Effects of risk factors on periodontal disease defined by calibrated community periodontal index and loss of attachment scores.

OBJECTIVES: We evaluated whether and how the effects of risk factors on periodontal disease (PD) were modified by measurement errors using community periodontal index (CPI) and loss attachment (LA) in the community-based survey. METHODS: A pilot validation study was performed to estimate the rates of false negative and false positive for both CPI and LA in 31 subjects from different regions using measurements from 12 well-trained dentists and a senior periodontist as a gold standard. Afterward, a Taiwanese nationwide survey was conducted by enrolling 3,860 participants to estimate the effect of each risk factor on PD calibrated with both sensitivity and specificity of two indices. RESULTS: The values obtained for the sensitivity to false-positive ratio for CPI ranged widely from 1.12 to 7.71, indicating regional variation in both errors. The calibrated adjusted odds ratio for smoking vs non-smoking was higher than the uncalibrated odds ratio for PD defined by CPI (2.75 (2.01, 3.77) vs 2.02 (1.63, 2.52)) and LA (3.85 (2.44, 6.13) vs 1.93 (1.47, 2.54)) scores. Similar underestimation was noted for other risk factors. CONCLUSION: The effects of risk factors on PD measured using CPI and LA in a large population-based survey were underestimated without correcting for measurement errors.

Hepatitis C virus infection: a risk factor for Parkinson's disease.

Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory biomarkers. We analysed data from a community-based integrated screening programme based on a total of 62,276 subjects. We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron-glia coculture system in rats. The cytokine/chemokine array was performed to measure the differences of amounts of cytokines released from midbrain in the presence and absence of HCV. The crude odds ratios (ORs) for having PD were 0.62 [95% confidence interval (CI), 0.48-0.81] and 1.91 (95% CI, 1.48-2.47) for hepatitis B virus (HBV) and HCV. After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07-1.80), but not significantly different between HBV and PD. The HCV induced 60% dopaminergic neuron death in the midbrain neuron-glia coculture system in rats, similar to that of 1-methyl-4-phenylpyridinium (MPP(+) ) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD. In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP(+) .

Serum alpha-fetoprotein response can predict prognosis in hepatocellular carcinoma patients undergoing radiofrequency ablation therapy.

AIMS: To evaluate the clinical inference of serum alpha-fetoprotein (AFP) response in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). MATERIALS AND METHODS: Three hundred and thirteen previously untreated HCC patients were enrolled in the study. The optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA for those with a baseline AFP level of ≥100 ng/ml. The impact of AFP response on prognosis was analysed and prognostic factors were assessed. RESULTS: After a median follow-up of 26.7 ± 19.1 months, 49 patients died and 264 patients were alive. The cumulative 5 year survival rates were 75.3 and 57.4% in patients with an initial AFP of <100 ng/ml and ≥100 ng/ml, respectively (p = 0.003). In the 58 patients with a baseline AFP of ≥100 ng/ml and initial completed tumour necrosis after RFA, the cumulative 5 year survival rates were 62.4 and 25.7% in optimal and non-optimal AFP responders, respectively (p = 0.001). By multivariate analysis, the prothrombin time international normalized ratio >1.1 (p = 0.009), non-optimal AFP response (p = 0.023), and creatinine >1.5 mg/dl (p = 0.021) were independent risk factors predictive of poor overall survival. Besides, the cumulative 5 year recurrence rates were 83.4 and 100% in optimal and non-optimal AFP responders, respectively (p < 0.001). Multivariate analysis demonstrated platelet count ≤10(5)/mm(3) (p = 0.048), tumour size >2 cm (p = 0.027), and non-optimal AFP response (p < 0.001) were independent risk factors associated with tumour recurrence after RFA. CONCLUSIONS: Serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA.

Prediction of adverse perinatal outcome by maternal serum screening for Down syndrome in an Asian population.

