Clinical Expression Of Disease Research Articles

Review of possible links between the clinical expression of paratuberculosis and deficiency of macro and micronutrients.

Published information on aspects of the epidemiology of paratuberculosis was reviewed to examine the hypothesis that clinical expression of disease may be induced by deficiencies or imbalances of micronutrients. The progression of paratuberculosis and the development of clinical signs, although innately linked with the process of becoming infected with Mycobacterium avium subsp paratuberculosis, are mostly controlled by factors other than those predisposing to the acquisition of the organisms. There is strong evidence in the literature reviewed to suggest that soil acidification, excesses of iron and molybdenum, and deficiencies in copper and selenium and possibly other minerals and trace elements have a role in the disease process. The fact that no single nutritional supplement has been consistently found to produce clinical recovery suggests that the causal role of these factors is complex and may vary depending upon the geochemical environment. Altering the nutritional environment by appropriate trace element supplementation and liming, as well as decreasing the reliance on shallow-rooted pastures needing frequent fertiliser applications may assist in controlling the clinical expression of paratuberculosis. Such measures could produce a significant decrease in the incidence of clinical expression across flocks and herds.

Cross-sectional study of risk factors for the clinical expression of ovine Johne's disease on New South Wales farms.

To explore the environmental and management risk factors that promote the clinical expression of ovine Johne's disease on farms in New South Wales. Cross-sectional study. A questionnaire about the farm, flock and their management was mailed to all farmers known to keep infected sheep in the area zoned residual for ovine Johne's disease in New South Wales. The resultant data were analysed by multivariate statistical methods, specifically examining the factors associated with farmers reporting some mortality due to ovine Johne's disease; the reported annual incidence of ovine Johne's disease-associated mortality; the youngest age at which sheep die from ovine Johne's disease; whether scouring was a feature of the disease; and the season of peak mortality from ovine Johne's disease. Fine wool Merino sheep were more likely to die from ovine Johne's disease than other sheep types. Mortality was higher on farms with light sandy soils and those with a high proportion of improved pastures containing subterranean clover. Winter shearing was also associated with clinical expression. The time that the infection had been present on a farm was not strongly associated with mortality. Higher stocking density, high rainfall and access to open water, factors that are believed to aid transmission, were not found to be influential. Clinical expression appears to be principally associated with light infertile soils and their associated pastures and pasture improvement practices which may lead to micronutrient deficiencies or imbalances. Genetic effects are also important and are likely to be exacerbated by physiological stressors, such as winter shearing.

Executive processes in Parkinson's disease: FDG-PET and network analysis.

It is assumed widely that the clinical expression of Parkinson's Disease (PD), both motor and cognitive, is subtended by topographically distributed brain networks. However, little is known about the functional neuroanatomy of executive dysfunction in PD. Our objective was to validate further in a PD group the use of network analysis to assess the relationship between executive processes and pathological disorganization of frontostriatal networks. We studied 15 patients with idiopathic PD, and 7 age-matched normal controls, using resting [(18)F]fluorodeoxyglucose (FDG) and high-resolution positron emission tomography (PET). We carried out network analysis on regional metabolic data to identify specific covariation patterns associated with motor and executive dysfunction. We detected two independent patterns relating respectively to the two clinical abnormalities. The first pattern (principal component 1) was topographically similar to that described previously in other PD populations. Subject scores for this pattern discriminated patients from controls and correlated significantly with bradykinesia ratings (P = 0.013, r = 0.655) in PD patients. The second pattern (principal component 2) was characterized by relative ventromedial frontal, hippocampal, and striatal hypometabolism, associated with mediodorsal thalamic hypermetabolism. In the PD group, scores from this pattern correlated with scores on the conditional associative learning (CAL; P = 0.01, r = 0.690) and the Brown Peterson paradigm (BPP; P = 0.017, r = -0.651) tests, respectively assessing strategy and planning, and working memory. According to these findings, the networks subserving bradykinesia and executive dysfunction in PD seems to be topographically distinct and to involve different aspects of subcortico-cortical processing.

Recent advances in congenital nephrotic syndrome.

