Disease-modifying Factors Research Articles

The Relationship between Body Mass Index and Thyroid Cancer Pathology Features and Outcomes: A Clinicopathological Cohort Study

Obesity has been implicated as a predisposing and disease-modifying factor in cancer. Epidemiological studies suggest that obesity is associated with an increased risk of thyroid cancer; however, the relationships between obesity and thyroid cancer stage or behavior are uncertain. We hypothesized that a higher body mass index (BMI) would be associated with aggressive thyroid cancer features and a higher incidence of persistent/recurrent disease. Two hundred fifty-nine consecutive patients with thyroid cancer were enrolled in this retrospective cohort study. Histopathological tumor features, stage at diagnosis, and disease status during and at the end of the study were determined based on chart review. BMI was calculated at the first clinical visit to our institution. The relationships between BMI and these parameters were assessed. Mean follow-up time for the group was 6.2 yr (0.11-46 yr). No positive associations were identified between BMI and T, N, or M stage at diagnosis, vascular invasion, or recurrent or persistent disease on univariate or multivariate analyses. The absence of an association was also demonstrated on analysis by BMI quartiles. An unexpected inverse association was identified between BMI and nodal metastasis and tumor invasion on both univariate and multivariate analyses, suggesting that obesity may be associated with less aggressive tumor features, a finding that requires confirmatory studies. Although obesity has been associated with increased thyroid cancer incidence, a higher BMI was found not to be associated with more aggressive tumor features or a greater likelihood of recurrence or persistence over the analyzed time period.

Role of the neurotrophin network in eating disorders’ subphenotypes: Body mass index and age at onset of the disease

Eating disorders (ED) are severe psychiatric diseases that most likely result from, and are sustained by socio-cultural, psychological and biological factors. We explored whether members of the neurotrophin family are disease-modifying factors of quantitative traits, potentially contributing to the outcome or prognosis of the disease. We studied lifetime minimum and maximum body mass index (minBMI and maxBMI) and age at onset of the disease in a sample of 991 ED patients from France, Germany, Italy and Spain and analysed 183 genetic variants located in 10 candidate genes encoding different neurotrophins and their receptors. We used a hierarchical model approach to include prior genetic knowledge of the specific and found that variants in CNTF, in its receptor CNTFR, and in NTRK2 were significantly associated with a lower age at onset of the ED. In addition, one variant in NTRK1 was associated with a higher minBMI. The results suggest that for these two subphenotypes, CNTF, CNTFR, NTRK1 and NTRK2 might act as disease-modifying factors and add preliminary evidence to the global hypothesis that EDs are the result of complex interactions and reciprocal controls between the immune, endocrine and central nervous systems.

Anti-aquaporin-4 antibody induces astrocytic cytotoxicity in the absence of CNS antigen-specific T cells

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS). Anti-aquaporin-4 antibody (AQP4-Ab) is a highly specific serum autoantibody that is detected in patients with NMO. Several lines of evidence indicate that AQP4-Ab not only serves as a disease marker but also plays a pivotal role in the pathogenesis of NMO. Although the pathogenicity of AQP4-Ab in vivo has recently been demonstrated, the presence of CNS antigen-specific T cells is recognized as a prerequisite for the antibody to exert pathogenic effects. Thus, it remains unclear whether AQP4-Ab is the primary cause of the disease or a disease-modifying factor in NMO. Here we report that pre-treatment with complete Freund’s adjuvant (CFA) alone is sufficient for AQP4-Ab to induce astrocytic damage in vivo. Our results show the primary pathogenic role of AQP4-Ab in the absence of CNS antigen-specific T cells, and suggest that danger signals provided by nonspecific inflammation can be a trigger for those who harbor the autoantibody to develop NMO.

CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease

Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington's disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here, we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.

