Showing papers on "Normal diet published in 2003"

The serum protein α2–Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification

Abstract: Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein α2–Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as an important inhibitor of ectopic calcification acting on the systemic level. Ahsg-deficient mice are phenotypically normal, but develop severe calcification of various organs on a mineral and vitamin D–rich diet and on a normal diet when the deficiency is combined with a DBA/2 genetic background. This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation. The same underlying principle may contribute to many calcifying disorders including calciphylaxis, a syndrome of severe systemic calcification in patients with chronic renal failure. Taken together, our data demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide a novel therapeutic concept to prevent ectopic calcification accompanying various diseases.

Several Culinary and Medicinal Herbs Are Important Sources of Dietary Antioxidants

Abstract: We assessed the contribution of culinary and medicinal herbs to the total intake of dietary antioxidants. Our results demonstrate that there is more than a 1000-fold difference among antioxidant concentrations of various herbs. Of the dried culinary herbs tested, oregano, sage, peppermint, garden thyme, lemon balm, clove, allspice and cinnamon as well as the Chinese medicinal herbs Cinnamomi cortex and Scutellariae radix all contained very high concentrations of antioxidants (i.e., >75 mmol/100 g). In a normal diet, intake of herbs may therefore contribute significantly to the total intake of plant antioxidants, and be an even better source of dietary antioxidants than many other food groups such as fruits, berries, cereals and vegetables. In addition, the herbal drug, Stronger Neo-Minophagen C, a glycyrrhizin preparation used as an intravenous injection for the treatment of chronic hepatitis, boosts total antioxidant intake. It is tempting to speculate that several of the effects due to these herbs are mediated by their antioxidant activities.

Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion

Abstract: A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca2+ in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5−/− islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5−/− islets. Furthermore, exposure of LRP5+/+ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that Wnt/LRP5 signaling contributes to the glucose-induced insulin secretion in the islets.

Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice

Abstract: In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.

Randomized clinical trial of multimodal optimization and standard perioperative surgical care.

Abstract: Background: Multimodal optimization of surgical care has been associated with reduced hospital stay and improved physical function. The aim of this randomized trial was to compare multimodal optimization with standard care in patients undergoing colonic resection. Methods: Twenty-five patients requiring elective right or left hemicolectomy were randomized to receive a ten-point optimization programme (14 patients) or conventional care (11). The groups were similar in terms of age (64 versus 68 years), male : female sex ratio (6 : 8 versus 5 : 6) and Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) score (both 26). Outcome measures were recorded before operation and on postoperative days 1, 7 and 30. They included hand grip strength, lung spirometry, and pain and fatigue scores. Further outcome measures included time to achieve a predetermined mobilization target, time to resumption of normal diet, and length of stay. Results: Optimization was associated with maintained grip strength, earlier mobilization (46 versus 69 h; P = 0·043), and significantly lower pain and fatigue scores. Patients in the optimization group tolerated a regular hospital diet significantly earlier than controls (48 versus 76 h; P < 0·001). Optimization significantly reduced the median length of hospital stay (3 versus 7 days; P = 0·002). Conclusion: Optimization of surgical care significantly improved patients' physical and psychological function in the early postoperative period and facilitated early hospital discharge. Copyright © 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity.

Abstract: Dietary antioxidants protect laboratory animals against the induction of tumours by a variety of chemical carcinogens. Among possible mechanism of protection against chemical carcinogenesis could be mediated via-antioxidant-dependent induction of detoxifying enzymes. Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food colouring material and exhibits antiinflammatory antitumour, and antioxidant properties. In this study we therefore investigated the effect of dietary supplementation of curcumin on the activities of antioxidant and phase II-metabolizing enzymes involved in detoxification, and production of reactive oxygen species were quantified in ddY male mice. Dietary supplementation of curcumin (2%, w/v) to male ddY mice for 30 days significantly increased the activities of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and catalase to 189%, 179%, 189%, and 181% in liver and 143%, 134%, 167% and 115% in kidney respectively as compared with corresponding normal diet fed control (P<0.05-0.001). Parallel to these changes, curcumin feeding to mice also resulted in a considerable enhancement in the activity of phase II-metabolizing enzymes viz. glutathione S-transferase and quinone reductase to 1.7 and 1.8 times in liver and 1.1 and 1.3 times in kidney respectively as compared with corresponding normal diet fed control (P<0.05-0.01). In general, the increase in activities of antioxidant and phase II-metabolizing enzymes was more pronounced in liver as compared to kidney. The induction of such detoxifying enzymes by curcumin suggest the potential value of this compound as protective agent against chemical carcinogenesis and other forms of electrophilic toxicity. The significance of these results can be implicated in relation to cancer chemopreventive effects of curcumin against the induction of tumours in various target organs.

