The dose-response effects of uric acid on the prevalence of metabolic syndrome and electrocardiographic left ventricular hypertrophy in healthy individuals.

BACKGROUND AND AIM: Hyperuricemia (HUA) is associated with the prevalence of metabolic syndrome (MetS) and cardiovascular risks in various populations. HUA is also able to induce cardiomyocyte hypertrophy in mouse models. However, the dose-response effects of serum uric acid (SUA) on the prevalence of MetS and electrocardiographic left ventricular hypertrophy (LVH) are unclear. METHODS AND RESULTS: We retrospectively collected data from 18,932 individuals who underwent an annual health examination between 1/1/2016 and 12/31/2016. We excluded those with systemic diseases or missing questionnaires. The primary study endpoints were the prevalence of MetS and LVH, which were defined by the criteria for the Taiwanese population and the "SPRINT" trial. The cohort consisted of 17,913 individuals with a mean age of 31.2 years (SD 7.4) and a mean body mass index of 24.6 kg/m2 (SD 3.6); 87.1% of the individuals were men. The prevalence rates of HUA, MetS, and LVH were 29.5%, 9.4%, and 0.32%, respectively, in the overall study population. The HUA group was predominantly male and had significantly poorer lifestyle choices and greater laboratory cardiometabolic biomarker values than did the normouricemic group. However, the frequencies of physical activity were comparable between the two groups. After adjusting for confounders, SUA was associated with MetS (OR:1.473, 95% CI:1.408-1.540, P < 0.001) and LVH (OR:1.301, 95% CI:1.064-1.591, P = 0.01). CONCLUSION: We demonstrated that the dose-response effects of SUA are associated with the prevalence of MetS and electrocardiographic LVH in healthy individuals from Taiwan. Based on this evidence, future studies should investigate urate-lowering therapy and cardiovascular benefits in individuals with HUA (ClinicalTrials.gov number NCT03473951).

Statin use reduces the risk of dementia in elderly patients: a nationwide data survey and propensity analysis.

OBJECTIVES: The objective of this study was to examine the association between the use of statins and the risk of newly diagnosed dementia in an elderly population. DESIGN, SETTING AND PARTICIPANTS: Random samples of 1,000,000 individuals covered by the National Health Insurance in Taiwan were included in the analysis. All participants were 65 years or older without dementia and either did or did not start treatment with statins from 1 August 1997 to 31 December 2010. Patients with established dementia before the start of treatment were excluded. Baseline characteristics were matched (by propensity score) in those who did and did not receive statins. RESULTS: A total of 57,669 subjects were included in the analysis with approximately 12 years of follow-up. Propensity score matching identified 2003 patients who received statins and another 2003 patients who did not with comparable baseline characteristics. Adjusted hazard ratios (HRs) for dementia were significantly inversely associated with total or daily equivalent statin dosage (total accumulated dose: HRs 0.829, 0.720 and 0.385 from T1 to T3 vs. control, P < 0.001 for trend; mean daily dose: HRs 0.667, 0.798 and 0.503 from T1 to T3 vs. control, P < 0.001). The results remained robust after propensity adjustment. CONCLUSION: Independent of traditional risk factors, there was a decrease in newly diagnosed cases of dementia in elderly patients who had received a high total or daily dose of statins. The more potent statins (e.g. atorvastatin and rosuvastatin) seemed to be particularly effective in the prevention of dementia.

A functional variant in the promoter region regulates the C-reactive protein gene and is a potential candidate for increased risk of atrial fibrillation.

OBJECTIVES: In a large population-based cohort, the level of C-reactive protein (CRP) in patients at baseline predicts an increased risk of future development of atrial fibrillation (AF). The mechanism of this increased risk is unknown. Furthermore, both the molecular effects of CRP on atrial myocytes and fibroblasts and whether genetic variants in the CRP gene predispose to AF are also unknown. METHODS: A genetic association study between CRP gene polymorphisms and AF was performed in two independent populations (I: 100 AF patients and 101 controls; II: 348 AF patients and 356 controls), with functional studies to elucidate the mechanism of association. RESULTS: Three polymorphisms (T-861C, A-821G and C-390A/C-390T) were found in the 1-kb promoter of CRP. A triallelic polymorphism (C-390A/C-390T) captured all haplotype information and determined the CRP gene promoter activity and the plasma CRP level, and was in nearly complete linkage disequilibrium with G1059C polymorphism in exon 2. The -390A variant was associated with a higher CRP gene promoter activity, a higher plasma CRP level and a higher risk of AF. Patients with AF also had a higher plasma CRP level than controls. CRP significantly increased the inward L-type calcium current in atrial myocytes with no changes in other ionic currents. CRP did not affect the expressions of type I alpha 1 (COL1A1), type III alpha 1 (COL3A1) and type 1 alpha 2 (COL1A2) procollagens in atrial fibroblasts. CONCLUSION: A CRP gene promoter triallelic polymorphism was associated with CRP gene promoter activity, determined the plasma level of CRP, and predicted the risk of AF. The mechanism of this may be via augmention of calcium influx by CRP in atrial myocytes, but not because of atrial fibrosis.

