Showing papers by "Oregon Health & Science University published in 2006"

Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia

Abstract: BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa ...

Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Abstract: Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P

Postural Orientation and Equilibrium: What Do We Need to Know About Neural Control of Balance to Prevent Falls?

Abstract: Postural control is no longer considered simply a summation of static reflexes but, rather, a complex skill based on the interaction of dynamic sensorimotor processes. The two main functional goals of postural behaviour are postural orientation and postural equilibrium. Postural orientation involves the active alignment of the trunk and head with respect to gravity, support surfaces, the visual surround and internal references. Sensory information from somatosensory, vestibular and visual systems is integrated, and the relative weights placed on each of these inputs are dependent on the goals of the movement task and the environmental context. Postural equilibrium involves the coordination of movement strategies to stabilise the centre of body mass during both self-initiated and externally triggered disturbances of stability. The specific response strategy selected depends not only on the characteristics of the external postural displacement but also on the individual’s expectations, goals and prior experience. Anticipatory postural adjustments, prior to voluntary limb movement, serve to maintain postural stability by compensating for destabilising forces associated with moving a limb. The amount of cognitive processing required for postural control depends both on the complexity of the postural task and on the capability of the subject’s postural control system. The control of posture involves many different underlying physiological systems that can be affected by pathology or sub-clinical constraints. Damage to any of the underlying systems will result in different, context-specific instabilities. The effective rehabilitation of balance to improve mobility and to prevent falls requires a better understanding of the multiple mechanisms underlying postural control.

Culturing hippocampal neurons

Abstract: We provide protocols for preparing low-density dissociated-cell cultures of hippocampal neurons from embryonic rats or mice. The neurons are cultured on polylysine-treated coverslips, which are suspended above an astrocyte feeder layer and maintained in serum-free medium. When cultured according to this protocol, hippocampal neurons become appropriately polarized, develop extensive axonal and dendritic arbors and form numerous, functional synaptic connections with one another. Hippocampal cultures have been used widely for visualizing the subcellular localization of endogenous or expressed proteins, for imaging protein trafficking and for defining the molecular mechanisms underlying the development of neuronal polarity, dendritic growth and synapse formation. Preparation of glial feeder cultures must begin 2 weeks in advance, and it takes 5 d to prepare coverslips as a substrate for neuronal growth. Dissecting the hippocampus and plating hippocampal neurons takes 2-3 h.

Varenicline, an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation: A Randomized Controlled Trial

Abstract: ContextThe α4β2 nicotinic acetylcholine receptors (nAChRs) are linked to the reinforcing effects of nicotine and maintaining smoking behavior. Varenicline, a novel α4β2 nAChR partial agonist, may be beneficial for smoking cessation.ObjectiveTo assess efficacy and safety of varenicline for smoking cessation compared with sustained-release bupropion (bupropion SR) and placebo.Design, Setting, and ParticipantsRandomized, double-blind, parallel-group, placebo- and active-treatment–controlled, phase 3 clinical trial conducted at 19 US centers from June 19, 2003, to April 22, 2005. Participants were 1025 generally healthy smokers (≥10 cigarettes/d) with fewer than 3 months of smoking abstinence in the past year, 18 to 75 years old, recruited via advertising.InterventionParticipants were randomly assigned in a 1:1:1 ratio to receive brief counseling and varenicline titrated to 1 mg twice per day (n = 352), bupropion SR titrated to 150 mg twice per day (n = 329), or placebo (n = 344) orally for 12 weeks, with 40 weeks of nondrug follow-up.Main Outcome MeasuresPrimary outcome was the exhaled carbon monoxide–confirmed 4-week rate of continuous abstinence from smoking for weeks 9 through 12. A secondary outcome was the continuous abstinence rate for weeks 9 through 24 and weeks 9 through 52.ResultsFor weeks 9 through 12, the 4-week continuous abstinence rates were 44.0% for varenicline vs 17.7% for placebo (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.70-5.50; P<.001) and vs 29.5% for bupropion SR (OR, 1.93; 95% CI, 1.40-2.68; P<.001). Bupropion SR was also significantly more efficacious than placebo (OR, 2.00; 95% CI, 1.38-2.89; P<.001). For weeks 9 through 52, the continuous abstinence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95-4.91; P<.001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99-2.17; P = .057). Varenicline reduced craving and withdrawal and, for those who smoked while receiving study drug, smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discontinuation rates similar to those for placebo. The most common adverse events for participants receiving active-drug treatment were nausea (98 participants receiving varenicline [28.1%]) and insomnia (72 receiving bupropion SR [21.9%]).ConclusionVarenicline was significantly more efficacious than placebo for smoking cessation at all time points and significantly more efficacious than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks.Trial Registrationclinicaltrials.gov Identifier: NCT00141206

Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression

Abstract: Alzheimer’s disease (AD) is a complex, neurodegenerative disease characterized by the impairment of cognitive function in elderly individuals. In a recent global gene expression study of APP transgenic mice, we found elevated expression of mitochondrial genes, which we hypothesize represents a compensatory response because of mitochondrial oxidative damage caused by the over-expression of mutant APP and/ or amyloid beta (Ab). We investigated this hypothesis in a series of experiments examining what forms of APP and Ab localize to the mitochondria, and whether the presence of these species is associated with mitochondrial dysfunction and oxidative damage. Using immunoblotting, digitonin fractionation, immunofluorescence, and electron microscopy techniques, we found a relationship between mutant APP derivatives and mitochondria in brain slices from Tg2576 mice and in mouse neuroblastoma cells expressing mutant human APP. Further, to determine the functional relationship between mutant APP/Ab and oxidative damage, we quantified Ab levels, hydrogen peroxide production, cytochrome oxidase activity and carbonyl proteins in Tg2576 mice and age-matched wild-type (WT) littermates. Hydrogen peroxide levels were found to be significantly increased in Tg2576 mice when compared with age-matched WT littermates and directly correlated with levels of soluble Ab in Tg2576 mice, suggesting that soluble Ab may be responsible for the production of hydrogen peroxide in AD progression in Tg2576 mice. Cytochrome c oxidase activity was found to be decreased in Tg2576 mice when compared with age-matched WT littermates, suggesting that mutant APP and soluble Ab impair mitochondrial metabolism in AD development and progression. An increase in hydrogen peroxide and a decrease in cytochrome oxidase activity were found in young Tg2576 mice, prior to the appearance of Ab plaques. These findings suggest that early mitochondrially targeted therapeutic interventions may be effective in delaying AD progression in elderly individuals and in treating AD patients.

Craig's Restorative Dental Materials

Abstract: Craig's restorative dental materials , Craig's restorative dental materials , کتابخانه دیجیتال جندی شاپور اهواز

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Abstract: Objective Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). Methods Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15μg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and 18F-dopa uptake. Results At 6 months, mean percentage changes in “off” UPDRS motor score were −10.0% and −4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, −23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean 18F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). Interpretation Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome. Ann Neurol 2006

Molecular diagnosis of Burkitt's lymphoma.

Abstract: Background The distinction between Burkitt’s lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt’s lymphoma from diffuse large-B-cell lymphoma. Methods Tumor-biopsy specimens from 303 patients with aggressive lymphomas were profiled for gene expression and were also classified according to morphology, immunohistochemistry, and detection of the t(8;14) c-myc translocation. Results A classifier based on gene expression correctly identified all 25 pathologically verified cases of classic Burkitt’s lymphoma. Burkitt’s lymphoma was readily distinguished from diffuse large-B-cell lymphoma by the high level of expression of c-myc target genes, the expression of a subgroup of germinal-center B-cell genes, and the low level of expression of major-histocompatibility-complex class I genes and nuclear factor-κB target genes. Eight specimens with a pathological diagnosis of diffuse large-B-cell lymphoma had the typical gene-expression profile of Burkitt’s lymphoma, suggesting they represent cases of Burkitt’s lymphoma that are difficult to diagnose by current methods. Among 28 of the patients with a molecular diagnosis of Burkitt’s lymphoma, the overall survival was superior among those who had received intensive chemotherapy regimens instead of lower-dose regimens. Conclusions Gene-expression profiling is an accurate, quantitative method for distinguishing Burkitt’s lymphoma from diffuse large-B-cell lymphoma.

Adult consequences of fetal growth restriction.