Anthocyanin glycosides from berry fruit are absorbed and excreted unmetabolized by both humans and rats

Abstract: Anthocyanins, the red/blue pigments found in plants, are polyphenolic compounds consumed by humans and are part of a normal diet. Recent studies have shown that anthocyanins have substantial bioactivity including antioxidant activity and therefore may have beneficial effects on human health. Anthocyanins are a group of over 500 compounds of diverse structures containing different core phenolic aglycons and conjugated with sugars in a variety of glycosylation patterns. In this study, we have investigated the bioabsorption of 15 anthocyanins with structures containing different aglycons and conjugated sugars extracted from blueberry, boysenberry, black raspberry, and blackcurrant in both humans and rats. Intact and unmetabolized anthocyanins were detected in urine of rats and humans following dosing for all molecular structures investigated, thus demonstrating that anthocyanins with diverse molecular structure and from different dietary sources are bioavailable at diet relevant dosage rates. In addition, the relative concentrations of anthocyanins detected in urine following dosing varied, indicating that differences in bioavailability are due to variations in chemical structure. Our results suggest that the nature of the sugar conjugate and the phenolic aglycon are both important determinants of anthocyanin absorption and excretion in rats and humans.

Hibiscus sabdariffa extract inhibits the development of atherosclerosis in cholesterol-fed rabbits.

Abstract: Hibiscus sabdariffa L., a local soft drink material and medicinal herb, is usually used effectively in native medicines against hypertension, pyrexia, and liver disorders. Here, we report an extract, HSE (H. sabdariffa extract), which is designed to exhibit hypolipidemia and antiatherosclerotic effects in rabbits with experimental atherosclerosis. New Zealand White rabbits were fed with a normal diet, high cholesterol (1.3%), lard oil (3%) diet (HCD) with or without 0.5 or 1% HSE for 10 weeks. The levels of triglyceride, cholesterol, and low-density lipoprotein cholesterol (LDL-C) were lower in the serum of rabbits fed HCD plus HSE than in the serum of rabbits fed HCD. Feeding HSE (0.5 and 1% in the diet) to rabbits significantly reduced severe atherosclerosis in the aorta. Histopathological examination showed that HSE reduced foam cell formation and inhibited smooth muscle cell migration and calcification in the blood vessel of rabbits. These results suggest that HSE inhibits serum lipids and shows an antiatherosclerotic activity.

KLOTHO Allele Status and the Risk of Early-Onset Occult Coronary Artery Disease

Abstract: We previously identified a functional variant of KLOTHO (termed “KL-VS”), which harbors two amino acid substitutions in complete linkage disequilibrium and is associated with reduced human longevity when in homozygosity. Klotho-deficient mice display extensive arteriosclerosis when fed a normal diet, suggesting a potent genetic predisposition. To determine whether klotho influences atherosclerotic risk in humans, we performed cross-sectional studies to assess the association between the KL-VS allele and occult coronary artery disease (CAD) in two independent samples of apparently healthy siblings of individuals with early-onset (age <60 years) CAD (SIBS-I [N=520] and SIBS-II [N=436]). Occult CAD was defined as the occurrence of a reversible perfusion defect during exercise thallium scintigraphy and/or as an abnormal result of an exercise electrocardiogram (SIBS-I, n=97; SIBS-II, n=56). In SIBS-I, the KL-VS allele conferred a relative odds of 1.90 (95% confidence interval 1.21–2.98) for occult CAD, after adjusting for familial intraclass correlations (P<.005). Logistic regression modeling, incorporating known CAD risk factors, demonstrated that the KL-VS allele is an independent risk factor (P<.019) and that the imposed risk of KL-VS allele status is influenced by modifiable risk factors. Hypertension (P<.022) and increasing high-density lipoprotein cholesterol (HDL-C) levels (P<.022) mask or reduce the risk conferred by the KL-VS allele, respectively, whereas current smoking (P<.004) increases the risk. Remarkably concordant effects of the KL-VS allele and modifying factors on the risk of occult CAD were seen in SIBS-II. These results demonstrate that the KL-VS allele is an independent risk factor for occult CAD in two independent high-risk samples. Modifiable risk factors, including hypertension, smoking status, and HDL-C level, appear to influence the risk imposed by this allele.