Trends in Survival and Recovery From Stroke and Compression of Morbidity

See related article, pages 563–565. Substantial increases of life expectancy in developed countries are well documented, and further increases are anticipated in the 21st century.1 The question remains, however, whether this increased longevity can be achieved together with postponed functional limitation and disability or whether increasing life expectancy will yield greater disability.1 According to the Compression of Morbidity paradigm, “if the average age at first chronic infirmity is postponed, and if this postponement is greater than increases in life expectancy, then average cumulative lifetime morbidity will decrease, squeezed between a later onset and the time of death.”2 Although the biological foundation of compression of morbidity remains unknown, data from various clinical/epidemiological databases can be helpful in our understanding of short- and long-term trends for major diseases, including disease incidence, survival, and recovery. In developed countries, the number of people greater than age 65 is increasing. When people age, they become more susceptible to disease, and their risk of mortality dramatically increases. However, an explosion of recent advances in disease-modifying factors, including specific prevention strategies, treatments, and rehabilitation options, should lead to decreases in both disease incidence and mortality, resulting in positive trends in life extension and recovery rates. Worldwide, stroke remains 1 of the major causes of death and long-term disability. Stroke imposes substantial burden, both economic and social, on individuals, their families, and society.3 As with many other diseases, the incidence of stroke increases dramatically with age.4 The impact of stroke, and its challenge to health care systems, is expected to increase during the next decade, as the “baby boomers” enter older age. Fortunately, advances in early …

Stress en parodontale gezondheid

Periodontitis and periimplant infections are complex manifestations associated with several disease-modifying factors, such as causative pathogens and smoking. Although research into these factors has led to important progressions in the treatment of these infections in recent decades, the contribution of mental stress in the absence of pathogens or smoking is still unclear. Qualitative and quantitative assessment of mental stress might be an important instrument in periodontal and periimplant therapy.

Cathepsin D (C224T) Polymorphism in Sporadic and Genetic Creutzfeldt-Jakob Disease

Accumulation of cathepsin D immunoreactive lysosomes correlates with tissue pathology in sporadic Creutzfeldt-Jakob disease (CJD) brains. The C-to-T transition within exon 2 of the cathepsin D (CTSD) gene is associated with altered enzymatic activity. Possession of the TT genotype is a risk factor for variant CJD. To verify the association between the CTSD position 224T allele and the risk for and survival in sporadic and genetic CJD, we genotyped 540 sporadic, 101 genetic CJD, and 723 control individuals. Genotype data and duration of illness were compared using multiple logistic regression and Kruskal-Wallis test. Multivariate survival analysis was performed using Cox's regression model. The distribution of CTSD position 224 alleles was approximately the same in all groups. We observed a trend for shorter survival in sporadic CJD patients harboring the T allele at position 224 of the CTSD gene in particular in sporadic CJD patients with the prion protein gene position 129 MM genotype. We conclude that the CTSD position 224 polymorphism alone is not a significant risk or disease-modifying factor in sporadic or genetic CJD.

Susceptibility to AA amyloidosis in rheumatic diseases: A critical overview

Introduction Reactive systemic AA amyloidosis is one of the most severe complications of several chronic rheumatic disorders, particularly rheumatoid arthritis (RA), juvenile idiopathic arthritis, ankylosing spondylitis (AS), and the hereditary autoinflammatory syndromes. Organ and tissue damage results from the extracellular aggregation of proteolytic fragments of the circulating acute-phase reactant protein serum amyloid A (SAA) as insoluble amyloid fibrils. The kidneys, liver, and spleen are mostly targeted by AA amyloid deposits, and AA amyloidosis becomes clinically overt mainly when renal damage occurs, manifesting either as proteinuria, nephrotic syndrome, or derangement in renal function (1). Due to the risk of progression to end-stage renal disease and possible gastrointestinal and bladder bleeding, the occurrence of AA amyloidosis severely impacts the prognosis of patients with rheumatic disorders (2). In recent studies, amyloidosis has been reported as the cause of death in 5–17% of patients with RA (3). A sustained high concentration of SAA is the prerequisite for AA amyloidogenesis (Figure 1). However, AA amyloidosis actually develops in only a minority of patients with active, longstanding inflammatory diseases, indicating that significant disease-modifying factors might play a role in modulating either the occurrence, the rate of tissue deposition, or the induction of tissue damage in this form of amyloidosis. Here, we review genetic, biologic, and clinical factors underlying susceptibility to the development of AA amyloidosis in patients with chronic rheumatic disorders and provide a critical interpretation that also is supported by the well-characterized mouse model of the disease.

Mycobacterium-associated Lobular Panniculitis, Mimicking a Rheumatoid Nodule in a Patient With Rheumatoid Arthritis

Mycobacterium-associated lobular panniculitis can mimic a rheumatoid nodule and has been seldom reported in rheumatoid arthritis (RA). We describe a 69-year-old woman with RA who presented initially with fever and an indurated skin lesion on the right thigh. Lobular panniculitis was diagnosed after biopsy and was then treated with prednisolone. After this therapy, pulmonary infiltration developed and was later shown by transbronchial biopsy to be caused by Mycobacterium tuberculosis. The panniculitis skin lesion became smaller after prednisolone therapy and was further improved after antituberculosis drugs were added. Reexamination of the previously biopsied skin tissue disclosed acid-fast bacilli. Reactivation or new infection of M. tuberculosis is a current important issue in RA patients, especially after treatment with disease-modifying anti rheumatic drugs or antitumor necrosis factor agents. Mycobacterium-associated lobular panniculitis should be included in the differential diagnosis of indurated skin disorder in RA patients, and acid-fast staining or polymerase chain reaction examination of tuberculosis should be performed routinely on biopsied skin tissue.

Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease.

Phenotypic heterogeneity and genetic modifiers in prion disease caused by a Pro102Leu mutation in the PRNP gene

This Practice Point commentary describes the findings of a study by Webb et al. in which the researchers investigated phenotypic heterogeneity and disease-modifying factors in a large series of patients with inherited prion disease caused by a mutation in the PRNP gene that results in a Pro102Leu amino acid substitution. This mutation is traditionally associated with Gerstmann-Sträussler-Scheinker syndrome (GSS), and the clinical presentation in most patients in the study fitted into the GSS spectrum, but a subset presented with prominent cognitive impairment. In addition, the authors noted remarkable interfamilial and intrafamilial variability with respect to age at disease onset (range 27-66 years) and disease duration (range 7-132 months). Importantly, a polymorphism at PRNP codon 129 and the apolipoprotein E genotype were both identified as factors that modified the age at onset. These findings could have important implications for genetic counseling of individuals at risk from prion disease.

Accelerated Prion Replication in, but Prolonged Survival Times of, Prion-Infected CXCR3−/−Mice

Prion diseases have a significant inflammatory component. Glia activation, which is associated with increased production of cytokines and chemokines, may play an important role in disease development. Among the chemokines upregulated highly and early upregulated during scrapie infections are ligands of CXCR3. To gain more insight into the role of CXCR3 in a prion model, CXCR3-deficient (CXCR3(-/-)) mice were infected intracerebrally with scrapie strain 139A and characterized in comparison to similarly infected wild-type controls. CXCR3(-/-) mice showed significantly prolonged survival times of up to 30 days on average. Surprisingly, however, they displayed accelerated accumulation of misfolded proteinase K-resistant prion protein PrP(Sc) and 20 times higher infectious prion titers than wild-type mice at the asymptomatic stage of the disease, indicating that these PrP isoforms may not be critical determinants of survival times. As demonstrated by immunohistochemistry, Western blotting, and gene expression analysis, CXCR3-deficient animals develop an excessive astrocytosis. However, microglia activation is reduced. Quantitative analysis of gliosis-associated gene expression alterations demonstrated reduced mRNA levels for a number of proinflammatory factors in CXCR3(-/-) compared to wild-type mice, indicating a weaker inflammatory response in the knockout mice. Taken together, this murine prion model identifies CXCR3 as disease-modifying host factor and indicates that inflammatory glial responses may act in concert with PrP(Sc) in disease development. Moreover, the results indicate that targeting CXCR3 for treatment of prion infections could prolong survival times, but the results also raise the concern that impairment of microglial migration by ablation or inhibition of CXCR3 could result in increased accumulation of misfolded PrP(Sc).

Susceptibility to Guillain–Barré syndrome is not associated with CD1A and CD1E gene polymorphisms

Immune responses to microbial glycolipids that cross-react to neural epitopes may trigger the Guillain–Barré syndrome (GBS). CD1 molecules are involved in antigen presentation of glycolipids and variation in CD1 genes was recently reported to confer susceptibility to develop GBS. This hypothesis was tested by comparing single nucleotide polymorphisms (SNPs) of CD1A and CD1E in 312 well defined GBS patients and 212 healthy controls. SNPs in CD1A and CD1E were not associated with GBS susceptibility, specific clinical subgroups, anti-ganglioside antibodies, antecedent infections and prognosis. Based on this study, CD1 polymorphisms are not a susceptibility or disease modifying factor in GBS.