Differential association of proinflammatory cytokines with left ventricular diastolic dysfunction in subjects with and without continuous ambulatory peritoneal dialysis.

BACKGROUND AND AIMS: The association between inflammation and left ventricular (LV) diastolic dysfunction in continuous ambulatory peritoneal dialysis (CAPD) and non-CAPD patients is not established. The objective of this study was to test the above association and whether inflammation interacts with CAPD to increase LV diastolic dysfunction risks. METHODS AND RESULTS: 120 subjects with normal creatinine levels and 101 CAPD patients were recruited. Echocardiographic parameters were assessed in all patients. The participants were classified as having LV diastolic dysfunction by echocardiographic findings including mitral inflow E/A ratio < 1, deceleration time > 220 cm/s, or decreased peak annular early diastolic velocity in tissue Doppler imaging. Blood was sampled at the baseline for measurement of inflammation markers, including tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Subjects with LV diastolic dysfunction had higher proinflammation cytokines levels in both groups. Inflamed markers correlated significantly with echocardiography parameters for LV diastolic dysfunction in patients receiving CAPD. In a multivariate regression analysis adjusting for all the factors associated with LV diastolic dysfunction, inflammation is still significantly associated with left ventricular diastolic dysfunction (TNF-alpha, OR: 2.6, 95% CI: 2.0-3.35, p < 0.001; IL-6, OR: 1.26, 95% CI: 1.25-1.26, p = 0.01). In addition, the interaction of CAPD and inflammation significantly contributed to the development of LV diastolic dysfunction (CAPD∗ TNF-α: OR: 1.45, 95% CI: 1.13-1.79, P = 0.004). CONCLUSION: We found inflammation plays a vital role for LV diastolic dysfunction especially in CAPD patients. A synergistic effect between CAPD and inflammation, especially TNF-α, would further aggravate LV diastolic dysfunction.

Demonstrating the pharmacogenetic effects of angiotensin-converting enzyme inhibitors on long-term prognosis of diastolic heart failure.

The objective of this study was to evaluate the effects of angiotensin-converting enzyme (ACE) inhibitors and pharmacogenetic interaction on the survival of the patients with diastolic heart failure (DHF). A total of 285 subjects with DHF confirmed by echocardiography were recruited in the period between 1995 and 2003. Baseline characteristics (age, sex, prior history, medication, and echocardiographic findings) and genetic polymorphisms (ACE gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphisms of the angiotensin II type I receptor (AT1R)) were collected and matched (by propensity score) in those who received and those who did not receive ACE inhibitors. The patients were followed up to 10 years. Kaplan-Meier curves and Cox regression models were used to demonstrate the survival trend. The 85 patients who received ACE inhibitors and the other 85 patients who did not were found to have comparable baseline characteristics and polymorphism distribution. Prescription of ACE inhibitors was associated with a significant decrease in overall mortality (hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.24-0.83; P=0.01), and a lower rate of cardiovascular events at 4000 days (HR, 0.53; 95% CI, 0.32-0.90; P=0.02). In addition, ACE I/D gene D allele was associated with higher overall mortality as compared with the I allele (HR, 2.04; P=0.003). This effect was diminished in those who received ACE inhibitors. The use of ACE inhibitor was associated with a significant decrease in long-term mortality and cardiovascular events in the patients with DHF. Genetic variants in the renin-angiotensin system genes were also associated, but their effects could be modified by the use of ACE inhibitors.

Effects of obesity, physical activity, and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance in the National Health and Nutrition Survey 1999-2002.

