Preclinical Period Research Articles

Reducing the Risk of Developing Diabetes

Reducing the Risk of Developing Diabetes

First-degree Relatives of Patients with Rheumatoid Arthritis Exhibit High Prevalence of Joint Symptoms

The preclinical period of rheumatoid arthritis (RA) is characterized by the presence of autoantibodies such as anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Little is known about the joint symptom profile preceding onset of RA, and whether symptoms are associated with RA autoantibodies. Because first-degree relatives (FDR) of North American Native (NAN) RA probands exhibit multiple risk factors for development of future RA, we investigated the prevalence of joint symptoms in this high-risk population. We studied 306 FDR of NAN patients with RA, 323 NAN controls (NC), and 293 white controls (WC) having no family history of autoimmune diseases. Study subjects completed a questionnaire that asked whether they had pain, swelling, or morning stiffness in their hand joints, or in other joints. Serum samples were gathered at the same time and tested for the presence of ACPA, RF, and high-sensitivity C-reactive protein levels. In all cases, FDR were significantly more likely to report experiencing joint symptoms compared to the 2 control groups. FDR also exhibited a significantly higher prevalence of RA autoantibodies than the control groups. There were modest trends for joint symptoms to associate with RA autoantibodies, and individuals who were both ACPA-positive and RF-positive had the highest prevalence of joint symptoms. FDR of NAN patients with RA have a higher prevalence of joint symptoms compared to individuals with no family history of autoimmune disease. This finding is only partially explained by a high prevalence of RA autoantibodies in the FDR.

Mashed Potatoes and Maize

Mashed Potatoes and Maize

The Perception of Stress among Clinical Dental Students

ABSTRACT Objective To determine the prevalence of stress among clinical students from Faculty of Dentistry, King Abdul Aziz University, Jeddah. Materials and methods A cross-sectional descriptive study was carried out in May 2012 on fourth, fifth and sixth year clinical dental students from Faculty of Dentistry, King Abdul Aziz University, Jeddah, using a modified form of dental environment stress (DES) questionnaire. A total of 353 questionnaires were distributed and incomplete questionnaires were excluded from the study. SPSS version 15 was used to do statistical analysis. Results A total of 353 students were asked to complete the questionnaire and 232 (65.7%) responded; of these 120 (51.7%) were males and remaining 112 (48.3%) were females. More or less all the students were having stress. In male students severe stress was due to difficulty in getting suitable patient (51%) and the patient who were arriving late or not coming on appointment, p = 0.16, whereas in female they were having severe stress due to fear of failure (59%), p = 0.02, examination and grading (57%) and completing examination requirement (52%). In male, amount of academic overload was also main cause of severe stress (p = 0.03). Sixth-year students were having more stress due to amount of overload (59.1%), lack of time to do assigned work (53.4%), difficulty to get suitable patient (71.6%) and patient arriving late or not coming on appointment (64.8%). Fifth-year students were more stressed due to completing examination requirement (65.7%). Fourth-year students were having more stress due to fear of failure (58.4%) and examination and grading (58.4%). Conclusion The finding of this study show some considerable degree or severe stress among the students. Longitudinal studies that include preclinical dental students should be carried out to know how the pattern of stress varies during preclinical and clinical training period. How to cite this article Al-Samadani KH, Al-Dharrab A. The Perception of Stress among Clinical Dental Students. World J Dent 2013;4(1):24-28.