This review provides a concise update of the most recent literature related to the diagnosis and care of patients with congenital nephrotic syndrome. This topic is of particular interest in light of the rapidly growing body of literature regarding mutations of proteins such as nephrin and podocin that are expressed at or near the podocyte slit diaphragm. The phenotypic variance of patients with congenital nephrotic syndrome with nephrin and podocin mutations resulting from triallelic mutations represents an important advance in our understanding of the effect of multiple genetic mutations on clinical disease expression. Clinically, the management of patients with unilateral nephrectomy, rather than the classic bilateral nephrectomy, represents an efficacious alternative management strategy and may impart better chances of graft survival by allowing later transplantation. Identification of a subset of patients with congenital nephrotic syndrome at increased risk of recurrence who also have antinephrin antibodies may enhance our understanding of recurrent disease in congenital nephrotic syndrome after transplantation. Exciting recent findings in the genotypic/phenotypic correlations of patients with congenital nephrotic syndrome may not only modify our understanding of this disease but may also help to revolutionize our understanding of human genetics. Promising outcomes with unilateral nephrectomy in patients with congenital nephrotic syndrome have permitted transplantation to be delayed and may potentially decrease the risk of complications. New findings regarding recurrence of nephrotic syndrome in patients with congenital nephrotic syndrome after transplantation may lead to improved survival in future renal transplantations.

Tea Consumption and Cardiovascular Disease: Effects on Endothelial Function

Epidemiological studies suggest that tea consumption is associated with reduced cardiovascular disease risk, but the mechanisms for these observations have remained uncertain. In recent years, it has become apparent that the endothelium plays a central role in the regulation of vascular homeostasis and that endothelial dysfunction contributes to the pathogenesis and clinical expression of cardiovascular disease. This article reviews the evidence that human tea consumption has a beneficial effect on the vascular endothelium and the clinical implications of these findings.

Complement C3 F and BF S allotypes are risk factors for Chagas disease cardiomyopathy.

The heterogeneity in the clinical expression of Chagas disease gives strong evidences for the involvement of genetic factors on its pathogenesis. Several studies have indicated different markers of genetic susceptibility to Chagas cardiomyopathy. In the present study, we present evidence of association between complement C3 and BF allotypes, and the susceptibility to Chagas disease and the development of cardiomyopathy. C3, BF, C4A, C4B and C2 polymorphism were determined in 100 seropositive Chagasic patients [cardiomyopathic (CARD), n = 57; asymptomatic indetermined (IND), n = 43] and in 100 non-related seronegative healthy controls. Patients and controls were matched according to their ethnic and geographical origin. A significantly increased frequency of C3F was observed in patients with the CARD form (8/57 14.03%), when compared with those presenting the IND form (0/43, 0%; RR 7.0) and with the healthy controls (5/100, 5%; RR 3.1). A negative association of the BF S allotype was observed in the CARD patients (19/57 33.33%) and in the Chagas total (38/100 38.0%), when compared with the controls (55/100, 55.0%; RR 0.4). All other C3, BF, C4A, C4B and C2 alleles showed no significant differences. These results suggest the allele C3F as a susceptible marker for the progression of the CARD form. On the other hand, BF S may represent a protective role against severe CARD disease. These results corroborate the importance of the alternative pathway in Trypanosoma cruzi infection and indicate possible genetic markers of Chagas cardiomyopathy.

Hypothesis: dysregulation of immunologic balance resulting from hygiene and socioeconomic factors may influence the epidemiology and cause of glomerulonephritis worldwide

Glomerular diseases show diverse epidemiological characteristics throughout the world, which has been suggested to be caused by differences in genetics of the underlying populations or environmental exposure to the putative antigens or agents that either trigger or induce the disease. Recently, an alteration in immune balance of the T helper 1 (TH1) and T helper 2 (TH2) subsets has been implicated as a mechanism to explain the relative increase in allergic diseases in industrialized nations. According to the Hygiene Hypothesis, overcrowding and poor hygiene early in life may protect from atopic diseases because exposure to microbes predisposes in favor of a TH1-dominant response. Conversely, dominance of the TH2 subset would be responsible for the increasing incidence of allergies. We present the hypothesis that this imbalance may help explain the predilection for membranoproliferative glomerulonephritis (GN) and mesangial proliferative GN to be associated with developing and/or poor nations, whereas immunoglobulin A nephropathy and minimal change disease are observed more commonly in industrialized nations. The implication of the Hygiene Hypothesis is that clinical expression of immune-mediated renal disease would depend on the prevailing TH1/TH2 balance, rather than the etiologic agent, and it may help explain the epidemiological pattern of glomerular diseases worldwide.

Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease.