BACKGROUND AND AIMS: This study was designed to elucidate the effects of obesity, self-reported physical activity and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance. METHODS AND RESULTS: Data from 950 Caucasian subjects ranging in age from 19 to 49 years from the National Health and Nutrition Survey (NHANES), 1999-2002, were included to construct a population-based observational study. Cardiorespiratory fitness (VO(2) max) was predicted from a submaximal exercise stress test. Self-reported physical activity was measured by metabolic equivalent score transformed from a questionnaire. A structural equation model (SEM) was developed to examine the relationship between obesity, cardiorespiratory fitness, self-reported physical activity, and hypertension, inflammation, and insulin resistance. The model showed that obesity was positively linked to hypertension (B=0.50, P<0.001) and C-reactive protein (CRP; B=0.15, p<0.05), which in turn led to insulin resistance (B=0.44, P<0.05). Increased cardiorespiratory fitness was negatively associated with CRP (Γ=-0.23, P<0.01), but not correlated to hypertension after adjustment for potential confounding factors. No significant association was found between self-reported physical activity and hypertension, insulin resistance, and CRP. CONCLUSION: Obesity contributes to the development of hypertension, inflammation, and insulin resistance. Improved cardiorespiratory fitness might lead to clinical and biochemical improvement in insulin resistance by reducing the inflammatory state.

Using brachial-ankle pulse wave velocity to associate arterial stiffness with cardiovascular risks.

BACKGROUND AND AIMS: This study aimed to elucidate the relationship between brachial-ankle pulse wave velocity (baPWV) and conventional cardiovascular risk factors. METHODS AND RESULTS: A total of 192 subjects with low to intermediate risk was enrolled in a cardiovascular evaluation program. A multiple regression model was built to find significant cardiovascular biomarkers for predicting baPWV. A logistic regression model was developed to associate baPWV and other biomarkers with the risk of cardiac diastolic dysfunction. A total of 123 men (mean age: 52.6+/-12.0) and 69 women (mean age: 51.7+/-10.4) was included. Age, blood pressure, C-reactive protein, serum homocysteine, heart rate, and blood urea nitrogen were positively predictive of increased pulse wave velocity. In turn, baPWV increased the risk (odds ratio: 1.257 for each m/s, 95% CI: 1.105 approximately 1.430, p<0.001) and high-density lipoprotein decreased the risk for cardiac diastolic dysfunction (0.962 for each mg/dl, 95% CI: 0.925 approximately 1.000, p=0.05). The correlation between baPWV and Framingham 10-year risk was moderate (men: r=0.306, p=0.002; women r=0.548, p<0.001). CONCLUSION: The results suggest that baPWV is a composite risk factor for early atherosclerotic change and a predictor for the development of diastolic dysfunction and long-term cardiovascular risk.

Efficacy and safety of valsartan/hydrochlorothiazide fixed-dose combination compared with amlodipine monotherapy as first-line therapy for mild to moderate hypertension.

This double-blind, active- and randomized-controlled study compared the efficacy and safety of a fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily (n = 32) with amlodipine monotherapy 5 mg once daily (n = 33) for 8 weeks in patients with mild to moderate hypertension. Non-inferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), and daytime, night-time and 24-h SBP and DBP on ambulatory blood pressure monitoring. Between-group comparisons of adverse events and changes in laboratory parameters did not reach statistical significance, except for uric acid which showed a significant increase in the valsartan/hydrochlorothiazide group compared with the amlodipine group, but was still below the laboratory's upper limit of normal. In conclusion, the use of the fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily as a starting regimen in patients with mild to moderate hypertension was shown to have non-inferior efficacy and comparable safety for daily practice compared with amlodipine 5 mg once daily monotherapy.

Gender difference in clinical and genetic characteristics of Brugada syndrome: SADS-TW BrS registry.

