Orotic acid, a promoter of liver carcinogenesis induces DNA damage in rat liver

Orotic acid, a precursor of pyrimidine nucleotide biosynthesisand a promoter for liver carcinogenesis, when fed at 1% levelin a diet for 5 weeks resulted in liver DNA damage. The damagecan be monitored as alkali-labile lesions using alkaline sucrosegradients as well as alkaline elution technique. Furthermore,the induced DNA damage persists for up to three weeks afterwithdrawal of the orotic acid diet. The fad that several skin-tumourpromoters also induce DNA damage raises the question whetherDNA damage is a component in tumour promotion.     

A review of choledochal cyst in pediatric and adult patients

A review of 80 pediatric and 13 adult patients with choledochal cyst disease occurring in a multiracial population is presented to define the incidence, clinical pattern, surgical techniques, and complications seen over periods of 30 years (pediatric) and 15 years (adult patients). In pediatric patients, most cases are now being diagnosed at a much earlier age, usually in infancy or early childhood, presumably due to the ready availability of ultrasound. Adult patients, by contrast, present a complex picture of heptobiliary disease, and delay in diagnosis is not uncommon. Jaundice appears to be the predominant symptom and the classical triad (pain, jaundice, and mass) is seldom seen. The surgical technique emphasises complete excision of the cyst, including the distal end, as the critical factor in the prevention of late complications. Avoidance of anastomotic stricture depends on the apposition of gut to healthy duct wall and not on the size of the anastomosis alone. Postoperative results have been excellent with no immediate mortality and no evidence of cholangitis in patients with extrahepatic cysts. The morbidity is related to patients with persistent intrahepatic biliary dilatation, Caroli's disease, and carcinoma. While endoscopic intervention, hepatic resection, and liver transplantation have been utilized in the management of cystic disease in the liver, the outlook for patients with cholangiocarcinoma associated with choledochal cyst remains extremely poor, with no survivors in this series.     

Amniotic fluid levels of dimeric inhibins, pro-αC inhibin, activin A and follistatin in Down''s syndrome

OBJECTIVE: In the second trimester of pregnancy, inhibin A is significantly increased in maternal serum and decreased in amniotic fluid in Down's syndrome pregnancies compared to normal. We wished to further evaluate the levels of inhibin A, inhibin B, pro-alpha C inhibin, activin A and the binding protein follistatin in amniotic fluid in Down's syndrome and control pregnancies. DESIGN: Case-matched control study. PATIENTS: 29 Down's syndrome and 290 chromosomally normal control pregnancies were identified from records and amniotic fluid, collected at second trimester amniocentesis, retrieved from routine storage for analysis. MEASUREMENTS: Inhibin A, inhibin B, pro-alpha C inhibin, total activin A and follistatin were measured using sensitive and specific enzyme linked immunosorbent assays. RESULTS: The median (10th-90th percentiles) amniotic fluid inhibin A level in the control pregnancies increased from 334 (122-553) ng/l at 14 weeks' to 695 (316-1475) ng/l at 19 weeks' gestation. The corresponding figures for inhibin B and the alpha-subunit precursor inhibin pro-alpha C were 632 (185-1354) and 2062 (1237-3381) ng/l, respectively at 14 weeks' and 2439 (748-5307) and 3115 (2021-6567) ng/l, respectively at 19 weeks' gestation. Total activin A increased from 3795 (1554-5296) at 14 weeks' to 5086 (3059-8224) at 18 weeks' gestation. Expressed as multiples of the median (MoM) the median (95% CI) amniotic fluid levels of inhibin A, inhibin B, pro-alpha C inhibin and acitivin A in the Down's syndrome samples were 0.77 (0.59-0.85), 0.94 (0.63-1.23), 0.77 (0.49-0.84) and 0.77 (0.53-0.87), respectively. Compared to controls the levels of inhibin A, pro-alpha C inhibin and activin A were significantly lower in Down's syndrome pregnancies (P < 0.01, Mann-Whitney U test). Follistatin levels in the controls declined slightly from 2106 (1421-3538) ng/l at 14 weeks' to 1600 (1281-2543) ng/l at 18 weeks' gestation. Levels in the Downs' syndrome pregnancies were similar to controls. CONCLUSIONS: The data suggest that the production, secretion or metabolism of the inhibin alpha- and beta A-subunits is altered in Down's syndrome pregnancies in the second trimester.     

