Near visual acuity of dental hygienists with and without magnification.

OBJECTIVES: The aim of this study was (i) to evaluate the visual performance of dental hygienists in their clinical environment and (ii) to analyse the relationship between self-assessed and objectively measured visual acuity. METHODS: The near visual acuity of 191 dental hygienists and dental hygiene students was self-assessed with a visual analogue scale and objectively measured with miniaturized visual tests in a simulated clinical setting. The visual acuity was also measured with magnification aids if they were part of the individual clinical equipment. The influence of age and magnification on the near visual acuity was analysed. RESULTS: The visual performance with respect to dental working distance showed a variability of 300% in the dimension of the smallest recognized structure. A weak positive correlation between the self-assessed and objectively measured visual performance (Spearman's rank correlation = 0.27) and a highly significant impact of the test person's age and the use of loupes (both P < .0001) were found. Test subjects ≥40 years exhibited a similar visual acuity when using loupes compared to the visual acuity of test subjects <40 years without loupes. CONCLUSIONS: The visual performance with respect to dental working distance cannot be self-assessed and varies individually. Dental hygienists and students of dental hygiene with a weak near visual acuity were not aware of their deficiencies. Optical aids should be used to compensate for individual visual deficiencies and are mandatory above an age of 40 years due to the effects of presbyopia.

Effect of Magnification on the Precision of Tooth Preparation in Dentistry.

OBJECTIVES: To evaluate the impact of magnification aids on the precision of tooth preparation under simulated clinical conditions. METHODS AND MATERIALS: Two plastic blocks marked with a geometric shape were fixed in a dental phantom head: a circle as the distal surface of tooth 16 (UNS 3) and a y-shaped figure as the occlusal surface of tooth 36 (UNS 19). Sixteen dentists (mean age: 39 years; range: 26-67 years) prepared the geometric shapes from the inside to the boundary line with a cylindrical bur and water-cooling. The boundary line had to be touched but not erased. Chair-side assistance was provided to simulate the clinical situation. Tooth 16 was prepared under indirect vision via a dental mirror. Tooth 36 was prepared under direct vision A) without magnification aids, B) with Galilean loupes, 2.5× and light-emitting diode light, and C) with a microscope, 6.4× and coaxial light. The preparation procedure was performed three times in different sequences of the magnification devices and with a break of at least 1 week between each procedure. The correctly prepared contour and the incorrectly prepared areas were evaluated in relation to the whole circumference of the geometric shapes. RESULTS: For both values the precision was significantly higher when a microscope was used, followed by preparation using loupes; precision was lowest without magnification aids ( p<0.0001). This was true for both indirect and direct vision ( p<0.05). CONCLUSIONS: Magnification devices improved the precision of tooth preparation under simulated clinical conditions.

Plasma microRNA Profile Differentiates Crohn's Colitis From Ulcerative Colitis.

Background: Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn's disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn's colitis (CC) from ulcerative colitis. Methods: Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. Results: Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7-92.9). Conclusions: We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA-based assay to distinguish between these 2 conditions.

A Near Visual Acuity Test for Dentists.

Unimpaired near vision is crucial in dentistry, but appropriate visual tests at dental working distance are not publicly available. The aim of this study was to validate a novel visual triage test for dentists that is easy to use and freely available. The near visual acuity at 300 mm of 106 dental professionals (aged 21-65 years) was assessed with 1) a validated near visual test for scientific purposes miniaturized on a microfilm; 2) an experimental test using a US $5 bill, in which the first five words of each line in the Lincoln Memorial frieze had to be read under a dental operating light. The Spearman rank correlation coefficient of 0.784 revealed a strong correlation between the two tests (p<0.0001). The ability to read six or more words in the memorial frieze meant there was a 94% chance of having a validated near visual acuity greater than or equal to the median score of the dentists tested. If none of the words could be read, the chance of having a near visual acuity below the median of the peer group was 89%. The influence of the dentists' age and experience on their visual performance reported in former studies was corroborated with this new test. The US $5 bill offers a simple and easily available near visual test to rank individuals' near vision relative to that of other dentists and to recognize the progression of presbyopia with increasing age.

The timing of extraction of non-restorable first permanent molars: a systematic review.