BACKGROUND: Brugada syndrome (BrS) is a heritable sudden cardiac death (SCD) disease with male predominance. Information on gender difference of BrS remains scarce. AIM: To investigate the gender difference of BrS in Han Chinese. DESIGN: We consecutively enrolled 169 BrS patients (153 males and 16 females) from Han Chinese in Taiwan from 1998 to 2017. METHODS: Clinical characteristics, electrocardiographic parameters and SCN5A mutation status were compared between genders. RESULTS: The percentage of family history of SCD in females was slightly higher (31.3% vs. 15%, P = 0.15). Females exhibited longer QTc (457.8 ± 33.0 vs. 429.5 ± 42.1 ms, P < 0.01). Regarding cumulative event occurrence by age, Mantel-Cox test showed females had earlier age of onset of first cardiac events (SCD or syncope) than males (P = 0.049), which was mainly attributed to syncope (P < 0.01). Males with SCD exhibited longer QRS duration (114.2 ± 26.8 vs. 104.8 ± 15.3 ms, P = 0.02) and QTc (442.5 ± 57.4 vs. 422.9 ± 28.8 ms, P = 0.02). Males with syncope exhibited longer PR interval (181.2 ± 33.7 vs. 165.7 ± 27.1 ms, P = 0.01), whereas females with SCD or syncope had a trend towards slower heart rates (69.1 ± 9.6 vs. 82.2 ± 16.3 bpm, P = 0.10) than female with no or mild symptoms. There was no difference in the percentage of SCN5A mutation between genders. CONCLUSION: Gender difference is present in BrS. Females have longer QTc and suffer from syncope earlier than males. Risk of SCD in males is associated with boarder QRS complex and longer QTc, whereas risk of syncope is associated with longer PR interval in males and slower heart rate in females.

Renin-angiotensin system gene polymorphisms and diastolic heart failure.

BACKGROUND: Diastolic heart failure (DHF) refers to an abnormality of diastolic distensibility, filling or relaxation of the left ventricle. The genetic study of DHF is scarce in the literature. The association of renin-angiotensin system (RAS) and DHF are well known. We hypothesized that RAS genes might be the susceptible genes for DHF and conducted a case-control study to prove the hypothesis. MATERIALS AND METHODS: A total of 1452 consecutive patients were analysed and 148 patients with a diagnosis of DHF confirmed by echocardiography were recruited. We had two control populations. The first controls consisted of 286 normal subjects while the second were 148 matched controls selected on a 1-to-1 basis by age, sex, hypertension, diabetes and medication use. The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism; multilocus polymorphisms of the angiotensinogen gene; and the A1166C polymorphisms of the angiotensin II type I receptor (AT(1)R) gene were genotyped. RESULTS: In a single-locus analysis, the odds ratios (ORs) for DHF were significant with the ACE DD genotype and the AT(1)R 1166 CC plus AC genotype. In addition, the concomitant presence of ACE DD and AT(1)R 1166 CC/AC genotypes synergistically increased the predisposition to DHF. CONCLUSIONS: Genetic variants in the RAS genes may determine an individual's risk to develop DHF. There is also a synergistic gene-gene interaction between the RAS genes in the development of DHF.

Endovenous laser ablation of the incompetent small saphenous vein with a 980-nm diode laser: our experience with 3 years follow-up.

PURPOSE: To demonstrate the long-term treatment outcomes of endovenous laser ablation (EVA) of incompetent small saphenous veins (SSV) with a 980-nm diode laser. MATERIALS AND METHODS: Eighty-four patients (96 limbs), with varicose veins and reflux in the SSV on duplex ultrasound examination, were treated with a 980-nm diode laser under ultrasound- or fluoroscopy-guidance. Patients were evaluated at 1 week and 1, 3, 6 months, 1 year and yearly thereafter. RESULTS: In the 96 limbs, the technical success rate was 100%. The SSV remained closed in 89 of 93 limbs (96%) after 1 month, all of 82 limbs after 6 months, 77 limbs after 1 year, 71 limbs after 2 years and 55 limbs after 3 years. In four limbs where recanalisation was observed, repeat EVA was done resulting in successful obliteration of the SSV. No major complication occurred however bruising (27%), tightness or pain (13%) and paraesthesia (4.2%) were observed. CONCLUSION: Endovenous laser ablation with a 980-nm laser wavelength is an easy and safe procedure in incompetent SSVs. After successful treatment, there is a very low rate of recanalisation of the SSV, which suggests that the procedure will provide lasting results.

C-reactive protein gene polymorphism predicts the risk of thromboembolic stroke in patients with atrial fibrillation: a more than 10-year prospective follow-up study.

