore pairs. GFP-based proteins are structurally stable, relatively inert, and can be reliably attached to points of interest. The combination of easy access to the GFP-based FRET technique and its obvious usefulness in many applications can lead to complacency. Potential problems such as light contaminants, e.g., bleed-through and cross-talk, and inconsistent donor and acceptor concentrations are easily overlooked and can lead to errors in FRET calculation and data interpretation. In this article, we outline possible pitfalls of GFP-based FRET and approaches that address these issues, including a "Spectra FRET" technique that can be easily applied to live cell studies.

Animals↗
PubMed1999

Pharmacogenetics in the practice of laboratory medicine.

BACKGROUND: The clinical laboratory forms an essential bridge between fundamental discoveries in biological sciences and their transition into effective medical practice. The genetic basis for individuality in drug metabolism and response is the result of a finite number of inherited sequence variants (alleles) of genes encoding drug-metabolizing enzymes and drug receptors. Pharmacogenetics (PG) links differences in gene structure with pharmacological differences in pharmacokinetics and pharmacodynamics. The next step in the process of applying PG (or pharmacogenomic) information to individualized therapeutic management is dissemination of this information to practicing physicians by clinical laboratorians. Transitioning PG analysis into clinical practice will require professionals in laboratory medicine to identify relevant polymorphisms, develop sensitive and specific testing strategies, and, in conjunction with physicians and pharmacologists, communicate interpretive guidelines regarding appropriate indications for testing and rational dose adjustment. We review these concepts and provide examples of how PG can be applied to support therapeutic decision making.

Arylamine N-Acetyltransferase↗
PubMed2003

Shoulder: labrum and bicipital tendon.

Shoulder instability can be due to a single, acute traumatic event, generalized joint laxity, or repeated episodes of microtrauma. The later occurs in the throwing athlete. The most common lesion involving the labrum is the anterior inferior labral tear, associated with capsuloperiosteal stripping (classic Bankart lesion). A number of variants of the Bankart lesion have been described recently and include the ALPSA lesion, SLAP lesion, and HAGHL lesion, among others. Lesions of the long head of the biceps tendon can be seen in isolation (tears, tendinosis, dislocation) or in association with rotator cuff and labral lesions. Conventional MR and MR arthrography have been extensively used for the preoperative diagnosis of these lesions, with reportedly good accuracy. An understanding of the normal anatomy and biomechanics of the shoulder joint is essential for proper interpretation of the MRI manifestations of these conditions.

Athletic Injuries↗
PubMed2006

HIV-1 subtypes: epidemiology and significance for HIV management.

PURPOSE OF REVIEW: This review presents an update on the molecular epidemic patterns of HIV-1 infection and the effects of subtype-related genetic variability on transmission, disease progression, response to antiretroviral therapy and drug-resistance pathways. RECENT FINDINGS: The molecular epidemiology of HIV-1 infection is complex and evolving. The emergence of new variants reflects HIV-1 prevalence, subtype epidemiology and risk-behaviour patterns in different geographical areas. Evidence indicates that certain subtypes may have a transmission advantage while others display higher replicative efficiency. The molecular mechanisms underlying these differences are being identified and include both virus- and host-related factors. Although drug susceptibility varies and clinical evidence remains limited, current antiretroviral regimens appear to have comparable efficacy in patients infected with B and non-B subtypes. Subtype-related variability influences resistance pathways. However, the major treatment-associated resistance mutations seen in subtype B also confer resistance in non-B subtypes and vice versa. SUMMARY: Genetic differences among HIV-1 variants can influence the virus biological properties, susceptibility to existing and candidate antiretroviral drugs, and evolution of antiretroviral drug resistance. Further studies are required to define the impact of this variability on risk of transmission, disease outcomes, responses to antiretroviral therapy and resistance pathways. Meanwhile, plasma viral load and CD4 count remain the important predictors of disease outcome, regardless of the infecting subtype. Current antiretroviral regimens can be used reliably to treat patients with both B and non-B subtypes, and resistance interpretation algorithms provide adequate guidance. The limitations of current evidence should be acknowledged and instigate ongoing vigilance.