The SRD5A2 V89L polymorphism is associated with severity of disease in men with early onset prostate cancer

Emerging evidence indicates that testosterone (T), and not dihydrotestosterone (DHT), is the most relevant androgen that promotes carcinogenesis in the prostate. Steroid 5-alpha reductase type II (SRD5A2) catalyzes the irreversible conversion of T to DHT in male reproductive organs. Because the SRD5A2 gene is highly polymorphic at codon 89, two SRD5A2 isoforms are expressed that differ in K(m) and V(max) values. The more common and rapid catalytic isoform contains a valine residue at position 89; the slower-catalytic variant contains leucine at this position. Thirty-three men with early onset prostate cancer (PCa) were genotyped for the SRD5A2 V89L substitution and other polymorphisms in genes encoding receptors or enzymes that play important roles in pathways of steroid metabolism to ascertain if they were associated with standard clinical measures of disease progression at the time of diagnosis. The expression of at least one SRD5A2 leucine allele in young men with PCa was associated with more significant disease at the time of presentation, as was defined by pretreatment PSA level, clinical staging and Gleason score when compared with affected subjects harboring the more common SRD5A2 valine variant. A dosage effect of a single leucine allele was evident in heterozygotes, as values of their clinical and pathological variables were consistently situated between the extremes of the homozygous V or L phenotypes. The SRD5A2 leucine isoform appears to be acting in a dose-dependent manner as a significant disease-modifying factor in young men diagnosed with PCa.

Role of staphylococcal superantigens in upper airway disease

Chronic rhinosinusitis with nasal polyps often represents a chronic severe inflammatory disease of the upper airways and may serve as a model for lower airway diseases such as late-onset intrinsic asthma. Enterotoxins derived from Staphylococcus aureus have been implicated in the pathophysiology of nasal polyps as disease-modifying factors; recent findings using therapeutic proof-of-concept approaches support this hypothesis. Nasal polyps (chronic rhinosinusitis with nasal polyps) are characterized by a T-helper-2 dominated cytokine pattern that includes interleukin-5 and formation of immunoglobulin E. This is in contrast to chronic rhinosinusitis without polyps, which exhibits T-helper-1 biased cytokine release. It is now evident that the cytokine environment is decisive regarding the impact of S. aureus derived enterotoxins, which function as superantigens. S. aureus enterotoxin B further shifts the cytokine pattern in nasal polyps toward T-helper-2 cytokines (increases greater than twofold for interleukin-2, interleukin-4 and interleukin-5), but it disfavours the T-regulatory cytokines interleukin-10 and transforming growth factor-beta1. Furthermore, S. aureus derived enterotoxins influence local immunoglobulin synthesis and induce polyclonal immunoglobulin E production, which may contribute to severe inflammation via activation of mast cells. From this new understanding of chronic rhinosinusitis with nasal polyps, new therapeutic approaches emerge such as anti-interleukin-5, anti-immunoglobulin E, and antibiotic treatment. These may enlarge the nonsurgical armentarium.

Possible disease-modifying factors: the mannan-binding lectin pathway and infections in hereditary angioedema of children and adults

IntroductionHereditary angioedema (HAE) is caused by mutations in the C1inh gene, leading to dysfunction of the C1-esterase inhibitor (C1-INH). C1-INH interacts with MASP-1 and MASP-2 proteases, participating in the mannan-binding lectin (MBL) pathway of complement activation. The aim of the study was to investigate the contribution of possible changes in MBL/MASP-2 complex activity and Helicobacter pylori, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections to the severity and frequency of clinical symptoms of HAE.Materials and MethodsThe study was performed in 65 patients with HAE and 113 healthy persons. The parameters measured were C1-INH, C4, MBL concentration and MBL/MASP-2 complex activity, and serological markers of H. pylori, HBV, and HCV infection. Scores for the frequency and severity of HAE symptoms were determined.ResultsHAE scores were significantly higher in patients whose C1-INH activity did not exceed 10% than in patients with activity of 10-52% (p=0.016). No significant differences were found in the median levels of MBL concentration and MBL/MASP-2 complex activity between patients and the control group. There was a slight association between contact with H. pylori in patients and HAE symptom score (p=0.052, not significant). Adult patients showed a 2.6-times higher frequency of anti-HBc than the general population. HBV DNA was negative in anti-HBc(+) patients.ConclusionsThese results suggest that the MBL complement activation pathway itself does not contribute to the frequency of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant).

Abatacept: A novel therapy approved for the treatment of patients with rheumatoid arthritis

An enhanced understanding of the immunopathology of rheumatoid arthritis (RA) has led to the development of novel therapies that target specific events occurring in the immune cascade that underlies the disease. In December 2005, abatacept became the first therapy to be approved by the US Food and Drug Administration for the treatment of adult patients with moderately to severely active RA who have exhibited an inadequate response to traditional disease-modifying antirheumatic drugs or tumor necrosis factor antagonists. This article summarizes the characteristics and clinical profile of abatacept. Abatacept is a fully human soluble recombinant fusion protein that acts by binding to CD80/CD86 on antigen-presenting cells and inhibiting interaction with CD28 on T cells, thus preventing one of the co-stimulatory signals needed for full T-cell activation. It is indicated for reducing signs and symptoms of the disorder, inducing a major clinical response, slowing the progression of structural damage, and improving physical function in this patient population. Data on abatacept compiled to date demonstrate significant efficacy, combined with a consistent safety profile and tolerability, in a wide range of patients with RA, including those with an inadequate response to methotrexate or to tumor necrosis factor antagonists.