To determine if geoclimatic factors may influence the nature and frequency of dermatomyositis (DM), polymyositis, and associated autoantibodies around the world. We assessed, in the first global evaluation of these conditions, the relationship between 13 geoclimatic variables that may modulate disease and the relative proportion of DM and its associated autoantibody anti-Mi-2, directed against an SNF2-superfamily helicase associated with the nucleosome remodeling and histone acetylation and deacetylation complex, in a global myositis population. Altogether, 919 consecutive patients from populations at 15 locations were studied. Univariate and multivariate analyses demonstrated that of the variables evaluated, surface ultraviolet (UV) radiation intensity (irradiance) most strongly contributed to the relative proportion of DM and was strongly related to the proportion of anti-Mi-2 autoantibodies (weighted r = 0.939, P < 4 x 10(-7) and weighted r = 0.69, P = 0.02, respectively). Published ethnogeographic immunogenetic allele frequencies imply that the striking differences in the proportion of DM- and DM-specific autoantibodies observed around the world are not the result of inherent global variations in known genetic risk factors. These data suggest that UV radiation exposure may modulate the clinical and immunologic expression of an autoimmune disease in different populations around the world.

Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb.

Clinical expression of Hirschsprung disease (HSCR) requires the interaction of multiple susceptibility genes. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR. We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients. Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB signaling pathways are also critical for the normal development of other tissues, including the kidneys and neural crest-derived melanocytes. Our data demonstrate that interaction between these genes is restricted to the enteric nervous system and does not affect renal, coat color, and retinal choroid development.

Human mitochondrial complex I deficiency: investigating transcriptional responses by microarray.

NADH:ubiquinone oxidoreductase (complex I) deficiency is one of the most frequently encountered defects of the mitochondrial energy generating system. A deficiency of this enzyme complex leads to a wide variety in clinical disease expression. The cell biological consequences of such mutations, however, are poorly understood. We investigated transcriptional responses in fibroblast cell lines harboring mutations in the five different nuclear DNA encoded subunits using a mitochondria-targeting microarray. Expression profiles of cell lines cultured under conditions that favor glycolytic metabolism were compared to profiles when cultured under conditions favoring oxidative metabolism. Approximately 60 genes displayed differential expression under these conditions in either all mutated cell lines or selected cell lines only. A marked induction of metallothioneins as well as ATP1G1 transcripts was detected in all patient cell lines. Transcriptional responses such as the induction of heat shock protein transcripts, decreased PDK1,BNIP3 and mitochondrial genome encoding gene transcripts occurred in selected patient cell lines. The observed transcript profile points to a common, putative defensive, response relating to oxidative stress. Although further investigations of other human OXPHOS system diseases is warranted, these results clearly underline that functional genomics holds for the study of inherited metabolic disease.

Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease.

To test the hypothesis that the APOE epsilon4 allele is associated with the clinical manifestations of AD through an association with the pathologic hallmarks of disease. Participants were older Catholic nuns, priests, and brothers who agreed to annual neurologic and neuropsychological evaluation for AD and other common neurologic conditions and brain autopsy at the time of death. There were 77 persons without dementia and 51 with probable AD; 38 participants had one or more epsilon4 alleles. In logistic regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with the likelihood of clinical AD (odds = 3.46, 95% CI = 1.44 to 8.33). However, controlling for the effect of AD pathology, the association of the epsilon allele with clinical AD was reduced by >50% and was no longer significant (odds = 1.58, 95% CI = 0.56 to 4.43). Similarly, in linear regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with level of cognitive function proximate to death (regression coefficient = -0.477, p = 0.005). However, after controlling for the effect of AD pathology, the association of the epsilon4 allele with level of cognition was reduced by >80% and was no longer significant (regression coefficient = -0.093). Similar results were found in analyses using separate measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles, and in analyses of five different cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability). The APOE epsilon4 allele appears to be associated with the clinical manifestations of AD through an association with the pathologic hallmarks of AD rather than another mechanism.

Allergic rhinitis and asthma: the link further unraveled.

Allergic asthma and rhinitis are manifestations of the atopic syndrome. Although the diseases commonly occur together, it is still unclear why some allergic patients develop only asthma and others only rhinitis. The reason for the variety in clinical expression of allergic airway disease is not known. Besides a genetic predisposition, environmental factors contribute to the development of the allergic phenotype. Local and systemic inflammatory processes also seem to be involved, however, their exact contribution to the clinical picture of airway allergy still remains to be elucidated. Although it is clear that the condition of the upper airways has an impact on lower airway physiology, the mechanisms underlying this relation are far from being resolved. To date, most data point towards a systemic link between upper and lower airways, involving bloodstream and bone marrow. In this article, the latest developments with regard to nasobronchial interaction in allergic airway disease will be reviewed. Epidemiologic, experimental and clinical data underline the importance of a global approach in allergic rhinitis and asthma.