Essentials We studied the C-reactive protein (CRP) gene on stroke risk in atrial fibrillation (AF) patients. 725 patients with CRP triallelic polymorphism genotype were followed-up for more than 10 years. Patients with the A-390/T-390 allele of the CRP gene were more likely to get ischemic stroke. The triallelic polymorphism of the CRP is related to ischemic stroke in AF patients. SUMMARY: Background Little evidence is available regarding the impact of genetic polymorphisms on the risk of thromboembolic stroke in patients with atrial fibrillation (AF). An increasing body of evidence is demonstrating that inflammatory responses play an important role in the pathophysiology of AF. Objectives To investigate the effect of genetic polymorphisms of the C-reactive protein (CRP) gene on the incidence of thromboembolic stroke in patients with AF. Methods A total of 725 AF patients were longitudinally followed up for > 10 years; this is the largest and longest AF follow-up cohort with genetic data. CRP promoter triallelic polymorphisms (C-390A and C-390T) were genotyped, and CRP levels were divided into four quartiles. Results Patients with higher CRP levels were more likely to develop thromboembolic stroke than those with lower CRP levels (P<0.001, log-rank test for comparison of four quartiles). After adjustment for conventional risk factors, patients with higher CRP levels were more likely to develop thromboembolic stroke than those in the lowest CRP quartile (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.08-4.81; the lowest CRP quartile was the reference group). Patients carrying the A-390 or T-390 allele had higher CRP levels (3.35 ± 2.71 mg L-1 versus 2.43 ± 2.00 mg L-1 ), and were more likely to develop thromboembolic stroke, even after adjustment for conventional risk factors (HR 2.07, 95% CI 1.23-3.48). Conclusion The CRP triallelic polymorphism and the CRP level are associated with the risk of incident thromboembolic stroke in patients with AF.

A simple model for quantification of the radiobiological effectiveness of the 10B(n,alpha)7Li capture reaction in BNCT.

A simple model has been developed for predicting radiobiological effectiveness of the neutron capture reaction in boron neutron capture therapy. This model was derived from the relationship between the cell survival from the boron capture reaction, the intracellular boron concentration, and the thermal neutron fluence. We found that the cell-killing effect of the boron capture reaction was well described using a power function of the intracellular boron concentration. Hence the relationship between cell survival from the boron capture reaction, intracellular boron concentration, and the thermal neutron fluence could be determined using a simple mathematical equation. We consider that our current approach is more appropriate and realistic than the conventional theoretical mathematical model used to estimate the radiobiological effectiveness of the neutron capture reaction in boron neutron capture therapy.

Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells.

Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine (SAM), the principal methyl donor, and is essential to normal cell function. The two forms of MAT, liver specific and non-liver specific, are products of two genes, MAT1A and MAT2A, respectively. We have reported a switch from MAT1A to MAT2A gene expression in human liver cancer cells. In the current work, we examined whether the type of MAT expressed by the cell influences cell growth. HuH-7 cells were stably transfected with MAT1A and were subsequently treated with antisense oligonucleotides directed against MAT2A. MAT2A antisense treatment reduced the amount of MAT2A mRNA by 99% but had no effect on MAT1A mRNA. Cell growth and DNA synthesis rates were reduced by approximately 20-25% after transfection with MAT1A and by an additional 30-40% after MAT2A antisense treatment. SAM level and SAM:S-adenosylhomocysteine (SAH) ratio increased by 50-75% after MAT1A transfection and by an additional 60-80% after MAT2A antisense treatment. DNA methylation changed in parallel to changes in SAM level and SAM:SAH ratio. Supplementing untransfected HuH-7 cells with SAM in the culture medium increased SAM level, SAM:SAH ratio, and DNA methylation and decreased cell growth and DNA synthesis. In conclusion, cell growth is influenced by the type of MAT expressed. The mechanism likely involves changes in SAM:SAH ratio and DNA methylation.

Interactions between Escherichia coli RNA polymerase and lambda repressor. Mutations in PRM affect repression of PR.

The rightward operator, OR, of bacteriophage lambda is part of a complex regulatory region that includes PRM, the promoter for repressor synthesis by a prophage, the rightward early promoter PR, and three repressor-binding sites, OR1, OR2 and OR3. By binding to OR2, repressor blocks transcription from PR and simultaneously stimulates the formation of open complexes between RNA polymerase and PRM. In this letter, we describe a test of the hypothesis that the interaction between RNA polymerase bound at PRM and repressor bound at OR2 increases the apparent affinity of repressor for OR. One implication of this hypothesis is that the amount of repressor required for repression of PR should be inversely correlated with PRM promoter strength. This is indeed the case. The amount of repressor required for 50% repression of PR is decreased by prmup-1, an "up" mutation of PRM, and is increased by prm- mutations. An unexpected finding is that in addition to their effect on the apparent affinity of repressor for OR, mutations in the -35 region of PRM alter the shape of repressor-titration curves. We propose that these mutations alter the interaction between RNA polymerase bound at PRM and repressor bound at OR2 in such a way that cooperativity in the binding of repressor to OR1 and OR2 is also disrupted.