Abstract: Low birthweight in relation to the length of gestation, is now known to be associated with increased rates of coronary heart disease and the related disorders stroke, hypertension and type 2 diabetes. These associations extend across the whole range of birthweight, which implies that normal variations in nutrient delivery to the fetus have profound long-term effects. The associations are thought to reflect the body's plasticity during development, by which its structure and function can be permanently changed by the intra uterine and early post natal environment. Slow growth during infancy and rapid weight gain after the age of two years exacerbate the effect of slow fetal growth. Cardiovascular disease and type 2 diabetes arise through a series of interactions between environmental influences and the pathways of development that precede them.

Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

Abstract: Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those ...

Educational Strategies to Promote Clinical Diagnostic Reasoning

Abstract: This article considers how doctors learn to reason in the clinical environment and recommends practical approaches that clinical teachers can use to promote the development of strong diagnostic reasoning skills in their students.

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010

Abstract: As in previous years, the consensus group to consider the use of biological agents in the treatment of rheumatic diseases met during the 13th Annual Workshop on Advances in Targeted Therapies in April, 2011. The group consisted of rheumatologists from a number of universities among the continents of Europe, North America, South America, Australia and Asia. Pharmaceutical industry support was obtained from a number of companies for the annual workshop itself, but these companies had no part in the decisions about the specific programme or about the academic participants at this conference. Representatives of the supporting sponsors participated in the initial working groups to supply factual information. The sponsors did not participate in the drafting of the consensus statement. This consensus was prepared from the perspective of the treating physician. In view of the new data for abatacept, B cell-specific agents, interleukin 1 (IL-1) antagonists, tocilizumab (TCZ) and tumour necrosis factor α blocking agents (TNF inhibitors), an update of the previous consensus statement is appropriate. To allow ease of updating, the 2010 (data from March 2009 to January 2010) updates are incorporated into the body of the article, while 2011 updates (February 2010–January 2011) are separated and highlighted. The consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 1.1 We have modified the Shekelle annotation by designating all abstracts as ‘category D evidence’, whether they describe well-controlled trials or not, as details of the study were often not available in the abstracts. Further, the number of possible references has become so large that reviews are sometimes included; if they contain category A references, they will be referred to as category A evidence. The rheumatologists and bioscientists who attended …

A cascade of disparities: health and health care access for people with intellectual disabilities.

Abstract: People with ID represent approximately 2% of the population and, as a group, experience poorer health than the general population. This article presents recent conceptualizations that begin to disentangle health from disability, summarizes the literature from 1999 to 2005 in terms of the cascade of disparities, reviews intervention issues and promising practices, and provides recommendations for future action and research. The reconceptualization of health and disability examines health disparity in terms of the determinants of health (genetic, social circumstances, environment, individual behaviors, health care access) and types of health conditions (associated, comorbid, secondary). The literature is summarized in terms of a cascade of disparities experienced by people with ID, including a higher prevalence of adverse conditions, inadequate attention to care needs, inadequate focus on health promotion, and inadequate access to quality health care services. Promising practices are reviewed from the perspective of persons with ID, providers of care and services, and policies that influence systems of care. Recommendations across multiple countries and organizations are synthesized as guidelines to direct future action. They call for promoting principles of early identification, inclusion, and self-determination of people with ID; reducing the occurrence and impact of associated, comorbid, and secondary conditions; empowering caregivers and family members; promoting healthy behaviors in people with ID; and ensuring equitable access to quality health care by people with ID. Their broadscale implementations would begin to reduce the health disparity experienced by people with ID.

Epidemiology and costs of chronic obstructive pulmonary disease.

Abstract: SERIES “THE GLOBAL BURDEN OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE” Edited by K.F. Rabe and J.B. Soriano Number 1 in this Series Chronic obstructive pulmonary disease (COPD) is a leading but under-recognised cause of morbidity and mortality worldwide 1. The prevalence of COPD in the general population is estimated to be ∼1% across all ages rising steeply to >10% amongst those aged ≥40 yrs. The prevalence climbs appreciably higher with age. The 30-yr projections for the global increase in COPD from 1990–2020 are startling. COPD is projected to move from the sixth to the third most common cause of death worldwide, whilst rising from fourth to third in terms of morbidity within the same time-frame 2. The cofactors responsible for this remarkable increase are the continued use of tobacco, coupled with the changing demographics of the world, such that many more people, especially those in developing countries, are living into the COPD age range. COPD is under-diagnosed not only in its early stages, but even when lung function is severely impaired. This is perhaps surprising, since simple and inexpensive spirometers that are suitable in clinical practice are now available, and lung function is a powerful predictor of all-cause mortality, regardless of smoking status. No other disease that is responsible for comparable morbidity, mortality and cost is neglected by healthcare providers as much as COPD. It may well be that the true burden of the disease is not fully appreciated, and the message that COPD is both preventable and treatable has yet to be fully understood by most healthcare providers. The hope is that highlighting these facts will help to raise the profile of COPD and begin to change long-held attitudes. Up to 2001, only 32 prevalence surveys of COPD had been reported 3. This is remarkable given the hundreds …