Early Mechanisms of Pathobiology Are Revealed by Transcriptional Temporal Dynamics in Hippocampal CA1 Neurons of Prion Infected Mice

Prion diseases typically have long pre-clinical incubation periods during which time the infectious prion particle and infectivity steadily propagate in the brain. Abnormal neuritic sprouting and synaptic deficits are apparent during pre-clinical disease, however, gross neuronal loss is not detected until the onset of the clinical phase. The molecular events that accompany early neuronal damage and ultimately conclude with neuronal death remain obscure. In this study, we used laser capture microdissection to isolate hippocampal CA1 neurons and determined their pre-clinical transcriptional response during infection. We found that gene expression within these neurons is dynamic and characterized by distinct phases of activity. We found that a major cluster of genes is altered during pre-clinical disease after which expression either returns to basal levels, or alternatively undergoes a direct reversal during clinical disease. Strikingly, we show that this cluster contains a signature highly reminiscent of synaptic N-methyl-D-aspartic acid (NMDA) receptor signaling and the activation of neuroprotective pathways. Additionally, genes involved in neuronal projection and dendrite development were also altered throughout the disease, culminating in a general decline of gene expression for synaptic proteins. Similarly, deregulated miRNAs such as miR-132-3p, miR-124a-3p, miR-16-5p, miR-26a-5p, miR-29a-3p and miR-140-5p follow concomitant patterns of expression. This is the first in depth genomic study describing the pre-clinical response of hippocampal neurons to early prion replication. Our findings suggest that prion replication results in the persistent stimulation of a programmed response that is mediated, at least in part, by synaptic NMDA receptor activity that initially promotes cell survival and neurite remodelling. However, this response is terminated prior to the onset of clinical symptoms in the infected hippocampus, seemingly pointing to a critical juncture in the disease. Manipulation of these early neuroprotective pathways may redress the balance between degeneration and survival, providing a potential inroad for treatment.

Differences in Natural History between Breast Cancers in BRCA1 and BRCA2 Mutation Carriers and Effects of MRI Screening-MRISC, MARIBS, and Canadian Studies Combined

It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40.

A01 What are we looking for in a Huntington disease (HD) drug?

Therapeutic interventions (TI) can be drugs, devices, or complex interventions. Category independent, a TI must produce a clinical benefit that the patient perceives as RELEVANT for his or her well-being. This benefit must compensate the risks and the overall burden the intervention represents for the individual, the family and the society. We are looking for drugs in HD that can produce a sufficiently large effect (or can contribute to such an effect in combination with other TI) in one or more of the affected domains of HD (motor, behaviour, cognition, metabolism) with an acceptable safety profile. The beneficial effect can be either the deferral of the disease manifestation or the reduction of symptom intensity; or both. HD is a neurodegenerative disorder not simpler than Alzheimer9s or Parkinson9s disease, sharing progressive selective neuronal death, long-term compensatory mechanisms and numbers of accessory pathogenic processes, which might be useful as auxiliary therapeutic targets. The underlying pathogenic processes are evidently similar, demonstrated by the current efforts of the scientific community revising the concepts of the evolution in these diseases. Regarding the commonalities, it is considered that there is a preclinical period without detectable clinical or biomarker changes, a presymptomatic period where only biomarkers indicate changes, a premanifest period with robust biomarker and first clinical changes and finally the manifest period with manifestation of classical symptoms of the disease. Drugs that will be used in these different periods will have very different characteristics. It is contentious whether or not a drug should be considered in the early periods of slow progressing diseases like HD if its safety profile is riskier than for example, aspirin as prophylaxis for myocardial infarction. This situation will be different for juvenile HD. There is plenty of room for different trade-offs between the benefits and the risks, depending on the risk acceptance of individuals and the society, compliance issues and time horizons. HD is a monogenetic, fully penetrant disease which gives HD a head start advantage over the other neurodegenerative diseases in the search for targeted drugs. By knowing the gene and its ultimate product, it was possible to design the first specific interventions using iRNA technologies, which will enter clinical trials soon (early 2013). However, they are extremely interesting but highly experimental interventions. For issues as important as pharmacokinetics, techniques of application, brain diffusion, and dosage details still must be worked out. This will bring the discussion to the ideal characteristics of a drug being fully brain penetrant, and what technical challenges are acceptable if a TI offers a realistic promise of efficacy. In summary, in our search for drugs for HD, we expect to develop TI which are effective and have a manageable safety profile. In addition, we hope (1) to learn which is a drug9s best target population and to establish appropriate subgroups; (2) to define the proper disease phase in which drugs can be used for optimal results; and (3) to find the ideal dosage, regime and drug combination (as in chemotherapy protocols).