Nutritional modulation of DNA repair in a human intervention study

Abstract: DNA oxidation is a potential cause of cancer in humans. It is well-known that fruits and vegetables protect against cancer, and this may be in part because they contain antioxidants, which decrease the level of oxidation of DNA. However, there are other possible mechanisms, such as an enhancement of cellular repair of this damage. A randomized cross-over study was carried out on healthy human subjects, who were given kiwifruit as a supplement to their normal diet, for 3-week periods at different ‘doses’, with 2-week washout periods between doses. Endogenous oxidation of bases in lymphocyte DNA, and the resistance of the DNA to oxidation ex vivo, were assessed using single cell gel electrophoresis (the ‘comet assay’). The capacity to repair DNA base oxidation was measured with an in vitro test, and levels of expression of repair-related genes OGG1 and APE1 were assessed by semi-quantitative RT–PCR. Concentrations of dietary antioxidants were measured in plasma. The antioxidant status of plasma and of lymphocytes was increased by consumption of kiwifruit. Levels of endogenous oxidation of pyrimidines and purines in DNA were markedly decreased, and DNA repair measured on a substrate containing 8-oxo-7,8-dihydroguanine was substantially increased (without change in levels of OGG1 or APE1 mRNA). The magnitude of these effects was generally not related to the number of kiwifruits consumed per day. Kiwifruit provides a dual protection against oxidative DNA damage, enhancing antioxidant levels and stimulating DNA repair. It is probable that together these effects would decrease the risk of mutagenic changes leading to cancer.

Fish oil supplementation reduces severity of exercise-induced bronchoconstriction in elite athletes.

Abstract: In elite athletes, exercise-induced bronchoconstriction (EIB) may respond to dietary modification, thereby reducing the need for pharmacologic treatment. Ten elite athletes with EIB and 10 elite athletes without EIB (control subjects) participated in a randomized, double-blind crossover study. Subjects entered the study on their normal diet, and then received either fish oil capsules containing 3.2 g eicosapentaenoic acid and 2.2 g docohexaenoic acid (n-3 polyunsaturated fatty acid [PUFA] diet; n = 5) or placebo capsules containing olive oil (placebo diet; n = 5) taken daily for 3 weeks. Diet had no effect on preexercise pulmonary function in either group or on postexercise pulmonary function in control subjects. However, in subjects with EIB, the n-3 PUFA diet improved postexercise pulmonary function compared with the normal and placebo diets. FEV1 decreased by 3 ± 2% on n-3 PUFA diet, 14.5 ± 5% on placebo diet, and 17.3 ± 6% on normal diet at 15 minutes postexercise. Leukotriene (LT)E4, 9α, 11β-prostagl...

The physiology of cellular liporegulation

Abstract: ▪ Abstract Here we explore the physiologic role of leptin as a liporegulatory hormone responsible for maintaining intracellular homeostasis in the face of wide variations in caloric intake. Normally, rats can tolerate a 60% fat diet because 96% of the surplus fat is deposited in adipocytes. In contrast, when leptin is congenitally absent or inactive, even on a normal diet, unutilized dietary fat is deposited in nonadipose tissues, causing dysfunction (lipotoxicity) and possible cell death (lipoapoptosis). We theorize that in diet-induced obesity, acquired leptin resistance may also develop as the result of increase in certain leptin resistance factors. Acquired leptin resistance occurs in aging, obesity, Cushing's syndrome, and acquired lipodystrophy, and preliminary evidence suggests that ectopic lipid deposition is increased. We speculate that the metabolic syndrome may be the human equivalent of the lipotoxic syndrome of rodents.