Characterization of a doubly mutant derivative of the lambda PRM promoter. Effects of mutations on activation of PRM.

The mutation, prmE37, located at -14 in the PRM promoter of bacteriophage lambda, reduces PRM function dramatically both in vitro and in vivo. In a search for second-site revertants of prmE37, we isolated a double mutant that exhibits a partially restored Prm+ phenotype. The second-site mutation (at -31) is identical to the mutation prmup-1. The activity of the doubly mutant (pseudo-revertant) promoter, prmE37prmup-1, was investigated in vivo using a PRM-lacZ fusion phage and found to be intermediate between that of prmE37 and wild-type PRM. However, the relative strength of the prmE37prmup-1 promoter was greater than expected following superinfection of a lambda lysogen. Since nalidixic acid was found to preferentially inhibit transcription from the doubly mutant promoter under these conditions, we suggest that DNA supercoiling favors activation of this promoter by repressor. In runoff transcription assays in the absence of repressor, the activity of wild-type PRM and the doubly mutant promoter were the same. However, while addition of repressor significantly stimulated wild-type PRM, it had little or no effect on the activity of the doubly mutant promoter. Values of KB, the equilibrium constant for formation of closed complexes, and kf, the rate constant for isomerization of closed to open complexes, were determined in abortive initiation assays, and the product of kfKB was used as a measure of promoter strength. The results of these assays are in agreement with those obtained in runoff transcription assays. In the absence of repressor, values of kfKB for the doubly mutant promoter and wild-type PRM are the same; however, tau obs, the time required for open complex formation, is significantly greater for the double mutant than for wild-type PRM at all RNA polymerase concentrations used for the abortive initiation analysis. In the presence of repressor, the doubly mutant promoter is stronger than the prmE37 promoter, but much weaker than wild-type PRM. This is due to the fact that kf for the doubly mutant promoter is increased 2.5-fold by repressor, but KB is reduced to the same extent. These two effects counteract each other, so that repressor has no net effect on the strength of the prmE37prmup-1 promoter in vitro. In contrast, repressor increases kf for wild-type PRM eightfold and increases overall promoter strength (KBkf) nearly fivefold. In the presence of repressor, the effects of the two mutations, prmE37 and prmup-1, on kf are independent. This observation is discussed in relation to revised models for open complex formation.

Predicting cancer risks from dental computed tomography.

Dental computed tomography (CT) has become a common tool when carrying out dental implants, yet there is little information available on its associated cancer risk. The objective of this study was to estimate the lifetime-attributable risk (LAR) of cancer incidence that is associated with the radiation dose from dental CT scans and to evaluate the effect of scan position, sex, and age on the cancer risk. This retrospective cohort study involved 505 participants who underwent CT scans. The mean effective doses for male and female patients in the maxilla group were 408 and 389 µSv (P = 0.055), respectively, whereas the mean effective doses for male and female patients in the mandible groups were 475 and 450 µSv (P < 0.001), respectively. The LAR for cancer incidence after mandible CT scanning varied from 1 in 16,196 for a 30-y-old woman to 1 in 114,680 for a 70-y-old man. The organ-specific cancer risks for thyroid cancer, other cancers, leukemia, and lung cancer account for 99% of the LAR. Among patients of all ages, the estimated LAR of a mandible scan was higher than that of a maxilla scan. Furthermore, the LAR for female thyroid cancer had a peak before age 45 y. The risk for a woman aged 30 y is roughly 8 times higher than that of a woman aged 50 y. After undergoing a dental CT scan, the possible cancer risks related to sex and age across various different anatomical regions are not similar. The greatest risk due to a dental CT scan is for a mandible scan when the woman is younger than 45 y. Given the limits of the sample size, machine parameters, and the retrospective nature of this study, the results need to be interpreted within the context of this patient population. Future studies will be of value to corroborate these findings.

Monoclonal antibodies specific for rat relaxin. III. Passive immunization with monoclonal antibodies throughout the second half of pregnancy reduces cervical growth and extensibility in intact rats.