OBJECTIVE: To investigate the association between adverse perinatal outcomes and abnormal elevations of serum marker levels (alpha-fetoprotein [AFP] and free beta-hCG) or a false-positive screen for Down syndrome. METHODS: Pregnancy outcome information was available for 5885 Taiwanese women under 35 years of age who had second-trimester maternal serum screening for Down syndrome, using AFP and free beta-hCG, and delivered a chromosomally normal fetus. Those with AFP at least 2.0 multiples of the median (MoM), free beta-hCG at least 2.5 MoM, or a false-positive screen (risk ratio at least 1:270) were identified, and the risk for adverse perinatal outcome was assessed. RESULTS: A serum AFP level at least 2.0 MoM (n = 176, 3.0%) was significantly associated with the occurrence of preterm delivery, low Apgar scores, small-for-gestational-age infants, low birth weight or very low birth weight, fetal death, premature rupture of membranes, oligohydramnios, and a higher incidence of perinatal mortality. A serum free beta-hCG level at least 2.5 MoM (n = 416, 7.1%) was significantly associated with low birth weight, an abnormally adherent placenta, and the occurrence of meconium-stained amniotic fluid. A higher incidence of fetal structural anomalies other than neural tube or abdominal wall defects, large-for-gestational-age infants, and postpartum hemorrhage was observed for a calculated risk of at least 1:270 (n = 311, 5.3%) independent of the other biochemical markers. CONCLUSION: Asian women with unexplained elevations of serum AFP or free beta-hCG, or a false-positive screen for Down syndrome are at increased risk for various adverse perinatal outcomes. Careful fetal ultrasound examination and thoughtful strategy for perinatal management are warranted for these patients.

The problem scar.

Through deeper understanding of the physiology of wound healing and physico-chemical principles of scarring, biomedical science facilitates the development of new strategies in treatment and prevention of problem scars. It is important for practicing physicians and surgeons to be better aware of the full range of available techniques to control scar formation, and for any medical intervention to be planned in such a way that potential problems are apprehended and minimized or avoided. This article describes the clinical applications of recent research in scar control in order to provide such guidance.

Silicone implants and the inhibition of cancer.

The safety of augmentation mammaplasty and its relationship to breast cancer has been a much debated topic. The authors previously showed a decreased incidence of breast cancer in rats who had received silicone implants 2 weeks before carcinogen stimulation. The present study was designed to determine (1) whether this protective effect is influenced by the location of the implant, and (2) whether tumor incidence could also be altered in spontaneous mammary tumor-forming animals, the C3H/OuJ mice. (1) A total of 110 rats received either a silicone implant or a sham operation in one of three locations: inframammary region, dorsum, or intraperitoneal cavity. Methylnitrosoured (MNU) injections occurred 14 days after implantation. Animals were examined weekly for tumor growth and were killed 250 days after MNU injection. Animals with silicone implants beneath the mammary gland had a statistically significant lower incidence of breast cancer formation (11.5 percent) compared with both dorsally implanted animals (45.8 percent) and sham controls (64 percent). (2) Sixty C3H/OuJ mice underwent implantation of either a silicone implant, free silicone gel, silicone sheet, or a sham operation. At 50 weeks of age, after weekly examinations, the animals were killed. The cancer incidence in mice with silicone implants was 17 percent compared with 50 percent found in sham controls. Exposure to a silicone prosthesis at an early age does not seem to increase tumor incidence and may even have a locally protective effect against breast cancer formation.

Frostbite of the upper extremity.