Frequency of aberrant subclavian artery, arch laterality, and associated intracardiac anomalies detected by echocardiography

Tetralogy of Fallot is generally considered to be the most common congenital heart defect associated with an aberrant subclavian artery (ASA), but the prevalence of ASA in patients with other cardiac anomalies is not well described. The pediatric echocardiography database, with 15,871 initial echocardiograms, was searched for all patients with ASA. Arch laterality and associated intracardiac anomalies were documented for each patient. ASA was found in 226 patients, of whom 171 had a left aortic arch (LAA) and 55 had a right aortic arch (RAA). The occurrence of ASA was 1% in patients with LAA (171 of 15,650) and 25% in patients with RAA (55 of 221; p = 0.001). Intracardiac anatomy was normal in 32% of patients with ASA/LAA and 25% with ASA/RAA. Conotruncal anomalies occurred more frequently with ASA/RAA than ASA/LAA (36% vs 18%; p = 0.01). Atrioventricular canal defects accounted for 10% and left-sided cardiac obstructive lesions accounted for 11% of subjects with ASA/LAA. ASA was rarely associated with d-transposition of the great arteries (1 of 226) and double-outlet right ventricle (5 of 226). The prevalence of ASA was highest in patients with interrupted aortic arch (11 of 38; 29%). In patients with tetralogy of Fallot, the overall prevalence of ASA was 8% (34 of 447), but was higher with RAA (16 of 103; 16%). The highest prevalence of ASA occurred in the subgroup of patients with tetralogy of Fallot with pulmonary atresia and RAA (6 of 25; 24%). In conclusion, ASA was more common in patients with RAA, especially with conotruncal anomalies. In patients with LAA, hypoplastic left heart syndrome, aortic coarctation, and atrioventricular canal defects were commonly associated with ASA.     

Effect of discontinuation of estrogen,calcitriol, and the combination of both on bone density and bone markers

In a 5-yr randomized prospective study we examined the treatment effect of estrogen replacement therapy/hormone replacement therapy (ERT/HRT), calcitriol, ERT/HRT and calcitriol, or placebo for 3 yr and the effect of discontinuation of therapy for 2 more yr on bone mineral density (BMD), calciotropic hormones, markers of bone remodeling, and calcium absorption in 489 elderly women. The treatment phase of the study was double-blinded. After discontinuing therapy for 2 yr, there was rapid bone loss in all 3 treatment groups, and most of the decrease in BMD occurred in the first year. In the ERT/HRT group, spine BMD increased 5.5% in yr 3, decreased 3.2% in yr 4, and decreased 0.7% in yr 5; femoral neck BMD increased 3.7% in yr 3, decreased 2.5% in yr 4, and decreased 0.4% in yr 5; total body BMD increased 2.1% in yr 3, decreased 1.4% in yr 4, and decreased 0.6% in yr 5. In the combination group, spine BMD increased 7.1% in yr 3, decreased 4.3% in yr 4, and decreased 0.3% in yr 5; femoral neck BMD increased 4.5% in yr 3, decreased 3.0% in yr 4, and decreased 0.01% in yr 5; total body BMD increased 2.2% in yr 3, decreased 1.5% in yr 4, and decreased 0.6% in yr 5. In the calcitriol group, spine BMD increased 1.8% in yr 3, decreased 1.8% in yr 4, and showed no change in yr 5; femoral neck BMD increased 0.2% in yr 3, decreased 0.2% in yr 4, and decreased 0.6% in yr 5; total body BMD decreased 0.4% in yr 3, decreased 0.6% in yr 4, and decreased 0.4% in yr 5. Compared with placebo, all treated groups at yr 5 had significantly higher total body BMD; only the combination group had significantly higher spine BMD (3.4%; P < 0.001) and total hip BMD (2.4%; P < 0.01.) compared with the placebo group. Compared with baseline, only spine BMD in the combination group was significantly higher (2.6%; P < 0.001) at yr 5. The increase in calcium absorption and the decrease in serum PTH levels in the calcitriol groups were reversed after discontinuation of treatment, and the decrease in bone markers was reversed in the hormone-treated groups. These results suggest that discontinuation of ERT/HRT and/or calcitriol therapy in elderly women leads to a decrease in much of the BMD gained on treatment; however, in the combination group there was a statistically significant residual effect on spine BMD.     