Newborn Screening: Toward a Uniform Screening Panel and System—Executive Summary

Abstract: The Maternal and Child Health Bureau commissioned the American College of Medical Genetics to outline a process of standardization of outcomes and guidelines for state newborn screening programs and to define responsibilities for collecting and evaluating outcome data, including a recommended uniform panel of conditions to include in state newborn screening programs. The expert panel identified 29 conditions for which screening should be mandated. An additional 25 conditions were identified because they are part of the differential diagnosis of a condition in the core panel, they are clinically significant and revealed with screening technology but lack an efficacious treatment, or they represent incidental findings for which there is potential clinical significance. The process of identification is described, and recommendations are provided.

Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis

Abstract: ContextConcern regarding the adverse effects of estrogen and other hormones for treating menopausal symptoms has led to demand for other options; however, the efficacy and adverse effects of nonhormonal therapies are unclear.ObjectiveTo assess the efficacy and adverse effects of nonhormonal therapies for menopausal hot flashes by reviewing published randomized controlled trials.Data SourcesMEDLINE (1966-October 2005), PsycINFO (1974-October 2005), and the Cochrane Controlled Clinical Trials Register Database (1966-October 2005) were searched for relevant trials that provided data on treatment of menopausal hot flashes using 1 or more nonhormonal therapies.Study SelectionAll English-language, published, randomized, double-blind, placebo-controlled trials of oral nonhormonal therapies for treating hot flashes in menopausal women measuring and reporting hot flash frequency or severity outcomes.Data ExtractionTrials were identified, subjected to inclusion and exclusion criteria, and reviewed. Data on participants, interventions, and outcomes were extracted and trials were rated for quality based on established criteria. A meta-analysis was conducted for therapies with sufficient trials reporting hot flash frequency outcomes.Data SynthesisFrom 4249 abstracts, 43 trials met inclusion criteria, including 10 trials of antidepressants, 10 trials of clonidine, 6 trials of other prescribed medications, and 17 trials of isoflavone extracts. The number of daily hot flashes decreased compared with placebo in meta-analyses of 7 comparisons of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (mean difference, −1.13; 95% confidence interval [CI], −1.70 to −0.57), 4 trials of clonidine (−0.95; 95% CI, −1.44 to −0.47), and 2 trials of gabapentin (−2.05; 95% CI, −2.80 to −1.30). Frequency was not reduced in meta-analysis of trials of red clover isoflavone extracts and results were mixed for soy isoflavone extracts. Evidence of the efficacy of other therapies is limited due to the small number of trials and their deficiencies. Trials do not compare different therapies head-to-head and relative efficacy cannot be determined.ConclusionThe SSRIs or SNRIs, clonidine, and gabapentin trials provide evidence for efficacy; however, effects are less than for estrogen, few trials have been published and most have methodological deficiencies, generalizability is limited, and adverse effects and cost may restrict use for many women. These therapies may be most useful for highly symptomatic women who cannot take estrogen but are not optimal choices for most women.

The mitochondrial permeability transition from in vitro artifact to disease target

Abstract: The mitochondrial permeability transition pore is a high conductance channel whose opening leads to an increase of mitochondrial inner membrane permeability to solutes with molecular masses up to ≈ 1500 Da. In this review we trace the rise of the permeability transition pore from the status of in vitro artifact to that of effector mechanism of cell death. We then cover recent results based on genetic inactivation of putative permeability transition pore components, and discuss their meaning for our understanding of pore structure. Finally, we discuss evidence indicating that the permeability transition pore plays a role in pathophysiology, with specific emphasis on in vivo models of disease.

