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Disease Expression (disease + expression)

Distribution by Scientific Domains

Medical Sciences	61%
Life Sciences	27%

Selected Abstracts

Adams,Oliver Syndrome: A Sporadic Occurrence With Minimal Disease Expression

PEDIATRIC DERMATOLOGY, Issue 1 2008
TARUN NARANG M.D.
We report a child with the sporadic form of the disease who had minimal disease expression, illustrating the wide clinical spectrum of the syndrome. [source]

Antisense therapeutics for neurofibromatosis type 1 caused by deep intronic mutations,

HUMAN MUTATION, Issue 3 2009
Eva Pros
Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting 1:3,500 individuals. Disease expression is highly variable and complications are diverse. However, currently there is no specific treatment for the disease. NF1 is caused by mutations in the NF1 gene, approximately 2.1% of constitutional mutations identified in our population are deep intronic mutations producing the insertion of a cryptic exon into the mature mRNA. We used antisense morpholino oligomers (AMOs) to restore normal splicing in primary fibroblast and lymphocyte cell lines derived from six NF1 patients bearing three deep intronic mutations in the NF1 gene (c.288+2025T>G, c.5749+332A>G, and c.7908-321C>G). AMOs were designed to target the newly created 5, splice sites to prevent the incorporation of cryptic exons. Our results demonstrate that AMO treatment effectively restored normal NF1 splicing at the mRNA level for the three mutations studied in the different cell lines analyzed. We also found that AMOs had a rapid effect that lasted for several days, acting in a sequence-specific manner and interfering with the splicing mechanism. Finally, to test whether the correction of aberrant NF1 splicing also restored neurofibromin function to wild-type levels, we measured the amount of Ras-GTP after AMO treatment in primary fibroblasts. The results clearly show an AMO-dependent decrease in Ras-GTP levels, which is consistent with the restoration of neurofibromin function. To our knowledge this is the first time that an antisense technique has been usedsuccessfully to correct NF1 mutations opening the possibility of a therapeutic strategy for this type of mutation not only for NF1 but for other genetic disorders. Hum Mutat 30, 454,462, 2009. © 2009 Wiley-Liss, Inc. [source]

MDM2 SNP309 T>G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2007
Bente A. Talseth
Abstract Disease expression in hereditary nonpolyposis colorectal cancer (HNPCC) cannot be readily explained by mutation site in the respective DNA mismatch repair genes associated with this disorder. One explanation is the role of modifying genes that can either promote or prevent disease development on a background of increased risk. Two single nucleotide polymorphisms in MDM2 and TP53 have been shown to be associated with younger ages of disease onset in HNPCC (TP53) and Li-Fraumeni syndrome (MDM2). In this study 220 HNPCC patients were examined, from Australia and Poland, all characterized at the molecular level to determine the frequency of the MDM2 SNP309 T>G and to assess its influence on disease expression. The results were then pooled with the results of a previous study to assess the combined influence of the MDM2 SNP309 T>G and TP53 SNP R72P. A significant difference was observed between CRC patients and unaffected MMR gene mutation carriers over the age of 45 years (p = 0.01). The unaffected MMR gene mutation carriers over the age of 45 years who carry the G allele have a reduced risk of developing CRC. The results indicate that the MDM2 SNP309, alone or in combination with TP53 R72P, does not influence age of diagnosis of CRC in individuals with HNPCC. In conclusion, the data indicates the G allele of MDM2 SNP309 might have a protective effect on disease development in HNPCC patients and that age of diagnosis of CRC is not associated with MDM2 SNP309 or TP53 R72P either as single SNPs or combined. © 2006 Wiley-Liss, Inc. [source]

Individual-based Computational Modeling of Smallpox Epidemic Control Strategies

ACADEMIC EMERGENCY MEDICINE, Issue 11 2006
Donald S. Burke MD
In response to concerns about possible bioterrorism, the authors developed an individual-based (or "agent-based") computational model of smallpox epidemic transmission and control. The model explicitly represents an "artificial society" of individual human beings, each implemented as a distinct object, or data structure in a computer program. These agents interact locally with one another in code-represented social units such as homes, workplaces, schools, and hospitals. Over many iterations, these microinteractions generate large-scale macroscopic phenomena of fundamental interest such as the course of an epidemic in space and time. Model variables (incubation periods, clinical disease expression, contagiousness, and physical mobility) were assigned following realistic values agreed on by an advisory group of experts on smallpox. Eight response scenarios were evaluated at two epidemic scales, one being an introduction of ten smallpox cases into a 6,000-person town and the other an introduction of 500 smallpox cases into a 50,000-person town. The modeling exercise showed that contact tracing and vaccination of household, workplace, and school contacts, along with prompt reactive vaccination of hospital workers and isolation of diagnosed cases, could contain smallpox at both epidemic scales examined. [source]