Monitoring Huntington's disease progression through preclinical and early stages.

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder that typically begins in middle adulthood. The neurodegenerative process that underlies HD, however, likely begins many years before clinical diagnosis. Since genetic testing can identify individuals that will develop HD during this preclinical period, clinical trials aiming to slow disease progression will likely focus on this phase of the illness in an effort to delay disease onset. How to best measure the efficacy of potential disease-modifying therapies in preclinical HD remains a complex challenge. This article will review the clinical and imaging measures that have been assessed as potential markers of disease progression in preclinical and early symptomatic HD.

Gender Modulates the APOE 4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels

We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.

Environmental Triggers of Type 1 Diabetes

Type 1 diabetes (T1D) is perceived as a progressive immune-mediated disease, the clinical diagnosis of which is preceded by an asymptomatic preclinical period of highly variable duration. It has long been postulated that the disease process leading to overt T1D is triggered by an infectious agent, the strongest candidate being a diabetogenic enterovirus. The initiation and progression of the disorder likely requires, in addition to genetic T1D susceptibility, a trigger, an exogenous antigen capable of driving the development of this disease. This may be a dietary antigen similar to gluten in celiac disease. Recent data further suggests that the initiation of autoimmunity is preceded by inflammation reflected by a proinflammatory metabolic serum profile. The cause of the inflammation remains open, but given that the intestinal microbiome appears to differ between individuals who progress to clinical T1D and nonprogressors, one may speculate that changes in the gut microflora might contribute to the inflammatory process.

Premorbid Personality and the Risk of Parkinson's Disease (P07.132)

Objective: To evaluate the association of Parkinson9s disease (PD) with premorbid personality indicators in early adult life. Background PD has been shown to be associated with premorbid personality characteristics such as inflexibility, anti-social behavior and caution. Most studies of parkinsonian premorbid personality relied on subjective reports of personality in early life, which may be subject to recall bias. Design/Methods: In-person assessments of 89 cases with PD and 99 controls were completed at an academic medical center. Risk-taking activities and behaviors, routinization, smoking and alcohol consumption from ages 20-35 were used as indicators of early-adult life personality. Logistic regression analysis was employed to examine associations between early-adult personality indicators and risk for PD controlling for age, sex and education. Results: The risk for PD was associated with taking or wanting to take fewer activity risks as a young adult in the total sample (OR=0.78 (95% CI 0.63-0.97)) and among women (OR=0.69 (95% CI 0.50-0.95)). The risk for PD among women also was associated with greater preference for a routine lifestyle as a young adult (OR=1.63 (95% CI 1.05-2.53)). When other personality indicators were included in the model, the association between risk-taking as a young adult and PD remained unchanged. Conclusions: PD was associated with taking or wanting to take more activity risks and a greater desire for routinization during young adulthood, consistent with the presence of a distinct premorbid personality. These findings suggest that personality characteristics in early life may be useful in the identification of individuals at higher risk for PD and provide insight into the pre-clinical period of the disease. Disclosure: Dr. Sullivan has nothing to disclose. Dr. Mortimer has received personal compensation for activities with Davies, McFarland, and Carroll. Dr. Wang has nothing to disclose. Dr. Zesiewicz has received personal compensation for activities with Teva Pharmaceuticals as a speaker. Dr. Zesiewicz has received research support from Bobby Allison Ataxia Research Center, National Ataxia Foundation, Astellas Pharmaceuticals, Pfizer, Friedreich9s Ataxia Research Alliance, Takeda, Biovail Corporation, Southern Illinois University, and Allon Pharmaceuticals. Dr. Brownlee has received personal compensation for activities with Amylin Pharmaceuticals, Eli Lilly & Company, and Boehringer Ingelheim Pharmaceuticals, Inc. Dr. Borenstein has nothing to disclose.