Phenotypic variation among brothers with the McLeod neuroacanthocytosis syndrome

McLeod syndrome is an X-linked multisystem disorder affecting red blood cells, the peripheral and central nervous systems, and skeletal and cardiac muscle. No clear correlations of the clinical findings with the genotype of XK mutations have yet been uncovered. Here, we report the clinical features and progression in 10 affected brothers from 4 families with McLeod syndrome. There is significant variation in clinical presentation within families, including in causes of morbidity and mortality. This phenotypic variation, despite shared mutations, suggests the action of disease-modifying factors that may explain some of the difficulties with genotype-phenotype correlation in McLeod syndrome.

Functional correlates of Apolipoprotein E genotype in Frontotemporal Lobar Degeneration

BackgroundIt has been recently demonstrated that in Frontotemporal Lobar Degeneration (FTLD) memory deficits at presentation are commoner than previously thought. Apolipoprotein E (ApoE) genotype, the major genetic risk factor in sporadic late-onset Alzheimer Disease (AD), modulates cerebral perfusion in late middle-age cognitively normal subjects. ApoE ε4 homozygous have reduced glucose metabolism in the same regions involved in AD.The aim of this study was to determine whether ApoE genotype might play a key-role in influencing the cerebral functional pattern as well as the degree of memory deficits in FTLD patients.MethodsFifty-two unrelated FTLD patients entered the study and underwent a somatic and neurological evaluation, laboratory examinations, a brain structural imaging study, and a brain functional Single Photon Emission Tomography study. ApoE genotype was determined.ResultsApoE genotype influenced both clinical and functional features in FTLD. ApoE ε4-carriers were more impaired in long-term memory function (ApoE ε4 vs. ApoE non ε4, 6.3 ± 3.9 vs. 10.1 ± 4.2, p = 0.004) and more hypoperfused in uncus and parahippocampal regions (x,y,z = 38,-6,-20, T = 2.82, cluster size = 100 voxels; -32,-12,-28, T= 2.77, cluster size = 40 voxels).ConclusionThe present findings support the view that ApoE genotype might be considered a disease-modifying factor in FTLD, thus contributing to define a specific clinical presentation, and might be of relevance for pharmacological approaches.

Seasonal pattern of tuberculosis in Hong Kong

Summer predominance of tuberculosis (TB) was reported previously in temperate regions. No consistent data were available for lower latitudes. The monthly TB notification data in Hong Kong from 1991 to 2002 were examined for seasonal fluctuation. A seasonal model was then developed after standardization by period, sex, age, history of TB, form of disease, and bacteriological status. The raw monthly counts showed remarkably consistent seasonal fluctuation across different periods, sexes, and age groups. A sine model was fitted for 82 104 notifications (adjusted R(2) = 0.373, P < 0.001). A summer peak was observed with seasonal fluctuation of 18.4% (P < 0.001), which was substantially higher than that reported previously for temperate regions. The amplitudes of fluctuation were 35.0, 15.0, 19.0, and 20.2% for those aged < or =14, 15-34, 35-64, and >/=65 years, respectively (all P < 0.001). No gender difference was noted (18.2% vs 19.0%, P = 0.790). Seasonal pattern was detected among new cases (18.6%, P < 0.001), but not retreatment cases (5.2%, P = 0.333). Culture-positive cases showed greater fluctuation than culture-negative cases (29.4% vs 6.4%, P < 0.001). No significant difference was found between pulmonary and extrapulmonary cases (16.8% vs 21.6%, P = 0.356). TB cases notified in summer were more likely to be smear-positive [odds ratio (OR) 1.100, 95% confidence interval (CI) 1.045-1.158, P < 0.001] and culture-positive (OR 1.175, 95% CI 1.121-1.232, P < 0.001) than those notified in winter, even after stratification by other key variables. A consistent seasonal pattern was found, with variable amplitudes of fluctuation in different subgroups and differing disease characteristics in different seasons. These observations are suggestive of the presence of a seasonal disease-modifying factor.