MDM2 SNP309 T>G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients

Disease Status in Autosomal Dominant Osteopetrosis Type 2 Is Determined by Osteoclastic Properties,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2006
Kang Chu
Abstract Asymptomatic gene carriers and clinically affected ADO2 subjects have the same ClCN7 mutation. We examined osteoclastic bone resorption in vitro as well as osteoclast formation, several markers, acid secretion, and cytoskeletal structure. We found that ADO2 expression results from osteoclast specific properties. Introduction: Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. However, of those individuals with a ClCN7 mutation, one third are asymptomatic gene carriers who have no clinical, biochemical, or radiological manifestations. Disease severity in the remaining two thirds is highly variable. Materials and Methods: Human peripheral blood mononuclear cells were isolated and differentiated into osteoclasts by stimulation with hRANKL and human macrophage-colony stimulating factor (hM-CSF). Study subjects were clinically affected subjects, unaffected gene carriers, and normal controls (n = 6 in each group). Pit formation, TRACP staining, RANKL dose response, osteoclast markers, acid secretion, F-actin ring, and integrin ,v,3 expression and co-localization were studied. Results: Osteoclasts from clinically affected subjects had severely attenuated bone resorption compared with those from normal controls. However, osteoclasts from unaffected gene carriers displayed similar bone resorption to those from normal controls. In addition, the resorption lacunae from both unaffected gene carriers and normal controls appeared much earlier and spread much more rapidly than those from clinically affected subjects. As time progressed, the distinction between clinically affected subjects and the other two groups increased. No significant difference was found in acidic secretion or osteoclast formation between the three groups. Osteoclast cytoskeletal organization showed no difference between the three groups but there was low cellular motility in clinically affected subjects. Conclusions: Osteoclasts from the unaffected gene carriers, in contrast to those from the clinically affected subjects, functioned normally in cell culture. This finding supports the hypothesis that intrinsic osteoclast factors determine disease expression in ADO2. Further understanding of this mechanism is likely to lead to the development of new approaches to the treatment of clinically affected patients. [source]

Maximized virulence in a sterilizing pathogen: the anther-smut fungus and its co-evolved hosts

JOURNAL OF EVOLUTIONARY BIOLOGY, Issue 6 2008
D. B. SLOAN
Abstract Host sterilization is a common feature of sexually transmitted diseases (STDs). Because host reproductive failure may free up resources for pathogen reproduction and transmission, theory predicts that selection on sterilizing pathogens will favour maximum virulence (i.e. complete sterilization). We examined patterns of infection in sexually transmitted anther-smut fungi (Microbotryum) on four of their host species in the Caryophyllaceae. Using controlled fungal matings and experimental inoculations, we compared disease expression in inoculations ranging from host-specific pathogens to hybrids and cross-species treatments. Our data support the existence of host-specific sibling species within the genus Microbotryum based on a low infection rate from cross-inoculations and reduced fitness for hybrid pathogens. These patterns of host specificity and reproductive isolation, however, were not absolute. We did observe some successful cross-species and hybrid infections, but the expression of disease was frequently incomplete, including only partial host sterilization and the failed dehiscence of pathogen spores. The prevalence of these maladapted disease phenotypes may greatly inhibit the emergence of novel host pathogen combinations. Infections by hybrid pathogen genotypes were intermediate, in terms of both infection rate and the normality of disease symptoms, between host-specific and cross-inoculated pathogens. In addition, the frequency with which hybrid and cross-inoculated anther-smut pathogens were able to infect but not sterilize new hosts supports the prediction that sterilizing STDs are under selection to maximize virulence in natural populations. [source]