Discovery of ((S)-5-(Methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone As a Potent and Selective IKur Inhibitor

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.

Surface Plasmon Resonance Reveals a Different Pattern of Proinsulin Autoantibodies Concentration and Affinity in Diabetic Patients

Type 1 diabetes mellitus (DM) is characterized by autoimmune aggression against pancreatic beta cells resulting in absolute deficiency of insulin secretion. The first detectable sign of emerging autoimmunity during the preclinical asymptomatic period is the appearance of diabetes-related autoantibodies. In children at risk for type 1 DM, high-affinity Insulin autoantibodies reactive to proinsulin, are associated with diabetes risk. Autoantibodies are usually measured by radioligand binding assay (RBA) that provides quasi-quantitative values reflecting potency (product between concentration and affinity) of specific autoantibodies. Aiming to improve the characterization of the specific humoral immune response, we selected surface plasmon resonance (SPR) as an alternative method to measure proinsulin autoantibodies (PAA). This novel technology has allowed real time detection of antibodies interaction and kinetic analysis. Herein, we have employed SPR to characterize the PAA present in sera from 28 childhood-onset (mean age 8.31±4.20) and 23 adult-onset diabetic patients (≥65 years old, BMI<30) in terms of concentration and affinity. When evaluating comparatively samples from both groups, childhood-onset diabetic patients presented lower PAA concentrations and higher affinities (median 67.12×10−9 M and 3.50×107 M−1, respectively) than the adults (median 167.4×10−9 M and 0.84×107 M−1, respectively). These results are consistent with those from the reference method RBA (Standard Deviation score median 9.49 for childhood-onset group and 5.04 for adult-onset group) where the binding can be directly related to the intrinsic affinity of the antibody, suggesting that there is a different etiopathogenic pathway between both types of clinical presentation of the disease. This technology has shown to be a useful tool for the characterization of PAAs parameters as an alternative to radioimmunoassay, with high versatility and reproducibility associated to low occupational and environmental risk. However, this technology is not eligible for routine marker screening, but this is a powerful technique for a fine description of the thermodynamic parameters of antigen-antibody interaction.

Elevated Serum C-Reactive Protein Relates to Increased Cerebral Myoinositol Levels in Middle-Aged Adults

C-reactive protein (CRP), a systemic marker of inflammation, is a risk factor for late life cognitive impairment and dementia, yet the mechanisms that link elevated CRP to cognitive decline are not fully understood. In this study we examined the relationship between CRP and markers of neuronal integrity and cerebral metabolism in middle-aged adults with intact cognitive function, using proton magnetic resonance spectrocospy. We hypothesized that increased levels of circulating CRP would correlate with changes in brain metabolites indicative of early brain vulnerability. Thirty-six individuals, aged 40 to 60, underwent neuropsychological assessment, a blood draw for CRP quantification, and 1H MRS examining N-acetyl-aspartate, myo-inositol, creatine, choline, and glutamate concentrations in occipito-parietal grey matter. Independent of age, sex and education, serum CRP was significantly related to higher cerebral myo-inositol/creatine ratio (F(4,31) = 4.74, P = 0.004), a relationship which remained unchanged after adjustment for cardiovascular risk (F(5,30) = 4.356, CRP β = 0.322, P = 0.045). Because these biomarkers are detectable in midlife they may serve as useful indicators of brain vulnerability during the preclinical period when mitigating intervention is still possible.

Estimates of the potential risk of radiation-related cancer from screening in the UK

Estimates of the potential risk of radiation-related cancer from screening in the UK

Prevención de la diabetes mellitus 2

Diabetes mellitus type 2, DM2-is a metabolic disorder characterized by hyperglycaemia. This feature causes vascular and nerve disorders that are the basis of long-term complications. The twin-DM2 due to both its aetiology and its broad preclinical period allows strategies to be made that prevent or delay its onset (primary prevention) or to allow early detection (secondary prevention), or once diagnosed, delay or prevent the onset of complications (tertiary prevention). The application or screening tests for the disease is still a controversial issue and hygienic use of dietary or pharmacological treatments in pre-diabetics is recommended to decrease the incidence of this disease.