Relaxin is required for normal delivery in the rat. The mechanism(s) whereby relaxin contributes to rapid and safe delivery of the fetuses, however, has not been established. The purpose of this investigation was to determine if relaxin enables normal delivery by promoting the growth and modifying the tensile properties of the uterine cervix. To that end, a monoclonal antibody specific for rat relaxin, designated MCA1, was used to passively neutralize endogenous relaxin in intact pregnant rats. MCA1 or PBS vehicle was administered iv to rats daily from days 12-22 of pregnancy. Cervices were removed at 1200 h on day 22. Cervices obtained from MCA1-treated rats were much smaller and far less extensible than cervices obtained from control rats. Moreover, cervices from MCA1-treated rats were less able to accommodate stress created by extension than cervices from control rats. Passive neutralization of relaxin had no influence on 1) the weights of other reproductive tissues (uterus, placenta, and ovary), 2) the number of fetuses, and 3) the viability of fetuses. The present study indicates that in the rat endogenous relaxin is required for promoting cervical growth and softening during the second half of pregnancy. This work supports the hypothesis that the influence of endogenous relaxin on birth is attributable, at least in part, to its effects on the cervix.

Functional significance of MMP-9 in tumor necrosis factor-induced proliferation and branching morphogenesis of mammary epithelial cells.

Tissue remodeling is a key process involved in normal mammary gland development, with matrix metalloproteinases (MMPs) playing an important role in this process. Our laboratory has demonstrated that tumor necrosis factor (TNF) stimulates branching morphogenesis of mammary epithelial cells (MEC) within a reconstituted basement membrane. Studies were therefore undertaken to determine whether MMPs might mediate the effects of TNF. Using a primary culture model in which rat MEC grow three-dimensionally within a reconstituted basement membrane, we found that TNF stimulated secretion of MMP-9 but not MMP-2. To determine whether MMP-9 was involved in TNF-induced proliferation and branching morphogenesis, we used a peptide containing the prodomain sequence of MMPs and two MMP inhibitors. Both the prodomain peptide (5 x 10(-4)-10(-3) M), as well as BB-94 (10(-8)-10(-5) M) and CGS 27023A (10(-6)-10(-5) M), inhibited TNF-induced proliferation and branching morphogenesis in a concentration-dependent manner. Finally, to verify the specific requirement for MMP-9, we demonstrated that an MMP-9 neutralizing antibody blocked TNF-induced proliferation and branching morphogenesis. Together, these data suggest that TNF-regulated MMP-9 may play a role in the controlled invasion of the fad pad that occurs during normal mammary gland development and that misregulation of MMP-9 may contribute to the invasiveness of breast cancer.

Monoclonal antibodies specific for rat relaxin. IV. Passive immunization with monoclonal antibodies during the antepartum period reduces cervical growth and extensibility, disrupts birth, and reduces pup survival in intact rats.

The purpose of this investigation was to use an approach targeted specifically on endogenous relaxin to determine the influence of antepartum (days 20-22) relaxin on cervical modifications and birth in the rat. To that end, a monoclonal antibody specific for rat relaxin, designated MCA1, was used to neutralize endogenous relaxin in intact pregnant rats. MCA1 or PBS vehicle was administered iv to intact rats daily from days 20-22 of pregnancy. Cervices were removed at 1200 h on day 22. Cervices obtained from MCA1-treated rats were less extensible than cervices obtained from PBS-treated control rats. Furthermore, wet weight, dry weight, water content, and uronate content were lower in cervices obtained from MCA1-treated rats than in cervices from PBS-treated controls. Birth and maternal behavior of MCA1-treated and PBS-treated control rats were observed continuously from 2100 h on day 22 until day 2 postpartum (d2PP). MCA1-treated rats exhibited significantly prolonged durations of litter delivery as well as reduced incidences of live pups on d2PP compared with controls. There were lower incidences of normal maternal behavior observed at birth and on d1PP with MCA1-treated rats than with control rats. In addition, little or no milk was observed in the abdomen of most live pups of MCA1-treated rats on d2PP, whereas abundant milk was observed in the abdomen of all live pups of control rats. The mean live pup weight on d2PP was lower in the litters of MCA1-treated rats than in control litters. The present study indicates that in the rat endogenous relaxin is needed during the antepartum period for normal cervical growth and extensibility, normal litter delivery, and high postpartum pup survival. This work supports the hypothesis that the influence of endogenous relaxin on birth is attributable, at least in part, to its effects on the cervix.