AIM: To identify the ideal timing of first permanent molar extraction to reduce the future need for orthodontic treatment. MATERIALS AND METHODS: A computerised database and subsequent manual search was performed using Medline database, Embase and Ovid, covering the period from January 1946 to February 2013. Two reviewers (JE and ME) extracted the data independently and evaluated if the studies matched the inclusion criteria. Inclusion criteria were specification of the follow-up with clinical examination or analysis of models, specification of the chronological age or dental developmental stage at the time of extraction, no treatment in between, classification of the treatment result into perfect, good, average and poor. The search was limited to human studies and no language limitations were set. RESULTS: The search strategy resulted in 18 full-text articles, of which 6 met the inclusion criteria. By pooling the data from maxillary sites, good to perfect clinical outcome was estimated in 72% (95% confidence interval 63%-82%). Extractions at the age of 8-10.5 years tended to show better spontaneous clinical outcomes compared to the other age groups. By pooling the data from mandibular sites, extractions performed at the age of 8-10.5 and 10.5-11.5 years showed significantly superior spontaneous clinical outcome with a probability of 50% and 59% likelihood, respectively, to achieve good to perfect clinical result (p<0.05) compared to the other age groups (<8 years of age: 34%, >11.5 years of age: 44%). CONCLUSION: Prevention of complications after first permanent molars extractions is an important issue. The overall success rate of spontaneous clinical outcome for maxillary extraction of first permanent molars was superior to mandibular extraction. Extractions of mandibular first permanent molars should be performed between 8 and 11.5 years of age in order to achieve a good spontaneous clinical outcome. For the extraction in the maxilla, no firm conclusions concerning the ideal extraction timing could be drawn.

Visual Acuity and Experience with Magnification Devices in Swiss Dental Practices.

OBJECTIVES: The aims of the present study in Swiss dental practices were 1) to provide an update on the prevalence of different magnification devices, 2) to examine the relationship between self-assessed and objectively measured visual acuity, and 3) to evaluate the visual performance of dentists in the individually optimized clinical situation of their respective practices. METHODS AND MATERIALS: Sixty-nine dentists from 40 randomly selected private practices (n=20, <40 years; n=49, ≥40 years) participated in the study. A questionnaire was provided to evaluate the self-assessed near visual acuity and the experience with magnification devices. The objective near visual acuity was measured under standardized conditions on a negatoscope. The clinical situation, including the use of habitual optical aids, was evaluated with visual tests on a phantom head. RESULTS: A total of 64% of the dentists owned a dental loupe: 45% Galilean loupes, 16% Keplerian loupes, and 3% single lens loupes. In total, 19% of the questioned dentists owned a microscope in addition to the loupes. The correlation between the self-assessed and the objective visual performance of the dentists was weak (Spearman rank correlation coefficient=0.25). In the habitual clinical situation, magnification devices (p=0.03) and the dentist's age (p=0.0012) had a significant influence on the visual performance. CONCLUSIONS: Many dentists were not aware of their visual handicaps. Optical aids such as loupes or microscopes should be used early enough to compensate for individual or age-related visual deficiencies.

The impact of rapid palatal expansion on children's general health: a literature review.

AIM: The original indication for rapid palatal expansion was to treat skeletal maxillary constriction. As positive effects were clinically proven, the number of indications for rapid palatal expansion has continuously grown. The purpose of the present article was to review the literature and to evaluate the effect of rapid palatal expansion on nose breathing, natural head position, obstructive sleep apnoea syndrome, nocturnal enuresis and conductive hearing loss. CONCLUSION: It can be concluded that rapid palatal expansion is predominantly recommended in children with maxillary constriction. In those with normal occlusion, maxillary expansion can be considered as the really last choice of treatment when other treatment options in patients with nose breathing, obstructive sleep apnea syndrome (OSAS), nocturnal enuresis and conductive hearing loss (CHL) have failed. Therefore, collaboration between paediatricians, otolaryngologists, paediatric dentists and orthodontists will lead to the best treatment outcomes in the future.

A plasma microRNA panel for detection of colorectal adenomas: a step toward more precise screening for colorectal cancer.