Research agenda for pediatric gastroenterology, hepatology and nutrition: molecular basis of gastrointestinal diseases. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Research agenda for pediatric gastroenterology, hepatology and nutrition: molecular basis of gastrointestinal diseases. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Effects of estrogen on the vascular wall: vasomotor function and inflammation.

Time for primary review 33 days. Far from being only an anatomic barrier to prevent the influx of circulating blood into the vessel wall, the endothelium is a metabolically active organ system that maintains vascular homeostasis. The endothelium modulates vascular tone, regulates local cellular growth and the deposition of the extracellular matrix, protects the vessel from the potentially harmful consequences of substances and cells circulating in the blood, and mediates the hemostatic, inflammatory, and reparative responses to local injury. Nitric oxide (NO) produced by the endothelium plays a pivotal role in maintaining vascular health and protecting against vascular injury. Conditions such as hypercholesterolemia [1], systemic hypertension [1], and estrogen deficiency [2] have been associated with impaired functions of the endothelium. As a result of impairment, the vessel wall may promote inflammation, oxidation of lipoproteins, smooth muscle cell proliferation, extracellular matrix deposition or lysis, accumulation of lipid-rich material, the activation of platelets (which promote clotting), and thrombus formation. All of these consequences of endothelial dysfunction may contribute to the development and clinical expression of atherosclerosis and coronary heart disease [3,4]. This hypothesis is supported by serial angiographic studies carried out before and after a myocardial infarction, which indicate that the underlying plaque responsible for unstable angina and myocardial infarction usually produces an arterial narrowing of less than 50% before the acute event [5,6]. Indeed, a recent angiographic study suggests that the positive correlation between the number of severely diseased arteries and coronary mortality may not just be related to the number of arteries with 70% or greater stenosis, but may also be tied to the amount of minor plaque disease in other vessels [7]. These observations have driven a search for other mechanisms, including the potential association of endothelial dysfunction and associated inflammation with plaque rupture, … * Tel.: +82-32-460-3683; fax: +82-32-460-3117 kwangk{at}ghil.com

Immune-mediated inflammatory disorders

Abstract Rheumatoid arthritis (RA) causes pain and loss of function as a result of damage to synovial joints. The damage is caused by inflammation that is driven by cell-cell messengers or cytokines such as tumour necrosis factor α (TNFα). Blockade of TNF with new therapeutic agents such as infliximab, etanercept and adalimumab produces considerable clinical benefits for individuals with severe RA. However, it has recently been realized that the same treatment is also effective in several other diseases, including ankylosing spondylitis, psoriasis and inflammatory bowel disease. Despite very different clinical expression of disease, these conditions share common inflammatory pathways, a response to anti-TNF therapy, and the negative consequences of systemic inflammation. To reflect the similarities between them, they have been termed the ‘immune-mediated inflammatory disorders' (IMIDs). Author Biography Christopher J Edwards MD FRCP is Consultant Rheumatologist and Honorary Senior Lecturer in the Department of Rheumatology at Southampton General Hospital, Southampton, UK.

Bases Genéticas do Diabetes Mellitus Tipo 2

A patogênese do diabetes mellitus tipo 2 (DM2) é complexa, associando fatores genéticos e fatores ambientais. A hiperglicemia é secundária à combinação de defeitos tanto na sensibilidade à insulina quanto na disfunção das células beta-pancreáticas. Vários estudos estabeleceram claramente a importância dos fatores genéticos na predisposição ao DM2. No momento, conhecemos alguns genes implicados em formas monogênicas de diabetes (MODY, diabetes mitocondrial). No entanto, nas formas mais comuns da doença de caráter poligênico, conhecemos apenas poucos genes que são associados à doença de uma forma reprodutível nos diferentes grupos populacionais estudados. Cada um destes poligenes apresenta um papel isolado muito pequeno, atuando na modulação de fenótipos associados ao diabetes. Nestas formas tardias poligênicas de DM2 é evidente a importância dos fatores ambientais que modulam a expressão clínica da doença. Nesta revisão abordamos os avanços mais relevantes das bases genéticas do DM2.

Subcortical hyperintensities in Alzheimer's disease: associated clinical and metabolic findings.