Iridovirus infections in finfish , critical review with emphasis on ranaviruses

JOURNAL OF FISH DISEASES, Issue 2 2010
R J Whittington
Abstract Viruses in three genera of the family Iridoviridae (iridoviruses) affect finfish. Ranaviruses and megalocytiviruses are recently emerged pathogens. Both cause severe systemic disease, occur globally and affect a diversity of hosts. In contrast, lymphocystiviruses cause superficial lesions and rarely cause economic loss. The ranavirus epizootic haematopoietic necrosis virus (EHNV) from Australia was the first iridovirus to cause epizootic mortality in finfish. Like other ranaviruses, it lacks host specificity. A distinct but closely related virus, European catfish virus, occurs in finfish in Europe, while very similar ranaviruses occur in amphibians in Europe, Asia, Australia, North America and South America. These viruses can be distinguished from one another by conserved differences in the sequence of the major capsid protein gene, which informs policies of the World Organisation for Animal Health to minimize transboundary spread of these agents. However, limited epidemiological information and variations in disease expression create difficulties for design of sampling strategies for surveillance. There is still uncertainty surrounding the taxonomy of some putative ranaviruses such as Singapore grouper iridovirus and Santee-Cooper ranavirus, both of which cause serious disease in fish, and confusion continues with diseases caused by megalocytiviruses. In this review, aspects of the agents and diseases caused by ranaviruses are contrasted with those due to megalocytiviruses to promote accurate diagnosis and characterization of the agents responsible. Ranavirus epizootics in amphibians are also discussed because of possible links with finfish and common anthropogenic mechanisms of spread. The source of the global epizootic of disease caused by systemic iridoviruses in finfish and amphibians is uncertain, but three possibilities are discussed: trade in food fish, trade in ornamental fish, reptiles and amphibians and emergence from unknown reservoir hosts associated with environmental change. [source]

GAP43 overexpression and enhanced neurite outgrowth in mucopolysaccharidosis type IIIB cortical neuron cultures

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2010
Michaël Hocquemiller
Abstract Behavioral manifestations mark the onset of disease expression in children with mucopolysaccharidosis type III (MPSIII, Sanfilippo syndrome), a genetic disorder resulting from interruption of the lysosomal degradation of heparan sulfate. In the mouse model of MPSIII type B (MPSIIIB), cortical neuron pathology and dysfunction occur several months before neuronal loss and are primarily cell autonomous. The gene coding for GAP43, a neurite growth potentiator, is overexpressed in the MPSIIIB mouse cortex, and neurite dystrophy was reported in other types of lysosomal storage diseases. We therefore examined the development of the neuritic trees in pure populations of MPSIIIB mouse embryo cortical neurons grown for up to 12 days in primary culture. Dynamic observation of living neurons and quantification of neurite growth parameters indicated more frequent neurite elongation and branching and less frequent neurite retraction, resulting in a relative overgrowth of MPSIIIB neuron neuritic trees, involving both dendrites and axons, compared with normal controls. Neurite overgrowth was concomitant with more than twofold increased expression of GAP43 mRNAs and proteins. Correction of the genetic defect leads to expression of the missing lysosomal enzyme, normal GAP43 mRNA expression, and reduced neurite outgrowth. These results indicate that heparan sulfate oligosaccharide storage modifies GAP43 expression in MPSIIIB cortical neurons with potential consequences for neurite development and neuronal functions that may be relevant to clinical manifestations. © 2009 Wiley-Liss, Inc. [source]

Photosynthetic Responses of a Temperate Liana to Xylella fastidiosa Infection and Water Stress

JOURNAL OF PHYTOPATHOLOGY, Issue 1 2004
A. J. McElrone
Abstract Xylella fastidiosa is a xylem-limited bacterial plant pathogen that causes bacterial leaf scorch in its hosts. Our previous work showed that water stress enhances leaf scorch symptom severity and progression along the stem of a liana, Parthenocissus quinquefolia, infected by X. fastidiosa. This paper explores the photosynthetic gas exchange responses of P. quinquefolia, with the aim to elucidate mechanisms behind disease expression and its interaction with water stress. We used a 2 × 2-complete factorial design, repeated over two growing seasons, with high and low soil moisture levels and infected and non-infected plants. In both years, low soil moisture levels reduced leaf water potentials, net photosynthesis and stomatal conductance at all leaf positions, while X. fastidiosa -infection reduced these parameters at basally located leaves only. Intercellular CO2 concentrations were reduced in apical leaves, but increased at the most basal leaf location, implicating a non-stomatal reduction of photosynthesis in leaves showing the greatest disease development. This result was supported by measured reductions in photosynthetic rates of basal leaves at high CO2 concentrations, where stomatal limitation was eliminated. Repeated measurements over the summer of 2000 showed that the effects of water stress and infection were progressive over time, reaching their greatest extent in September. By reducing stomatal conductances at moderate levels of water stress, P. quinquefolia maintained relatively high leaf water potentials and delayed the onset of photosynthetic damage due to pathogen and drought-induced water stress. In addition, chlorophyll fluorescence measurements showed that P. quinquefolia has an efficient means of dissipating excess light energy that protects the photosynthetic machinery of leaves from irreversible photoinhibitory damage that may occur during stress-induced stomatal limitation of photosynthesis. However, severe stress induced by disease and drought eventually led to non-stomatal decreases in photosynthesis associated with leaf senescence. [source]

Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literature

JOURNAL OF VIRAL HEPATITIS, Issue 6 2005
M. Ramos-Casals
Summary., To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjögren's syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjögren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia. [source]

Gene expression profile of Huh-7 cells expressing hepatitis C virus genotype 1b or 3a core proteins

LIVER INTERNATIONAL, Issue 5 2009
Valerio Pazienza
Abstract Background: The liver disease expression in chronic hepatitis C patients is variable and may partially depend on the sequence of the infecting viral genotype. Aim: To identify some hepatitis C virus (HCV) genotype-specific virus,host interactions potentially leading to clinically significant consequences. Methods: We compared the gene expression profile of Huh-7 cells transiently expressing the core protein of HCV genotype 1b and 3a using microarray technology. Results: Thirty-two genes were overexpressed in Huh-7 transfected with the HCV genotype 1b core protein and 57 genes in cells transfected with the genotype 3a core protein. On the other hand, we found 20 genes downregulated by core 1b and 31 genes by core 3a. These included genes involved in lipid transport and metabolism, cell cycle, immune response and insulin signalling. Conclusion: The expression of HCV core proteins of different genotypes leads to a specific gene expression profile. This may account for the variable disease expression associated with HCV infection. [source]

Adams,Oliver Syndrome: A Sporadic Occurrence With Minimal Disease Expression

Allograft diabetic nephropathy may progress to end-stage renal disease

PEDIATRIC TRANSPLANTATION, Issue 4 2004
Moro O. Salifu
Abstract:, Mesangial expansion and glomerular basement membrane thickening characteristic of diabetic nephropathy recur in diabetic recipients of renal allografts from non-diabetic donors but progression to renal failure is minimally documented. Three female renal allograft recipients (aged 40, 62 and 73 yr), who developed end-stage renal disease (ESRD) due to recurrent diabetic nephropathy (two patients) and de novo diabetes (one patient) are reported. Onset of proteinuria, uncontrolled hypertension, azotemia, renal allograft pathologic findings and the need for hemodialysis were analyzed. None of the kidney donors (one cadaver, two living related) had known diabetes or perturbed glucose metabolism pre-transplantation. The three patients presented had different varieties of diabetes; type 1, type 2 and new onset diabetes after transplantation (NODAT). In each subject, proteinuria was detected by dipstick at a mean of 8.3 yr (range 8,9) post-transplantation and increased to the nephrotic range (3.7,4.8 g/day) inducing hypoalbuminemia and azotemia. A histopathologic diagnosis of allograft diabetic nephropathy was made in a mean of 11.7 yr (range 10,14), based on glomerular basement membrane thickening, nodular and diffuse intercapillary glomerulosclerosis, arteriolosclerosis, and tubular atrophy with marked tubular basement membrane thickening characteristic of advanced diabetic nephropathy. All three patients manifested uremia and resumed hemodialysis. Two patients died from sepsis within 2 months and one patient died 2.5 yr later after resumption of maintenance hemodialysis. We infer that recurrent or de novo diabetic nephropathy in renal allografts follows a clinical decade-long course irrespective of diabetes. Reports of ESRD due to allograft diabetic nephropathy (ADN) have been limited because of shorter survival of diabetic transplant recipients and few kidney biopsies performed in patients with chronic allograft dysfunction. The occurrence of allograft diabetic nephropathy in some, but not all patients, however, suggests that individual genetic variability modulates disease expression. [source]

The Essence of Linkage-based Imprinting Detection: Comparing Power, Type 1 Error, and the Effects of Confounders in Two Different Analysis Approaches

ANNALS OF HUMAN GENETICS, Issue 3 2010
David A. Greenberg
Summary Imprinting is critical to understanding disease expression. It can be detected using linkage information, but the effects of potential confounders (heterogeneity, sex-specific penetrance, and sex-biased ascertainment) have not been explored. We examine power and confounders in two imprinting detection approaches, and we explore imprinting-linkage interaction. One method (PP) models imprinting by maximising lod scores w.r.t. parent-specific penetrances. The second (DRF) approximates imprinting by maximising lods over differential male-female recombination fractions. We compared power, type 1 error, and confounder effects in these two methods, using computer-simulated data. We varied heterogeneity, penetrance, family and dataset size, and confounders that might mimic imprinting. Without heterogeneity, PP had more imprinting-detecting power than DRF. PP's power increased when parental affectedness status was ignored, but decreased with heterogeneity. With heterogeneity, type 1 error increased dramatically for both methods. However, DRF's power also increased under heterogeneity, more than was attributable to inflated type 1 error. Sex-specific penetrance could increase false positives for PP but not for DRF. False positives did not increase on ascertainment through an affected "mother". For PP, non-penetrant individuals increased information, arguing against using affecteds-only methods. The high type 1 error levels under some circumstances means these methods must be used cautiously. [source]