Human capacity for physiologic adaptation to cold is minimal; we survive by insulating ourselves with protective clothing. In addition to the irreversible direct injury caused by ice crystallization, the authors have outlined four possible mechanisms by which indirect injury may damage tissue. Other than rapid rewarming, there is no uniformly accepted protocol for the treatment of frostbite injury. Attempting to sort out the world's literature on frostbite in an effort to present a comprehensive treatment protocol is a daunting task. In addition to the probably irreversible direct injury caused by ice crystallization, the authors have outlined at least four possible mechanisms by which indirect injury may damage tissue. The literature is full of various treatment protocols that allegedly are beneficial despite addressing different mechanisms. Mills described 10 different categories of medications, each addressing one of four possible mechanisms, used in the clinical treatment of frostbite injury over a 30-year period. Analyzing this information is even more confusing when one realizes that there is little uniformity in animal models employed to generate these data. This is further complicated by the lack of clinical correlation with the most common experimental model--liquid nitrogen rapid freezing. The risk of frostbite is highest when psychiatric disturbance, intoxication, or unplanned circumstances lead to cold exposure without adequate protective clothing. As tissue freezes, both direct and indirect factors cause injury. Most therapies have been aimed at limiting indirect injury, in an attempt to limit progressive tissue loss. Rapid rewarming is universally accepted, but the benefits of other modalities are still controversial. Traditionally, observation and delayed amputation have been employed to manage frostbite. More recently, triple-phase bone scans have been used to distinguish between tissue that is irreversibly destined for necrosis and tissue that is at-risk for necrosis, but potentially salvageable. Early operation can be used to provide at-risk tissue with a new blood supply and preserve both function and length in the upper extremity.

A prognostic model for patients with hepatocellular carcinoma within the Milan criteria undergoing non-transplant therapies, based on 1106 patients.

BACKGROUND: The Milan criteria are used to select candidates with small hepatocellular carcinoma (HCC) for liver transplantation. Due to severe shortage of donors, majority of patients within the Milan criteria need to seek alternative treatments. AIM: To propose a prognostic model for these patients undergoing non-transplant therapies. METHODS: A total of 1106 HCC patients, who were within the Milan criteria and received non-transplant therapies were retrospectively analysed. Patients were randomly assigned to the derivation and validation set according to treatments. A prognostic model was constructed from independent predictors of survival identified in the multivariate Cox model of the derivation set and was confirmed in the validation set. RESULTS: In the Cox model, serum bilirubin ≥1.5 mg/dL [risk ratio (RR): 1.525, P = 0.016], α-fetoprotein (AFP) ≥100 ng/mL (RR: 1.728, P < 0.001), mild ascites (RR: 1.705, P = 0.025) and moderate/severe ascites (RR: 4.163, P < 0.001) were independent predictors of poor survival in the derivation set (n = 553). A prognostic model with a total of 0-4 points was derived with the sum of three variables: 1 point each for bilirubin ≥1.5 mg/dL, AFP ≥100 ng/mL and mild ascites, and 2 points for moderate/severe ascites. This scoring system accurately predicted the survival in the validation set (n = 553; P < 0.001). The model consistently discriminated the survival in patients stratified by curative and noncurative treatments (both P values <0.001). CONCLUSION: The newly proposed prognostic scoring model, based on serum bilirubin and AFP level, and severity of ascites, is informative to predict the survival in non-transplant HCC patients within the Milan criteria.

Cancer risk in patients with pyogenic liver abscess: a nationwide cohort study.

BACKGROUND: There has been no large-scale population-based study on the relationship between pyogenic liver abscesses (PLA) and subsequent cancer risk. AIM: To estimate all cancer risk following a diagnosis of PLA. METHODS: Based on Taiwan's National Health Insurance Research Database, 1257 patients with PLA without prior cancers in the period 1996-2008 were identified and followed-up. The standard incidence ratio (SIR) of each cancer was calculated as the number of observed cancer cases arising among the PLA patients divided by the expected case number of cancer cases according to the national cancer rates. RESULTS: Of the 1257 PLA patients identified, 598 (47.6%) had diabetes mellitus. After a median (±s.d.) follow-up of 3.33 ± 3.45 years, 186 were diagnosed with cancers, including 56 liver cancer, 22 biliary tract cancer and 40 colorectal cancer patients. Patients with PLA had a higher risk of all cancers (SIR, 3.83; 95% CI, 3.30-4.42), liver cancer (SIR, 7.87; 95% CI, 5.94-10.21), biliary tract cancer (SIR, 34.58; 95% CI, 21.67-52.36) and colorectal cancer (SIR, 5.27; 95% CI, 3.76-7.18). The highest SIRs of all cancers, liver cancer, biliary tract cancer and colorectal cancer occurred within 90 days of follow-up (360.82; 95% CI, 278.46-459.91, 257.28; 95% CI, 186.17-346.56, 1153.38; 95% CI 694.08-1801.24, and 52.63; 95% CI 25.2-96.8 respectively). CONCLUSIONS: Pyogenic liver abscesses may herald the onset of cancer, especially hepato-biliary and colon cancer. Further surveys should be conducted for the detection of occult cancers in such patients.