The authors measured subcortical hyperintensities (SH) on magnetic resonance images (MRI) in 18 patients with probable Alzheimer's disease and examined the relationships of SH severity with cortical metabolic function and clinical symptoms. Severity of SH was not correlated with absolute metabolic rates in cortical lobes. However, anterior SH severity was inversely correlated with frontal/ parietal metabolic ratios after covarying for cognitive impairment. SH severity in some areas was associated with the severity of global neuropsychiatric symptoms, but marked effects on individual symptoms were not apparent. The small sample size and multiple variables limit conclusions that can be drawn. These preliminary findings indicate that subcortical MRI hyperintensities may play a role in the pathophysiology and clinical expression of Alzheimer's disease.

Leishmania priming of human dendritic cells for CD40 ligand-induced interleukin-12p70 secretion is strain and species dependent.

A major question in the study of leishmaniasis is what dictates clinical disease expression produced by different Leishmania species, i.e., cutaneous versus systemic and healing versus nonhealing. Animal models using a Leishmania species associated with self-limiting cutaneous disease (L. major) have revealed that protective immunity requires CD40/CD40 ligand (CD40L)-dependent, interleukin-12 (IL-12)-driven Th1 responses. We recently showed that L. major can prime human dendritic cells (DCs) for CD40L-triggered IL-12p70 secretion and that these cells can drive a Th1 response in autologous T cells from sensitized individuals. Here we show that in contrast to L. major, Leishmania species responsible for visceral disease (L. donovani), as well as species associated with persistent, cutaneous lesions and occasional systemic disease (L. tropica), did not induce CD40L-dependent IL-12p70 production, despite comparable levels of uptake by DCs. Up-regulated surface expression of CD40 did not correlate with IL-12p70 production, and appreciable CD40L-induced IL-12p40 secretion was observed in uninfected as well as infected DCs, regardless of species. Reverse transcription-PCR analysis confirmed that the production of heterodimeric IL-12 was limited by expression of IL-12p35 mRNA, which was dependent on both a microbial priming signal and CD40 engagement for its high-level induction. The intrinsic differences in the ability of Leishmania species to prime DCs for CD40L-dependent IL-12p70 secretion may account, at least in part, for the evolution of healing and nonhealing forms of leishmanial disease.

Can intestinal helminth infections (geohelminths) affect the development and expression of asthma and allergic disease?

There are close parallels between inflammation associated with allergic disease and that caused by infections with helminth parasites. Both allergy and helminth infections are associated with elevated levels of IgE, tissue eosinophilia and mastocytosis, and CD4+ T cells that preferentially secrete the Th2 cytokines IL-4, IL-5, and IL-13 [1,2]. There is good evidence that the expression of inflammation caused by helminth infections can be modulated by the host immune response [3], and that the failure of the expression of similar mechanisms among individuals predisposed to allergy may be responsible for the clinical expression of allergic disease [4]. Further, there is accumulating evidence that helminth infections, particularly those caused by intestinal helminth parasites (or geohelminths) may be capable of modulating the expression of allergic disease [5‐8]. This review will examine the evidence for such a modulatory role of intestinal helminth infections (geohelminths) and will provide evidence that the expression of allergic inflammation in different regions of the Tropics may depend partly on local differences in the endemicity of geohelminth infections.

Poisons in the air: a cause of chronic disease in children.

Children represent the largest subpopulation of those susceptible to the adverse effects of air pollution. Compared to adults, children express a greater vulnerability, which can be explained by differences in: the circumstances of exposure related to age, their activities, their child status, differences in lung anatomy and physiology, differences in the clinical expression of disease, and their organ maturity. Many factors have to be assessed in order to evaluate the severity of toxic exposures: pollutant solubility, particle size, concentration, reactivity of pollutants, and pattern of ventilation. Within the numerous air pollutants, some are of special concern for children. For example, ozone has been shown to affect the lungs of healthy school children, especially asthmatics. Airborne particles, nitrogen oxides, sulfur oxides, and acid aerosols have also been shown to induce acute respiratory symptoms, asthma, and bronchitis. Of particular importance is carbon monoxide, which, under certain circumstances, may be found in highly toxic concentrations indoors where children spend most of their time. Special attention has to be given to children's unique differences in order to evaluate the clinical consequences of their toxic exposures. This circumstance emphasizes the key roles of poison centers, clinical toxicologists, and pediatricians, all of whom can collaborate on the identification, assessment, and surveillance of toxic risk for child health and development.