OBJECTIVE: The main objective of this study was to investigate the potential use of circulating microRNAs (miRNAs) as biomarkers of colorectal (CR) adenomas. BACKGROUND: Detection of precancerous lesions such as CR adenoma is a key to reduce CR cancer (CRC) mortality. There is a great need for accurate, noninvasive biomarkers for detection of CR adenoma and CRC. MiRNAs are non-protein-coding RNAs that regulate gene expression. Our prior work investigated the dysregulation of 5 plasma miRNAs in CRC patients. As intended, we undertook a more comprehensive plasma-miRNA screening study in patients with CR adenoma and CRC. METHODS: We screened for 380 plasma-miRNAs using microfluidic array technology (Applied BioSystems) in a screening cohort of 12 healthy controls, 9 patients with CR adenomas, and 20 patients with CRC. A panel of the most dysregulated miRNAs (P < 0.05, False Discovery Rate: 5%) was then validated in a blinded cohort of 26 healthy controls, 16 patients with large adenomas, and 45 patients with CRC. RESULTS: A panel of 8 plasma miRNAs (miR-532-3p, miR-331, miR-195, miR-17, miR-142-3p, miR-15b, miR-532, and miR-652) distinguished polyps from controls with high accuracy [area under curve (AUC) = 0.868 (95% confidence interval [CI]: 0.76-0.98)]. In addition, a panel of 3 plasma miRNAs (miR-431, miR-15b, and miR-139-3p) distinguished Stage IV CRC from controls with an [AUC = 0.896 (95% CI: 0.78-1.0)]. Receiver-operating-characteristic curves of miRNA panels for all CRC versus controls and polyps versus all CRC showed AUC values of 0.829 (95% CI: 0.73-0.93) and 0.856 (95% CI: 0.75-0.97), respectively. CONCLUSIONS: Plasma miRNAs are reliable, noninvasive, and inexpensive markers for CR adenomas. This miRNA panel warrants study in larger cohorts. Plasma-based assays could provide better screening compliance compared to fecal occult blood or endoscopic screening.

Plasma miR-21: a potential diagnostic marker of colorectal cancer.

OBJECTIVES: The main objective of this study was to investigate the potential use of circulating microRNAs (miRNAs) as biomarkers of sporadic colorectal cancer (CRC). BACKGROUND: CRC, a leading cause of death, is curable if detected early. There is an unmet need for an accurate, noninvasive biomarker of CRC. MiRNAs are non-protein-coding RNAs regulating gene expression that play a role in CRC development. METHODS: Levels of 380 miRNAs were determined using microfluidic array technology (Applied Biosystems) in a "training" set of 30 CRC patients from whom cancer and adjacent normal tissue were collected. The 4 most dysregulated miRNAs (P < 0.05, false discovery rate (FDR): 10%) were then validated in a second blinded "test" set of 16 CRC patients from whom cancer and normal adjacent tissue had been collected. Validated tissue miRNAs were then evaluated in a plasma "test" set consisting of 30 CRC patients and 30 individuals without CRC. The most dysregulated tissue miRNAs were then validated in an independent new plasma test set consisting of 20 CRC patients with 20 age-, -, and race-matched subjects without CRC. RESULTS: Nineteen of 380 miRNAs were dysregulated in CRC tissue in the tissue "training" set (P < 0.05, FDR: 10%). The 2 most upregulated (miR-31; miR-135b) and most downregulated (miR-1; miR-133a) miRNAs identified CRC in our "test" set with 100% sensitivity and 80% specificity. MiR-31 was more upregulated in stages III and IV compared with stages I and II (P < 0.05). In the "plasma" group, miR-21 differentiated CRC patients from controls with 90% specificity and sensitivity. CONCLUSIONS: Plasma miRNAs provide reliable and noninvasive markers for CRC. Plasma miR-21 warrants study in larger cohorts. It seems uniquely promising as a plasma biomarker for CRC.

Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer.

One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non-neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (P < 0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let-7e (P < 0.05) as well as in HCT-116 cells transfected with miR-17 (P < 0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines.

An alternative cyclin-D1 splice site is not linked to inflammatory bowel disease-associated neoplasia.