Review article: nutrition and adult inflammatory bowel disease.

Abstract: Summary Major advances in the understanding of the aetio-pathogenesis and genetics of inflammatory bowel disease have been accompanied by an escalation in the sophistication of immunomodulatory inflammatory bowel disease therapeutics. However, the basic ‘triple’ therapy (5-aminosalicylates, corticosteroids, azathioprine) and nutrition have maintained their central role in the management of patients with inflammatory bowel disease over recent decades. This review provides an overview of the supportive and therapeutic perspectives of nutrition in adult inflammatory bowel disease. The objective of supportive nutrition is to correct malnutrition in terms of calorie intake or specific macro- or micronutrients. Of particular clinical relevance is deficiency in calcium, vitamin D, folate, vitamin B12 and zinc. There is justifiably a growing sense of unease amongst clinicians and patients with regard to the long-term use of corticosteroids in inflammatory bowel disease. This, rather than arguments about efficacy, should be the catalyst for revisiting the use of enteral nutrition as primary treatment in Crohn's disease. Treatment failure is usually related to a failure to comply with enteral nutrition. Potential factors that militate against successful completion of enteral nutrition are feed palatability, inability to stay on a solid-free diet for weeks, social inconvenience and transient feed-related adverse reactions. Actions that can be taken to improve treatment outcome include the provision of good support from dietitians and clinicians for the duration of treatment and the subsequent ‘weaning’ period. There is evidence to support a gradual return to a normal diet through exclusion–re-introduction or other dietary regimen following the completion of enteral nutrition to increase remission rates. We also review the evidence for emerging therapies, such as glutamine, growth factors and short-chain fatty acids. The future may see the evolution of enteral nutrition into an important therapeutic strategy, and the design of a ‘Crohn's disease-specific formulation' that is individually tailored, acceptable to patients, cost-effective, free from adverse side-effects and combines enteral nutrition with novel pre- and pro-biotics and other factors.

Hyperlipidemia induced by a cholesterol-rich diet leads to enhanced peroxynitrite formation in rat hearts.

Abstract: Objective: We investigated the influence of experimental hyperlipidemia on the formation of cardiac NO, superoxide, and peroxynitrite (ONOO−) in rat hearts. Methods: Wistar rats were fed 2% cholesterol-enriched diet or normal diet for 8 weeks. Separate groups of normal and hyperlipidemic rats were injected twice intraperitoneally with 2×20 μmol/kg FeTPPS (5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III]), a ONOO− decomposition catalyst, 24 h and 1 h before isolation of the hearts. Results: A cholesterol diet significantly decreased myocardial NO content, however, myocardial Ca2+-dependent and Ca2+-independent NO synthase activity and NO synthase protein level did not change. Myocardial superoxide formation and xanthine oxidase activity were significantly increased; however, cardiac superoxide dismutase activity did not change in the cholesterol-fed group. Dityrosine in the perfusate, a marker of cardiac ONOO− formation, and plasma nitrotyrosine, a marker for systemic ONOO− formation, were both elevated in hyperlipidemic rats. In cholesterol-fed rats, left ventricular end-diastolic pressure (LVEDP) was significantly elevated as compared to controls. Administration of FeTPPS normalized LVEDP in the cholesterol-fed group. Conclusion: We conclude that cholesterol-enriched diet-induced hyperlipidemia leads to an increase in cardiac ONOO− formation and a decrease in the bioavailability of NO which contributes to the deterioration of cardiac performance and may lead to further cardiac pathologies.

Stricture of the proximal esophagus in head and neck carcinoma patients after radiotherapy.