Guidelines for colonoscopy surveillance after polypectomy: A consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society

Abstract: Adenomatous polyps are the most common neoplastic findings uncovered in people who undergo colorectal screening or have a diagnostic workup for symptoms. It was common practice in the 1970s for these patients to have annual follow-up surveillance examinations to detect additional new adenomas as well as missed synchronous adenomas. As a result of the National Polyp Study report in 1993, which demonstrated clearly in a randomized design that the first postpolypectomy examination could be deferred for 3 years, guidelines published by a gastrointestinal consortium in 1997 recommended that the first follow-up surveillance be 3 years after polypectomy for most patients. In 2003, these guidelines were updated, colonoscopy was recommended as the only follow-up examination, and stratification at baseline into lower and higher risk for subsequent adenomas was suggested. The 1997 and 2003 guidelines dealt with both screening and surveillance. However, it has become increasingly clear that postpolypectomy surveillance is now a large part of endoscopic practice, draining resources from screening and diagnosis. In addition, surveys have demonstrated that a large proportion of endoscopists are conducting surveillance examinations at shorter intervals than recommended in the guidelines. In the present paper, a careful analytic approach was designed addressing all evidence available in the literature to delineate predictors of advanced pathology, both cancer and advanced adenomas, so that patients can be more definitely stratified at their baseline colonoscopy into those at lower or increased risk for a subsequent advanced neoplasia. People at increased risk have either three or more adenomas, or high-grade dysplasia, or villous features, or an adenoma ≥1 cm in size. It is recommended that they have a 3-year follow-up colonoscopy. People at lower risk who have one or two small (<1 cm) tubular adenomas with no high-grade dysplasia can have a follow up in 5 to 10 years, whereas people with hyperplastic polyps only should have a 10-year follow up as average-risk people. Recent papers have reported a significant number of missed cancers by colonoscopy. However, high-quality baseline colonoscopy with excellent patient preparation and adequate withdrawal time should minimize this and reduce clinicians' concerns. These guidelines were developed jointly by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society to provide a broader consensus and thereby increase utilization of the recommendations by endoscopists. Adoption of these guidelines nationally can have a dramatic impact on shifting available resources from intensive surveillance to screening. It has been shown that the first screening colonoscopy and polypectomy produces the greatest effects on reducing the incidence of colorectal cancer in patients with adenomatous polyps.

Poly(ADP-ribose) (PAR) polymer is a death signal

Abstract: Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury.

Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review.

Abstract: ContextAbout 2% of all colorectal cancer occurs in the context of the autosomal dominantly inherited Lynch syndrome, which is due to mutations in mismatch repair genes. Potential risk-reducing interventions are recommended for individuals known to have these mutations.ObjectivesTo review cancer risks and data on screening efficacy in the context of Lynch syndrome (hereditary nonpolyposis colorectal cancer) and to provide recommendations for clinical management for affected families, based on available evidence and expert opinion.Data Sources and Study SelectionA systematic literature search using PubMed and the Cochrane Database of Systematic Reviews, reference list review of retrieved articles, manual searches of relevant articles, and direct communication with other researchers in the field. Search terms included hereditary non-polyposis colon cancer, Lynch syndrome, microsatellite instability, mismatch repair genes, and terms related to the biology of Lynch syndrome. Only peer-reviewed, full-text, English-language articles concerning human subjects published between January 1, 1996, and February 2006 were included. The US Preventive Services Task Force's 2-tier system was adapted to describe the quality of evidence and to assign strength to the recommendations for each guideline.Evidence SynthesisThe evidence supports colonoscopic surveillance for individuals with Lynch syndrome, although the optimal age at initiation and frequency of examinations is unresolved. Colonoscopy is recommended every 1 to 2 years starting at ages 20 to 25 years (age 30 years for those with MSH6 mutations), or 10 years younger than the youngest age of the person diagnosed in the family. While fully acknowledging absence of demonstrated efficacy, the following are also recommended annually: endometrial sampling and transvaginal ultrasound of the uterus and ovaries (ages 30-35 years); urinalysis with cytology (ages 25-35 years); history, examination, review of systems, education and genetic counseling regarding Lynch syndrome (age 21 years). Regular colonoscopy was favored for at-risk persons without colorectal neoplasia. For individuals who will undergo surgical resection of a colon cancer, subtotal colectomy is favored. Evidence supports the efficacy of prophylactic hysterectomy and oophorectomy.ConclusionsThe past 10 years have seen major advances in the understanding of Lynch syndrome. Current recommendations regarding cancer screening and prevention require careful consultation between clinicians, clinical cancer genetic services, and well-informed patients.