BACKGROUND: Inflammatory bowel diseases (IBD) encompass inflammatory disorders affecting the gastrointestinal tract, primarily ulcerative colitis (UC) and Crohn's disease (CD). The risk of developing colorectal cancer (CRC) is increased in patients with IBD. The CCND1 protein is the regulatory subunit of an enzyme that inactivates the retinoblastoma protein, a tumor suppressor protein, and promotes progression through the G1-S phase of the cell cycle. The CCND1 870G-A gene polymorphism influences susceptibility to colorectal cancer. The mutant allele of CCND1 in IBD-associated neoplasia leads to a greater frequency of alternate splicing during transcription, resulting in a more stable CCND1 protein. This creates a higher concentration of CCND1, facilitating easier passage through the G1/S checkpoint, abnormal cell cycle progression, and possibly carcinogenesis. METHODS: We conducted a case-control study involving 396 individuals with IBD. IBD subgroups included CD, UC, and indeterminate colitis (IC). We studied patients with sporadic colorectal cancer (n=75) and patients without gastrointestinal disease as a control group (n=93). We extracted DNA from blood and performed polymerase chain reaction followed by high-performance liquid chromatography to screen for mutations. We confirmed the polymorphism at nucleotide A870G in exon 4. For statistical analysis, we used exact analyses of two-way contingency tables. Power calculations were done and correction for multiple testing was performed by computing the false discovery rate (FDR). RESULTS AND DISCUSSION: Our study had a power of 75% at a 0.05 significance level. A870G SNP allele frequency in the IBD group was 44.8%, compared to 51.6% in the control population. Only the IC group showed a significant association with CCND1 splice site after correction for multiple testing (FDR=0.042). There were no differences between the other IBD groups and controls. CONCLUSION: We found an association between CCND1 A870G SNP and IC group only (p=0.014, FDR=0.042). However, our data do not show an association between CCND1 A870G SNP and CD-associated or UC-associated neoplasia.

Inflammatory bowel disease and African Americans: a systematic review.

BACKGROUND: Inflammatory bowel disease (IBD) is comprised of Crohn's disease (CD) and ulcerative colitis (UC). There are conflicting reports on whether African Americans have a more severe disease course, presentation, and more frequent extraintestinal manifestations (EIM). We examined the precise nature of this relationship by conducting a systematic review. METHODS: Using predefined inclusion criteria we searched multiple healthcare databases and Grey literature. Eight reports met the inclusion criteria. Using the parameters as defined in the Montreal classification and the presence or absence of EIM, we compared IBD in African Americans and Caucasians. RESULTS: Over 2000 IBD cases were pooled from 8 reports with African Americans comprising 17%. African Americans and Caucasians had similar distribution of types of IBD, with CD being more common than UC in both groups (CD 76% versus 68% and UC 24% versus 32%, respectively). With respect to CD, both groups presented with nonstricturing and nonpenetrating disease behavior (55% versus 41%) more frequently and had similar rates of ileocolonic disease location (42% versus 38%), and presence of perianal disease (26% versus 29%). In UC patients, proctitis was the most frequent initial presentation in both races. Joint complications were the most frequent EIM in both African Americans (52%) and Caucasians (60%). CONCLUSIONS: This study dispels the commonly held views that African Americans with IBD generally have more colonic disease, more severe disease behavior, and more perianal disease than Caucasians. African Americans also have similar variety and frequency of EIMs as compared to Caucasians.

CARD15 genotype-phenotype relationships in a small inflammatory bowel disease population with severe disease affection status.

Inflammatory bowel disease (IBD; MIM# 266600) is subdivided on the basis of clinical findings as either Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Three previously described mutations within the IBD susceptibility gene CARD15 (R702W, G908R, 1007fs) increase susceptibility to CD with a terminal ileal and/or ileocolonic location and fibrostenosing behavior. We undertook an association study using 477 unrelated IBD patients (248 CD, 172 UC, 57 IC) and 104 population controls to determine whether these previously described associations could be replicated in a small, accurately phenotyped cohort. Case-control and family-based approaches were employed to analyze CARD15 mutant allele and haplotype data. Analyses were initially performed in unstratified IBD cohorts. The R702W mutant allele was associated with CD on case-control analysis (q=0.036, P=.004), and 1007fs with CD on pedigree disequilibrium testing (P=.020). All 3 CARD15 mutations increased susceptibility to a variety of CD subphenotypic manifestations, including early-onset CD in individuals with a family history of IBD, and CD complicated by extraintestinal disease. We also present evidence to suggest that R702W may predispose to a more generalized form of CD. Additionally, we confirm that CARD15 mutations are associated with terminal ileal/ileocolonic, and to a lesser extent, fibrostenosing CD.

Association of ulcerative colitis with the inflammatory bowel disease susceptibility locus IBD2 in non-Jewish Caucasians and evidence of genetic heterogeneity among racial and ethnic populations with Crohn disease.