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin‐1c

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin‐1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)‐induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c‐deficient (Fbln1c^–/–) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild‐type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c^–/– mice with AAD also had reduced numbers of α‐smooth muscle actin‐positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)‐5, IL‐13, IL‐33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL‐5, IL‐33 and TNF levels in lung‐draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3‐positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL‐5 and IL‐13 from co‐cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium‐treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

An age-related decrease in creatinine clearance is associated with an increase in number of falls in untreated women but not in women receiving calcitriol treatment

CONTEXT: Decreased calcitriol production due to impaired renal function may be a significant risk factor for falls in normal aging population. OBJECTIVE: The objective of the study was to examine the association between creatinine clearance (CrCl) and the incidence of falls and fallers in groups treated with placebo, calcitriol, estrogen therapy (ET)/estrogen + progestin therapy (HT), and calcitriol + ET/HT. DESIGN: This was a 3-yr, double-blind, placebo-controlled study designed to test the efficacy of calcitriol and ET/HT on bone loss and falls with analysis by intention to treat and post hoc. SETTING: The study was conducted at an academic outpatient center. PARTICIPANTS: Four hundred eighty-nine normal elderly women aged 65-77 yr; 415 women completed the study. INTERVENTION: Subjects were randomized to placebo, calcitriol 0.25 mug twice a day, ET daily (conjugated equine estrogens 0.625 mg), HT (conjugated equine estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg) and calcitriol + ET/HT. MAIN OUTCOME MEASURES: Cumulative number of falls and fallers were compared between groups with 24-h urine CrCl less than 60 and 60 ml/min or greater. RESULTS: Calcitriol treatment decreased the number of fallers and falls. Low CrCl less than 60 ml/min was a predictor of the number of falls per person but not fallers in the placebo group (P = 0.007). In the low CrCl group (<60 ml/min), the rate of falls decreased on calcitriol by 53% [95% confidence interval (CI) -71% to -22%; P = 0.003], calcitriol + ET/HT by 61% (95% CI -76% to -37%; P = 0.001), and ET/HT by 25% (95% CI: -55% to +24%; not significant). Calcitriol reduced the rate of falls by 30% (95% CI -49% to -4%; P = 0.027) in the CrCl 60 ml/min or greater group. CONCLUSION: Calcitriol treatment decreases falls in all subjects but especially in elderly women with decreased renal function (<60 ml/min) and frequent fallers.     

Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: involvement of cell line-specific apoptotic mechanisms

Bioflavonoids are of considerable interest to human health as these serve as antioxidant and anticancer agents. Although epidemiological and experimental studies suggest that luteolin, a natural bioflavonoid, exhibits chemopreventive properties, its effectiveness as an antiproliferative agent against multidrug resistant (MDR) cancers is unclear. Thus, we assessed the antiproliferative effects of luteolin and associated molecular mechanisms using two MDR cancer cell lines that express high levels of P-glycoprotein and ABCG2. In this article, we demonstrate that luteolin induces apoptosis in P-glycoprotein- and ABCG2-expressing MDR cancer cells without affecting the transport functions of these drug transporters. Analysis of various proliferative signaling pathways indicated that luteolin-induced apoptosis involves reactive oxygen species generation, DNA damage, activation of ATR → Chk2 → p53 signaling pathway, inhibition of NF-kB signaling pathway, activation of p38 pathway and depletion of antiapoptotic proteins. Importantly, use of luteolin in these analyses also identified specific molecular characteristics of NCI-ADR/RES and MCF-7/Mito(R) cells that highlight their different tissue origins. These results suggest that luteolin possesses therapeutic potential to control the proliferation of MDR cancers without affecting the physiological function of drug transporters in the body tissues.     

Smoking is a risk factor for decreased physical performance in elderly women

BACKGROUND: In 487 elderly women aged 65-77 years, we examined the association of smoking with physical performance measures of muscle function and whether the effect of smoking on physical performance measures is mediated through its effect on vitamin D or estrogen metabolism. METHODS: Timed rise, timed walk at normal and fast speed, grip strength, and serum biochemical measurements were compared between smokers, past smokers, and nonsmokers. Analysis of covariance was used to compare physical performance variables while adjusting for confounding variables. RESULTS: Compared to nonsmokers and past smokers, current smokers were significantly (p <.05) slower on timed rise and timed walk tests and had decreased grip strength. From multivariate analysis, smoking, age, total body fat, and serum 1,25(OH)(2)D examined as quartiles were predictors of physical performance measures. The effect of current smoking on physical performance was equivalent to a normal age-related decline in physical performance tests of 7-11 years depending on the test. CONCLUSIONS: The results of this study suggest that current smoking is a risk factor for decreased muscle strength leading to decreased physical performance in elderly women. The effect of smoking on physical performance is in part mediated by its effect on 1,25(OH)(2)D metabolism. Smoking may also have an independent effect on physical performance possibly by a direct effect on muscle or through an effect on vascular function.