Prevention of type 1 diabetes

Type 1 diabetes is a chronic autoimmune condition characterized by destruction of insulin-producing β cells within the pancreatic islets. It is associated with considerable morbidity and mortality. Incidence levels are rising worldwide. Pubmed search (Nov 2010) using keywords: Type 1 diabetes, prevention, trials, immunotherapy. The causes of disease are multifactorial with genetic and environmental factors playing a part. There is a long pre-clinical period before the onset of overt symptoms, which may be amenable to therapeutic intervention to prevent disease. The exact nature of causative environmental factors is unknown and much debated. Immunotherapeutic intervention may therefore represent the best option for disease prevention. Enhancement of 'regulatory' immune mechanisms currently shows the most promise as an approach to disease prevention. Clinical trials of early immunotherapeutic intervention may be the answer to disease prevention.

Potential Role of Rapid Eye Movement Sleep Behavior Disorder in the Diagnosis of Neurodegenerative Diseases

…it appears plausible to assume that neuroprotective or disease-modifying therapies might have their greatest chance of success if given in these early preclinical disease periods. Thus, identifying individuals in the preclinical phase of a neurodegenerative condition is a research priority.

Predicting Alzheimer's risk: why and how?

Because the pathologic processes that underlie Alzheimer's disease (AD) appear to start 10 to 20 years before symptoms develop, there is currently intense interest in developing techniques to accurately predict which individuals are most likely to become symptomatic. Several AD risk prediction strategies - including identification of biomarkers and neuroimaging techniques and development of risk indices that combine traditional and non-traditional risk factors - are being explored. Most AD risk prediction strategies developed to date have had moderate prognostic accuracy but are limited by two key issues. First, they do not explicitly model mortality along with AD risk and, therefore, do not differentiate individuals who are likely to develop symptomatic AD prior to death from those who are likely to die of other causes. This is critically important so that any preventive treatments can be targeted to maximize the potential benefit and minimize the potential harm. Second, AD risk prediction strategies developed to date have not explored the full range of predictive variables (biomarkers, imaging, and traditional and non-traditional risk factors) over the full preclinical period (10 to 20 years). Sophisticated modeling techniques such as hidden Markov models may enable the development of a more comprehensive AD risk prediction algorithm by combining data from multiple cohorts. As the field moves forward, it will be critically important to develop techniques that simultaneously model the risk of mortality as well as the risk of AD over the full preclinical spectrum and to consider the potential harm as well as the benefit of identifying and treating high-risk older patients.

Behavioral, Neurochemical, and Electrophysiological Changes in an Early Spontaneous Mouse Model of Nigrostriatal Degeneration

In idiopathic Parkinson's disease, clinical symptoms do not emerge until consistent neurodegeneration has occurred. The late appearance of symptoms implies the existence of a relatively long preclinical period during which several disease-induced neurochemical changes take place to mask the existence of the disease and delay its clinical manifestations. The aim of this study was to examine the neurochemical, neurophysiological, and behavioral changes induced by the loss of nigrostriatal innervation in the En1+/-;En2-/- mouse, in the 10months following degeneration, compared to En2 null mutant mice. Behavioral analysis (Pole-test, Beam-walking test, and Inverted grid test) and field potential recordings in the striatum indicated that loss of ~70% of nigrostriatal neurons produced no significant functional effects until 8months of age, when En1+/-;En2-/- animals started to show frank motor deficits and electrophysiological alterations in corticostriatal plasticity. Similarly, alterations in dopamine homeostasis, dopamine turnover, and dopamine innervation were observed in aged animals compared to young En1+/-;En2-/- mice. These data suggests that in En1+/-;En2-/- mice nigrostriatal degeneration in the substantia nigra is functionally compensated.