Genomewide scanning has been used to identify chromosomal regions encoding susceptibility loci to inflammatory bowel disease (IBD). The greatest evidence for linkage to IBD has been reported for a region of chromosome 12q14 surrounding the microsatellite marker D12S83, with a logarithm of odds score of 5.47 and a positive transmission disequilibrium test, and which was subsequently named IBD2. We wished to confirm this locus by genotyping the highly polymorphic microsatellites D12S1022, D12S1056, and D12S83, spanning a continuous region on chromosome 12 of 342 kb, in a cohort of nonrelated individuals with ulcerative colitis (89 patients), Crohn disease (121 patients), and population-based control subjects (100 patients). In non-Jewish Caucasians, one D12S1022 allele, one D12S1056 genotype, and three D12S83 alleles were found to have statistically significant differences in distribution between the two disease groups and the control population. These data support a significant association of IBD with the IBD2 locus in close vicinity to the three markers studied. The replication of genetic risk loci in a case control association study may indicate susceptibility genes in this region and may facilitate identification of candidate genes for IBD. Subgroup analysis revealed a notable difference in genotype distribution among Jewish Caucasian and African American patients affected with Crohn disease when compared with similarly affected non-Jewish Caucasians. Using Fisher exact test, statistically significant distribution differences were observed for D12S1022 and D12S83. These data indicate that there may be significant genetic heterogeneity between different ethnic and racial IBD populations or may simply reflect differences in marker allele frequencies among populations.

Interferon-gamma gene polymorphisms and the development of sepsis in patients with trauma.

BACKGROUND: The outcome of patients with trauma does not always correlate with injury severity or premorbid health status. This study evaluates the relationship between polymorphisms in the first intron of the interferon-gamma gene and the development of sepsis after trauma. METHODS: DNA was extracted from peripheral leukocytes of patients with trauma and an injury severity score of 16 or greater. Data collected included demographics, injury mechanism, injuries sustained, development of sepsis, and outcome. A previously identified cytosine/adenine repeated polymorphism was amplified, alleles/genotypes identified, and the results correlated with patient outcome. RESULTS: Sixty-one patients were evaluated. Thirty patients (49%) became septic. The injury severity score, race, age, and gender distribution was similar for both the septic and nonseptic groups. Six alleles and 10 genotypes were identified. Alleles C (34%) and D (52%) were the most common. Patients who were septic had a 62% chance of having a D allele (P =.06), whereas they had only a 29% chance of having a C allele. Homozygotes for allele D (DD) were the most likely to become septic (65%). CONCLUSIONS: Homozygotes for the D allele (DD) of the interferon-gamma gene have an increased chance of developing sepsis after traumatic injury compared with other allelic combinations. This supports the hypothesis that genetic composition plays a role in patient outcome.

T-cell receptor gamma: a microsatellite marker for colorectal cancer.

BACKGROUND: T-cell receptor gamma (TCR-gamma) is involved in maintaining host cell integrity and homeostasis of the human immune system. We hypothesize that polymorphism of the TCR-gamma complex may be involved in the pathogenesis of colorectal cancer. METHODS: The microsatellite markers D7S1818 and D7S2206 located within the TCR-gamma antigen locus on chromosome 7p were amplified by polymerase chain reaction, and genotypes were determined for 22 patients with early onset of colorectal cancer (<60 years old) and for 38 population-based control subjects. RESULTS: Genotype BC of D7S1818 (P = .049) and haplotype AC of D7S1818/D7S2206 (P < or = .003) were associated with colorectal cancer as compared with the control population (extended Fisher's exact test). CONCLUSIONS: This study identifies a novel genetic and clinical association between TCR-gamma and early-onset colorectal cancer. Many young patients do not fulfill the criteria for hereditary colorectal cancer syndromes and are therefore not identified by established screening programs. Markers such as D7S1818 and D7S2206 may become useful in the identification of patients at risk of developing colorectal cancer and permit earlier therapeutic intervention.

Identification of candidate genes in ulcerative colitis and Crohn's disease using cDNA array technology.

Inflammatory bowel disease (IBD) follows a multigenic mode of inheritance, encompassing the clinically discrete phenotypes of ulcerative colitis (UC) and Crohn's disease (CD). The risk of malignant transformation of the colon increases with the duration and extent of IBD and is particularly high for patients with a longstanding history of UC. We wished to identify candidate genes that might be involved in disease pathogenesis based on functional plausibility and their putative role in IBD carcinogenesis. Polyadenylated mRNA (PolyA+ mRNA) preparation from inflamed intestinal mucosa of patients with a longstanding history of UC and CD was performed with subsequent hybridization of alpha phosphorus [alpha-32P]-deoxyadenotriphosphate-labeled complementary deoxyribonucleic acid (DNA) populations to nucleic acid arrays. Of 588 different human gene transcripts arrayed, secreted apoptosis-related protein 1 (Sarp1), frizzled (fz) homologues, and disheveled (dvl) were differentially expressed, being elevated in UC as compared to CD. These genes encode proteins involved in the Wingless-type (Wnt)/beta-catenin signaling pathway. The autonomous expression of Sarp1 and Sarp1-compatible fz receptor genes suggests that the Wnt pathway may be involved in UC carcinogenesis.