Abstract: BACKGROUND It is well recognized that many patients with head and neck carcinoma have problems with food intake and malnutrition. The objective of the current study was to determine the clinical pattern of patients with nonneoplastic stricture of the upper esophagus after radiotherapy for head and neck carcinoma. METHODS A retrospective chart study of 22 patients with stricture of the proximal esophagus diagnosed between 1993 and 1999 at Karolinska Hospital was performed. The dose volume histograms of the first 2 cm and 5 cm, respectively, of the proximal esophagus were calculated. RESULTS Five of the patients (23%) had total obliteration. The first 2 cm of the esophagus received at least 60 grays (Gy) in > 80% of the volume. Radiation injury was not reported to occur at doses < 60 Gy. There was a correlation found between dysphagia during radiotherapy and the development of proximal esophageal stricture. Stricture was diagnosed 1–60 months (median, 6 months) after radiotherapy. In 18 patients, the stricture was treated with single or repeated endoscopic dilation. These treatments allowed a nearly normal diet in 78% of the patients. CONCLUSIONS Stricture of the upper esophagus is one deglutition disorder that is reported to occur after radiotherapy for head and neck carcinoma. In the current study, the authors emphasize the importance of knowing the tolerance of the normal esophagus to irradiation as well as early diagnosis of stricture of the proximal esophagus because this condition may lead to physical and emotional distress. Cancer 2003;97:1693–700. © 2003 American Cancer Society. DOI 10.1002/cncr.11236

Daily grape juice consumption reduces oxidative DNA damage and plasma free radical levels in healthy Koreans.

Abstract: Grape contains flavonoids with antioxidant properties which are believed to be protective against various types of cancer. This antioxidative protection is possibly provided by the effective scavenging of reactive oxygen species (ROS), thus defending cellular DNA from oxidative damage and potential mutations. This study of healthy adults tested whether a daily regimen of grape juice supplementation could reduce cellular DNA damage in peripheral lymphocytes and reduce the amount of free radicals released. Sixty-seven healthy volunteers (16 women and 51 men) aged 19–57 years were given 480 ml of grape juice daily for 8 weeks in addition to their normal diet, and blood samples were drawn before and after the intervention. The DNA damage was determined by using the single cell gel (comet) assay with alkaline electrophoresis and was quantified by measuring tail length (TL). Levels of free radicals were determined by reading the lucigenin-perborate ROS generating source, using the Ultra-Weak Chemiluminescence Analyzer System. Grape juice consumption resulted in a significant decrease in lymphocyte DNA damage expressed by TL (before supplementation: 88.75±1.55 μm versus after supplementation: 70.25±1.31 μm; P=0.000 by paired t-test). Additionally, grape juice consumption for 8 weeks reduced the ROS/photon count by 15%, compared to the beginning of the study. The preventive effect of grape juice against DNA damage was simultaneously shown in both sexes. These results indicate that the consumption of grape juice may increase plasma antioxidant capacity, resulting in reduced DNA damage in peripheral lymphocytes achieved at least partially by a reduced release of ROS. Our findings support the hypothesis that polyphenolic compounds contained in grape juice exert cancer-protective effects on lymphocytes, limiting oxidative DNA damage possibly via a decrease in free radical levels.

Association of Aortic Atherosclerosis with Cerebral β-Amyloidosis and Learning Deficits in a Mouse Model of Alzheimer’s Disease

Abstract: High fat/high cholesterol diets exacerbate β-amyloidosis in mouse models of Alzheimer's disease (AD). It has been impossible, however, to study the relationship between atherosclerosis and β-amyloidosis in those models because such mice were on atherosclerosis-resistant genetic backgrounds. Here we report the establishment of AD model mice, B6Tg2576, that are prone to atherosclerosis. B6Tg2576 mice were produced by back-crossing Tg2576 mice, an AD mouse model overexpressing human amyloid β-protein precursor with the Swedish double mutation, to C57BL/6 mice, a strain susceptible to diet-induced atherosclerosis. An atherogenic diet induced aortic atherosclerosis and exacerbated cerebral β-amyloidosis in B6Tg2576 mice. Compared with age-matched non-transgenic littermates, B6Tg2576 mice developed significantly more diet-induced aortic atherosclerosis. Unexpectedly, normal diet-fed B6Tg2576 mice also developed fatty streak lesions (early atherosclerosis) in the aorta. The aortic atherosclerotic lesion area positively correlated with cerebral β-amyloid deposits in B6Tg2576 mice on both atherogenic and normal diets. Furthermore, behavioral assessments demonstrated that B6Tg2576 mice fed an atherogenic diet had more spatial learning impairment than those fed a normal diet. Our results suggest that synergistic mechanisms may be involved in the pathogenesis of atherosclerosis and AD. These findings may have important implications in the prevention and treatment of cardiovascular diseases as well as AD.

Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas.

Abstract: A diet lacking folic acid and choline and low in methionine (folate/methyl deficient diet, FMD diet) fed to rats is known to produce preneoplastic nodules (PNNs) after 36 weeks and hepatocellular carcinomas (tumors) after 54 weeks. FMD diet-induced tumors exhibit global hypomethylation and regional hypermethylation. Restriction landmark genome scanning analysis with methylation-sensitive enzyme NotI (RLGS-M) of genomic DNA isolated from control livers, PNNs and tumor tissues was performed to identify the genes that are differentially methylated or amplified during multistage hepatocarcinogenesis. Out of the 1250 genes analysed, 2 to 5 genes were methylated in the PNNs, whereas 5 to 45 genes were partially or completely methylated in the tumors. This analysis also showed amplification of 3 to 12 genes in the primary tumors. As a first step towards identifying the genes methylated in the PNNs and primary hepatomas, we generated a rat NotI-EcoRV genomic library in the pBluescriptKS vector. Here, we describe identification of one methylated and downregulated gene as the rat protein tyrosine phosphatase receptor type O (PTPRO) and one amplified gene as rat C-MYC. Methylation of PTPRO at the NotI site located immediate upstream of the trancription start site in the PNNs and tumors, and amplification of C-MYC gene in the tumors were confirmed by Southern blot analyses. Bisulfite genomic sequencing of the CpG island encompassing exon 1 of the PTPRO gene revealed dense methylation in the PNNs and tumors, whereas it was methylation free in the livers of animals on normal diet. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed significant decrease in the expression of PTPRO in the tumors and in a transplanted rat hepatoma. The expression of PTPRO mRNA in the transplanted hepatoma after demethylation with 5-azacytidine, a potent inhibitor of DNA methyltransferases, further confirmed the role of methylation in PTPRO gene expression. These results demonstrate alteration in methylation profile and expression of specific genes during tumor progression in the livers of rats in response to folate/methyl deficiency, and further implicate the potential role of PTPRO as a novel growth regulatory gene at least in the hepatocellular carcinomas.

Radiofrequency tonsil reduction: safety, morbidity, and efficacy.

Abstract: Objectives To evaluate the safety, morbidity, and efficacy of radiofrequency tissue volume reduction of tonsils using two different surgical techniques and to compare these two techniques with each other and with classic tonsillectomy Study Design A nonrandomized retrospective review of tonsil reductions was made between 2000 and 2002 using in vivo studies associated with tonsil reduction and tonsillectomy performed either in the hospital operating room or in the outpatient treatment area Methods We studied 150 patients and divided them into three main groups based on surgical technique Group A consisted of 50 consecutive patients who underwent tonsil “ablation,” Group B contained another 50 consecutive individuals who received tonsil “coblation,” and Group C consisted of 50 patients who underwent classic tonsillectomy (cold dissection) Each group consisted of two subcategories of children (age range, 1–12 y) and adults (age range, 12–60 y) with chronic tonsillar hypertrophy Most of the pediatric patients underwent adenoidectomy during the same surgical procedure Indications for tonsillectomy were those listed by the American Academy of Otolaryngology—Head and Neck Surgery A retrospective chart review was used to assess procedures, safety, morbidity, and efficacy of tonsil reduction and tonsillectomy Four specific end points of morbidity were investigated: pain, return to normal diet, return to normal activity, and use of pain medication Efficacy of tonsillectomy was determined by the clinical observation of the remaining tonsillar tissue and compared with pretreatment photographs of the tonsils Results There were no complications in any of the groups Efficacy was assessed based on the mean tonsil reduction and was found to be 100% for tonsillectomy, 86% for the tonsil coblation technique, but only 536% for the ablation technique Morbidity was minimal in groups A and B and significantly greater in Group C The number of pain days, narcotic-use days, and days before return to normal diet and activity were greatly reduced in groups A and B when compared with classic tonsillectomy (group C) Pain levels on day 1 were less than 3 (on a scale of 1–10) in groups A and B The number of pain days and narcotic-use days was less than 4 days in groups A and B Similarly, most patients returned to solid diet and normal activity by day 4 Pain levels, number of narcotic-use days, and number of days to return to normal diet and activity were significantly higher for classic tonsillectomy Conclusions Tonsil coblation has distinct advantages when compared with tonsil ablation and standard tonsillectomy Tonsil coblation resulted in greater than 86% elimination of tonsillar tissue in both children and adults In most patients, pain levels were minimal and limited to the first 48 hours after surgery Return to normal diet and activity was much earlier in the coblation group versus classic tonsillectomy