Anti-HIV Agents↗
PubMed2005

New and unusual O alleles at the ABO locus are implicated in unexpected blood group phenotypes.

BACKGROUND: In the ABO blood group system mutations in the A gene may lead to weak A subgroups owing to a dysfunctional 3-alpha-N-acetylgalactosaminyltransferase. STUDY DESIGN AND METHODS: Blood and DNA were investigated to correlate weak A phenotypes with genotype, and an overrepresentation of the infrequent O2 allele was observed. Consequently, 57 available O2 alleles were examined in detail. RESULTS: Two new O2 alleles were identified having mutations resulting in Gly229Asp with or without Arg217Cys. A recently described O2 variant (488C>T; Thr163Met) was also found. Surprisingly, both the original and the variant O2 alleles were associated with either O or Aweak phenotypes. Three novel O alleles surfaced in six other samples with suspected A subgroups. These were A1-like alleles having nonsense mutations causing premature truncation at codons 56, 107, or 181. A second example of the rare O3 allele was also identified. A newly described O1 allele having 768C>A was found to be the third most frequent O allele among Swedish donors. Of the five novel O alleles, three were incorrectly interpreted as A1 following routine ABO genotyping. CONCLUSION: Apparent O alleles lacking 261delG may cause weak A expression on red blood cells and/or inhibit anti-A production. A hypothesis that exchange of genetic material between principally dissimilar O alleles during mitosis ("autologous chimerism") restores glycosyltransferase activity in some cells would explain this interesting phenomenon.

ABO Blood-Group System↗
PubMed2006

Identification of a new leucine haplotype (ALQ) at codon 154 in the ovine prion protein gene in Spanish sheep.

Genetic susceptibility to scrapie is closely linked to variations at codons 136, 154, and 171 of the prion protein (PRNP) gene. This association between the PRNP genotype and susceptibility to scrapie is the basis of breeding programs for scrapie resistance in different countries. In this paper, we describe the method used with 2 Spanish dairy sheep breeds (Churra and Castellana) to ascertain the initial status of protection against scrapie as a first step toward adapting their breeding schemes to include resistance as a complementary selection criterion. The procedure for genotype identification is based on multiplex minisequencing methodology and has been shown to be accurate, easy to interpret, and to have a medium throughput. The frequency of the ARQ allele was similar in the 2 populations at nearly 70%. The ARR allele, associated with resistance in the homozygous state, reaches around 23% in Churras and nearly 20% in Castellanas. The high-risk VRQ allele appeared at a relatively low frequency in both breeds. No other haplotypes were found in these 2 breeds. Furthermore, in this screening we found a new allele carrying leucine at codon 154. This new genetic variant might play a role in susceptibility to scrapie because codon 154 belongs to a region considered to have an important role in conformational conversion of the cellular to the pathogenic protein.

Alleles↗
PubMedDate not supplied

Dentition development and budding morphogenesis.

The development of functional teeth in the mouse has been widely used as a model to study general mechanisms of organogenesis. Compared with other mammals, in which three incisors, one canine, four premolars, and three molars may occur even in each dental quadrant, the mouse functional dentition is strongly reduced. It comprises only one incisor separated from three molars by a toothless gap diastema at the location of the missing teeth. However, mouse embryos also develop transient vestigial dental primordia between the incisor and molar germs in both the upper and lower jaws. These rudimental structures regress, and epithelial apoptosis is involved in this process. The existence of the vestigial dental structures allowed a better assessment of the periodicity in the mouse dentition, which extends opportunities for the interpretation of molecular data on tooth development. We compared the dentition development with tentative models of budding morphogenesis in other epithelial appendages lungs and feathers. We suggested how developmental control by signaling molecules, including bone morphogenetic protein (Bmp), sonic hedgehog (Shh), and fibroblast growth factor (Fgf), can be similarly involved during budding morphogenesis of dentition and other epithelial appendages. We propose that epithelial apoptosis plays an important role in achieving specific features of dentition, whose development involves both budding and its more complex variant branching. The failure of segregation of the originating buds supports the participation of the concrescence of several tooth primordia in the evolutionary differentiation of mammalian teeth.

Animals↗