Updated thresholds for serum alanine aminotransferase level in a large-scale population study composed of 34 346 subjects.

BACKGROUND: The sensitivity of current upper limit of normal (ULN) of serum alanine aminotransferase (ALT) levels for detecting chronic liver disease has been challenged recently. AIM: To identify modulating factors for serum ALT levels and to refine its ULN threshold. METHODS: We enrolled 34 346 consecutive subjects who completed the health check-up at Taipei Veterans General Hospital from 2002 to 2009. ULN was set for healthy ALT level to the 95th percentile of the reference healthy population. RESULTS: A group of 21 282 subjects were used as a training set to define an ULN with the highest sensitivity; afterwards, this ULN was validated in another set of 13 064 subjects. A reference healthy population was selected from the training set after excluding subjects with any abnormalities in independent risk factors associated with elevated serum ALT level (>40 IU/L) by multivariate analysis like body mass index, waist circumference, glucose, cholesterol, high-density lipoprotein-cholesterol, triglyceride, hepatitis B virus surface antigen, anti-hepatitis C virus antibody and fatty liver. The new ULN of serum ALT level defined as the 95% percentile in the healthy population were 21 IU/L and 17 IU/L for men and women respectively. These cut-off values had the highest Youden's index and areas under the corresponding receiver operating curves among four widely applied thresholds in both the training and validation sets. CONCLUSIONS: The suggested threshold of upper limit of normal provides better discrimination between healthy and unhealthy status. Viral hepatitis, metabolic syndrome and fatty liver are the major risk factors of elevated serum alanine aminotransferase levels.

Comparison of the model for end-stage liver disease (MELD), MELD-Na and MELDNa for outcome prediction in patients with acute decompensated hepatitis.

BACKGROUND AND AIM: The model for end-stage liver disease (MELD) is used to predict the outcome of patients with cirrhosis. Incorporation of serum sodium (Na) into MELD may further increase its prognostic ability. Two Na-containing MELD models, MELD-Na and MELDNa, were proposed to enhance the prognostic ability. This study compared the predictive accuracy of these models for acute decompensated hepatitis. METHODS: We investigated the outcome of 182 patients with acute decompensated hepatitis. RESULTS: Twenty (11%) patients died at 3 months. The MELD-Na and MELDNa both had significantly higher area under the receiver operating characteristic curve (AUC) in comparison to MELD (MELD-Na: 0.908, MELDNa: 0.895, MELD: 0.823, p=0.004 and 0.001, respectively). Among 96 patients without specific antiviral treatment, the MELD-Na and MELDNa consistently had significantly higher AUC than the MELD (MELD-Na: 0.901, MELDNa: 0.882, MELD: 0.810, p=0.008 and 0.004, respectively). Three independent indicators, pre-existing cirrhosis (odds ratio [OR]: 5.67, 95% confidence interval [CI]: 1.72-18.7), serum albumin<3.7 g/dL (OR: 5.68, 95% CI: 1.18-27.03) and serum sodium (Na)<138 mequiv./L (OR: 10.0, 95% CI: 2.08-47.62), were associated with 3-month mortality. CONCLUSION: MELD-Na and MELDNa provide better prognostic accuracy than the MELD for patients with acute decompensated hepatitis. The adequacy of liver reserve determines the outcome of these patients.

Association of core promoter/precore mutations and viral load in e antigen-negative chronic hepatitis B patients.