Six Months of Gluten-Free Diet Do Not Influence Autoantibody Titers, but Improve Insulin Secretion in Subjects at High Risk for Type 1 Diabetes

Abstract: Removal of gluten from the diet can attenuate the intensity of autoimmunity and reduces the incidence of diabetes in the nonobese diabetic mouse. In this study, we tested whether a gluten-free diet could reduce autoimmunity in human preclinical type 1 diabetes. A trial consisting of 6 months of a gluten-free diet followed by another 6 months of normal gluten-containing diet was performed in 17 first-degree relatives with at least 2 antibodies among islet cell antibodies, glutamic acid decarboxylase autoantibodies, protein tyrosine islet antigen-2 autoantibodies, and insulin autoantibodies. Treatment effect was measured as autoantibody titers and acute insulin response to iv glucose tolerance test. Two subjects dropped out for lack of compliance to diet restrictions. Of the remaining 15 subjects, 3 developed diabetes. Autoantibody titers did not show significant changes after 6 months of gluten-free diet and again after return to normal diet. Acute insulin response to iv glucose tolerance test significantly increased in 12 of 14 subjects after the first 6 months of gluten deprivation (P = 0.04) and decreased in 10 of 13 subjects during the following 6-month period of normal diet (P = 0.07). Insulin sensitivity (homeostasis model assessment-insulin resistance) nonsignificantly improved after the gluten-free diet and subsequently decreased (P < 0.005) after 6 months of normal diet. These findings indicate that 6 months of gluten deprivation do not influence humoral autoimmunity, but may have a beneficial effect on preservation of beta-cell function in subjects at risk for type 1 diabetes.

Hypercholesterolemia Promotes P-Selectin–Dependent Platelet–Endothelial Cell Adhesion in Postcapillary Venules

Abstract: Objective— The objectives of this study were to determine whether hypercholesterolemia promotes platelet–endothelial cell (P/E) adhesion in murine postcapillary venules and define the contributions of endothelial or platelet associated P-selection to hypercholesterolemia-induced P/E interactions. Methods and Results— Wild-type (WT) or P-selectin deficient (P-sel −/− ) platelets were isolated and labeled with the fluorochrome CFSE and administered to either WT or P-sel −/− mice placed on a normal diet (ND) or high cholesterol diet (HCD). Intravital videomicroscopy was used to quantify platelet saltation and firm adhesion. HCD-WT mice exhibited a time-dependent increase in P/E cell interactions (relative to ND-WT). Flow cytometry revealed an increased expression of P-selectin on circulating platelets of HCD-WT mice at 2 weeks compared with ND-WT mice. When WT platelets were monitored in HCD-P-sel −/− mice, P/E adhesion was dramatically reduced. However, when P-sel −/− platelets were monitored in HCD-WT recipients, P/E adhesive interactions were reduced even further, comparable to ND-WT mice. Conclusions— These results indicate that elevated cholesterol levels promote P/E adhesion in postcapillary venules and that whereas both endothelial and platelet P-selectin contribute to hypercholesterolemia-induced recruitment of platelets, platelet-associated P-selectin seems to play a more important role in producing the prothrombogenic phenotype in venules.

Hypercholesterolemia and Hypertension Have Synergistic Deleterious Effects on Coronary Endothelial Function

Abstract: Objective— Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function. Methods and Results— Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (P<0.05 for both). In animals with coexistent HC and HT, the increase in oxi...