Dyskinesias and associated psychiatric disorders following streptococcal infections

CHILD: CARE, HEALTH AND DEVELOPMENT, Issue 6 2004
Richard Reading
Dyskinesias and associated psychiatric disorders following streptococcal infections . DaleRC, HeymanI, SurteesRAH, ChurchAJ, GiovannoniG, GoodmanR & NevilleBGR . ( 2004 ) Archives of Disease in Childhood , 89 , 604 , 610 . Background The classical extrapyramidal movement disorder following , haemolytic streptococcus (BHS) infection is Sydenham's chorea (SC). Recently, other post-streptococcal movement disorders have been described, including motor tics and dystonia. Associated emotional and behavioural alteration is characteristic. Aims To describe experience of post-streptococcal dyskinesias and associated comorbid psychiatric features presenting to a tertiary referral centre 1999,2002. Methods In all patients, dyskinetic movement disorders followed BHS pharyngeal infection. BHS infection was defined by pharyngeal culture of the organism, or paired streptococcal serology. Movement disorders were classified according to international criteria, and validated by experienced child neurologists. Psychiatric complications were defined using ICD-10 criteria using a validated psychiatric interview. Results In the 40 patients, the following dyskinetic movement disorders were present: chorea (n = 20), motor tics (n = 16), dystonia (n = 5), tremor (n = 3), stereotypies (n = 2), opsoclonus (n = 2) and myoclonus (n = 1). Sixty-five per cent of, the, chorea, patients, were, female,, whereas, 69% of the tic patients were male. ICD-10 psychiatric diagnoses were made in 62.5%. Using the same psychiatric instrument, only 8.9% of UK children would be expected to have an ICD-10 psychiatric diagnosis. Emotional disorders occurred in 47.5%, including obsessive-compulsive disorder (27.5%), generalized anxiety (25%) and depressive episode (17.5%). Additional psychiatric morbidity included conduct disorders (27.5%) and hyperkinetic disorders (15%). Psychiatric, movement and post-streptococcal autoimmune disorders were commonly observed in family members. At a mean follow-up of 2.7 years, 72.5% had continuing movement and psychiatric disorders. Conclusion Post-streptococcal dyskinesias occur with significant and disabling psychiatric comorbidity and are potential autoimmune models of common ,idiopathic' movement and psychiatric disorders in children. Multiple factors may be involved in disease expression including genetic predisposition, developmental status and the patient's sex. [source]

B cell epitope specificity in ANCA-associated vasculitis: does it matter?

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2004
Y. M. VAN DER GELD
SUMMARY Pauci-immune idiopathic small-vessel vasculitis is strongly associated with the presence of antineutrophil cytoplasm autoantibodies (ANCA). Antibodies to PR3 predominate in patients with Wegener's granulomatosis; antibodies to myeloperoxidase (MPO) are found more frequently in patients with microscopic polyangiitis. There is increasing in vivo and in vitro evidence for a pathogenic role of ANCA in systemic vasculitis based on associations of ANCA with disease activity. If ANCA are pathogenic, why is the course of disease different from one patient to another? Antibodies can recognize different binding sites (epitopes) on their corresponding antigens. Differences in binding specificity may influence the pathogenic potential of the antibodies. Differences between epitope specificity of ANCA between patients or changes in epitope specificity of ANCA in time in an individual patient may, accordingly, result in differences in disease expression. This review will focus on epitope specificity of autoantibodies in systemic autoimmune diseases and especially on the epitope specificity of PR3, and MPO,ANCA. We will discuss whether PR3,ANCA or MPO,ANCA recognize different epitopes on PR3 and MPO, respectively, and whether the epitopes recognized by ANCA change in parallel with the disease activity of ANCA-associated vasculitis. Finally, we will speculate if the direct pathogenic role of ANCA can be ascribed to one relapse- or disease-inducing epitope. Characterization of relapse- or disease-inducing epitopes bound by PR3,ANCA and MPO,ANCA is significant for understanding initiation and reactivation of ANCA-associated vasculitis. Elucidating a disease-inducing epitope bound by ANCA may lead to the development of epitope-specific therapeutic strategies. [source]