Wingless-type frizzled protein receptor signaling and its putative role in human colon cancer.

We wish to identify new candidate genes involved in the pathogenesis of human colon cancer to better understand the diversity of phenotype presentation that varies from individual to individual. Our working hypothesis is that genetic polymorphism of genes in the Wingless-type (Wnt) frizzled protein receptor pathway is associated with the susceptibility to develop colon cancer. The putative role of the Wnt pathway in sporadic human malignancy of the colon suggests involvement in inherited cancer as well. beta-catenin is the crucial messenger in frizzled receptor signaling, transmitting Wnt-ligand signals such as signals from secreted apoptosis-related proteins to the nucleus. It functions as a genome denunciator by initiating amplification of oncogenes. The net effect of beta-catenin depends on the magnitude of its accumulation in the cytoplasm and, therefore, upon expression profiles of genes in the Wnt pathway. We propose that variations in allelic frequencies of genes involved in the beta-catenin cascade may either promote or impede malignant transformation of the colon. If certain polymorphisms in Wnt signaling through beta-catenin predispose to colon cancer, this might manifest as decreased binding affinity of proteins such as axin or the adenomatous polyposis coli protein to beta-catenin. Association studies are proposed to test the hypothesis, which could serve as an initial step toward understanding the complexity of tumor biology. The clinical rationale in unraveling the genetic susceptibility to cancer lies in identification of a subgroup of individuals who may benefit from beta-catenin targeting agents, which could potentially overcome this genetic instability.

Ketoconazole and pulmonary failure after esophagectomy: a prospective clinical trial.

Thromboxane is a key mediator in pulmonary injury after esophageal resection. In this prospective trial we studied the clinical course and development of pulmonary alterations in patients undergoing esophagectomy and prophylactic treatment with a thromboxane synthase inhibitor. Thirty-eight consecutive patients undergoing esophageal resection were treated pre- and perioperatively with 3 x 200 mg ketoconazole. The clinical course was studied and pulmonary function was assessed according to the Murray score. A historical group of 118 patients undergoing esophagectomy for benign and malignant esophageal diseases served as controls. Patients in both groups were similar in terms of age, sex, and preoperative pulmonary function, as well as in the anesthetic and surgical procedures performed. However, in the ketoconazole group, more patients were at risk of pulmonary failure by receiving neoadjuvant radiochemotherapy (22/38) or undergoing thoracotomies (33/38) than control subjects (14/118 and 80/118, P < 0.05). Two out of 38 ketoconazole-treated patients developed acute lung injury after esophagectomy, as did 20/118 control patients (P < 0.05). This prospective non-randomized clinical study (in patients subjected to esophagectomy) provides further evidence that prophylactic thromboxane synthase inhibition by ketoconazole reduces the incidence of acute lung injury in patients at risk.

Association of susceptibility locus for inflammatory bowel disease on chromosome 16 with both ulcerative colitis and Crohn's disease.

A susceptibility locus for inflammatory bowel disease (IBD) on chromosome 16 (IBD1) has been linked to Crohn's disease in genome-wide linkage studies. We performed a case-control study with two markers for this locus using leukocyte DNA from 127 Crohn's patients, 83 ulcerative colitis patients, and 74 control patients. Allele, genotype, and haplotype frequencies of the polymerase chain reaction products were determined using autoradiography. Haplotype frequencies differed for ulcerative colitis and Crohn's disease, particularly for haplotype CC (22% ulcerative colitis vs 10% Crohn's disease, P = 0.002 Chi2 = 10.0) and haplotype CD (18% Crohn's disease vs 9% ulcerative colitis, P = 0.025 Chi2 = 5.02). These data demonstrate the association of the IBD1 locus with both ulcerative colitis and Crohn's disease in a group of unrelated IBD patients. The use of such microsatellite markers when combined with others, might help distinguish ulcerative colitis from Crohn's disease in patients with ambiguous clinical and histological features.