Apart from core promoter A1762T/G1764A and precore G1896A mutations, other hepatitis B virus (HBV) mutants are detected in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to determine the effects of those mutants on clinical manifestation and viral loads of genotypes B and C HBV. Seventy-nine HBeAg-negative CHB patients with hepatitis flare were enrolled in this study and their HBV precore/core region were sequenced. Serial biochemical profiles and viral loads were assessed and compared. Fifty-three patients (67%) were infected by genotype B HBV and 26 (33%) were infected by genotype C HBV. The clinical manifestation and HBV viral loads were comparable between the two groups. However, genotype B was significantly associated with precore G1896A mutation (92.5%), and more mutations within nucleotide 1809-1817 were detected in patients infected by genotype B as compared with those infected by genotype C (18.9%vs 3.8%). Most of the cases had mutations at the -2, -3 or -5 position from the precore AUG initiation codon. Triple core promoter mutations T1753C/A1762T/G1764A [corrected] appeared to be linked to genotype C rather than genotype B HBV (19.2%vs 1.9%; P = 0.013). In multivariate analysis, the presence of either triple core promoter 1753/1762/1764 mutation or nucleotide 1809-1817 mutation was the only factor associated with lower HBV viral load (<70 Meq/mL) (odds ratio = 9.01; 95% CI 1.11-71.43; P = 0.04). In conclusion, minor HBV variants with mutations in the core promoter and precore region were detectable in genotypes B and C. Such HBV variants are genotype specific and related to viraemia levels.

The 5' untranslated regions of the rat A2A adenosine receptor gene function as negative translational regulators.

The rat A2A adenosine receptor (A2A-R) gene contains two promoters, P1 and P2, which produce transcript 1 and transcript 2, respectively. These transcripts differ in the lengths of their 5' untranslated regions (5'UTR1: 514 bp, initiated from P1; 5'UTR2: 221 bp, initiated from P2) but encode the same protein. In the present study, we demonstrate that transcript 2 is present in various tissues at different levels, whereas transcript 1 is found only in the striatum. In the striatum, the level of transcript 2 is approximately 300-fold higher than that of transcript 1. The 5'UTR of both transcripts suppresses the expression of A2A-R and a firefly luciferase reporter gene at the translational level; this suppression is not observed after mutational inactivation of an "out-of-frame" upstream AUG codon. Translational suppression by the 5'UTR was also confirmed in cells using a bicistronic strategy. Collectively, these data suggest that P2 is the major promoter of the rat A2A-R gene. The 5'UTR of the rat A2A-R gene exerts an inhibitory effect on translation by an upstream open reading frame. Because the 5'UTR of the A2A-R gene possesses strong interspecies homology, translational suppression may be a general mechanism by which the expression of the A2A-R gene is regulated.

Analysis of clinical, biochemical and viral factors associated with early relapse after lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B patients in Taiwan.

The efficacy of lamivudine for HBeAg-negative chronic hepatitis B (CHB) Chinese patients has not been fully investigated. The role of the Hepatitis B virus (HBV) genotype on the treatment effect of lamivudine is controversial. Thirty-two consecutive patients with HBeAg-negative CHB were enrolled. All patients were treated with lamivudine 100 mg once daily of 7-12 months duration. The mean total period of follow-up since entry for all patients was 24 +/- 3.5 months. HBV genotypes were classified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and verified by sequencing. Precore (G1896A) and basic core promoter (BCP, A1762T & G1764A) mutations were determined by PCR and direct sequencing. Twenty-one (65.6%) patients were infected by genotype B and, 11 (34.4%) by genotype C. G1896A was predominant in genotype B infected patients (95.2%vs 63.6%, P = 0.037). At the end of treatment, 31 (96.8%) and 14 (43.8%) patients achieved biochemical and virological responses, respectively. The biochemical and virological response rates were 40.6 and 0% at 12 months after treatment. Eighteen (56.3%) patients had biochemical relapse within 12 months after withdrawal of lamivudine. By multivariate analysis, the pretreatment serum level of HBV DNA >/=12 Meq/mL was the only factor associated with early biochemical relapse (Odds ratio = 9.333, 95% CI = 1.497 approximately 58.197, P = 0.017). In conclusion, the virological effect of lamivudine for HBeAg-negative CHB is transient. Most patients had biochemical relapse within 12 months after lamivudine treatment regardless of HBV genotype. A high pretreatment viral load is the determinant for early biochemical relapse.