Dietary elecrolytes and cyclosporine toxicity. Experimental studies in spontaneuosly hypertensive rats

Cyclosporine-A (CsA) is widely used after organ transplantation to prevent rejection and in the treatment of autoimmune diseases. Hypertension and nephrotoxicity are common side-effects of CsA. Studies in patients on the prevention of the side-effects of CsA are difficult to conduct because the patients often receive a combination of different drugs thus making study of the side-effects of a single drug impossible. A challenge in experimental studies has been the lack of an animal model in which the side-effects concomitantly occur. Epidemiological data show an association between sodium (Na) intake and blood pressure. There is also evidence on low dietary intake of magnesium (Mg) and potassium (K) and high blood pressure. Our study was designed to develop an experimental model to study the side-effects of CsA in spontaneously hypertensive rats (SHR). On high dietary sodium, CsA caused hypertension, left ventricular hypertrophy (LVH), narrowing of the coronary arteries, small myocardial infarctions, and proteinuria, reduced creatinine clearance and histopathological renal injury in SHR. Loss of Mg into the urine caused by CsA resulted in Mg depletion in the tissues. Renal excretion of dopamine was reduced and the renin-angiotensin-aldosterone system was activated. We investigated the effects of dietary Mg and/or K and the calcium antagonist drug, isradipine, on the prevention of CsA toxicity. Dietary supplementation of Mg alone or in combination with K prevented from the deleterious pathophysiological and histopathological changes in the kidneys and the heart. K alone had little effect. Isradipine protected better than Mg from LVH, but the combination of isradipine and Mg was the most effective. Isradipine did not, however, protect against Mg loss. In our animal model, the combination of high dietary Na and treatment with CsA accelerated the development of the cardiovascular and renal changes clinically known as the side-effects of CsA. Dietary supplementation of Mg and K and reduction of Na intake and the calcium antagonist drug isradipine prevent from the deleterious effects of CsA.

Electrode kinetics of a nickel/cadmium cell and failure-mode prediction. Estimation of equivalent resistance of an internal short

A quantitative expression has been obtained for the equivalent resistance of an internal short in rechargeable cells under constant voltage charging.

Prevention of type 2 diabetes with lifestyle intervention - emphasis on dietary composition and identification of high-risk individuals

Type 2 diabetes is an increasing, serious, and costly public health problem. The increase in the prevalence of the disease can mainly be attributed to changing lifestyles leading to physical inactivity, overweight, and obesity. These lifestyle-related risk factors offer also a possibility for preventive interventions. Until recently, proper evidence regarding the prevention of type 2 diabetes has been virtually missing. To be cost-effective, intensive interventions to prevent type 2 diabetes should be directed to people at an increased risk of the disease. The aim of this series of studies was to investigate whether type 2 diabetes can be prevented by lifestyle intervention in high-risk individuals, and to develop a practical method to identify individuals who are at high risk of type 2 diabetes and would benefit from such an intervention. To study the effect of lifestyle intervention on diabetes risk, we recruited 522 volunteer, middle-aged (aged 40 - 64 at baseline), overweight (body mass index > 25 kg/m2) men (n = 172) and women (n = 350) with impaired glucose tolerance to the Diabetes Prevention Study (DPS). The participants were randomly allocated either to the intensive lifestyle intervention group or the control group. The control group received general dietary and exercise advice at baseline, and had annual physician's examination. The participants in the intervention group received, in addition, individualised dietary counselling by a nutritionist. They were also offered circuit-type resistance training sessions and were advised to increase overall physical activity. The intervention goals were to reduce body weight (5% or more reduction from baseline weight), limit dietary fat (< 30% of total energy consumed) and saturated fat (< 10% of total energy consumed), and to increase dietary fibre intake (15 g / 1000 kcal or more) and physical activity (≥ 30 minutes/day). Diabetes status was assessed annually by a repeated 75 g oral glucose tolerance testing. First analysis on end-points was completed after a mean follow-up of 3.2 years, and the intervention phase was terminated after a mean duration of 3.9 years. After that, the study participants continued to visit the study clinics for the annual examinations, for a mean of 3 years. The intervention group showed significantly greater improvement in each intervention goal. After 1 and 3 years, mean weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 kg and 0.9 kg in the control group. Cardiovascular risk factors improved more in the intervention group. After a mean follow-up of 3.2 years, the risk of diabetes was reduced by 58% in the intervention group compared with the control group. The reduction in the incidence of diabetes was directly associated with achieved lifestyle goals. Furthermore, those who consumed moderate-fat, high-fibre diet achieved the largest weight reduction and, even after adjustment for weight reduction, the lowest diabetes risk during the intervention period. After discontinuation of the counselling, the differences in lifestyle variables between the groups still remained favourable for the intervention group. During the post-intervention follow-up period of 3 years, the risk of diabetes was still 36% lower among the former intervention group participants, compared with the former control group participants. To develop a simple screening tool to identify individuals who are at high risk of type 2 diabetes, follow-up data of two population-based cohorts of 35-64 year old men and women was used. The National FINRISK Study 1987 cohort (model development data) included 4435 subjects, with 182 new drug-treated cases of diabetes identified during ten years, and the FINRISK Study 1992 cohort (model validation data) included 4615 subjects, with 67 new cases of drug-treated diabetes during five years, ascertained using the Social Insurance Institution's Drug register. Baseline age, body mass index, waist circumference, history of antihypertensive drug treatment and high blood glucose, physical activity and daily consumption of fruits, berries or vegetables were selected into the risk score as categorical variables. In the 1987 cohort the optimal cut-off point of the risk score identified 78% of those who got diabetes during the follow-up (= sensitivity of the test) and 77% of those who remained free of diabetes (= specificity of the test). In the 1992 cohort the risk score performed equally well. The final Finnish Diabetes Risk Score (FINDRISC) form includes, in addition to the predictors of the model, a question about family history of diabetes and the age category of over 64 years. When applied to the DPS population, the baseline FINDRISC value was associated with diabetes risk among the control group participants only, indicating that the intensive lifestyle intervention given to the intervention group participants abolished the diabetes risk associated with baseline risk factors. In conclusion, the intensive lifestyle intervention produced long-term beneficial changes in diet, physical activity, body weight, and cardiovascular risk factors, and reduced diabetes risk. Furthermore, the effects of the intervention were sustained after the intervention was discontinued. The FINDRISC proved to be a simple, fast, inexpensive, non-invasive, and reliable tool to identify individuals at high risk of type 2 diabetes. The use of FINDRISC to identify high-risk subjects, followed by lifestyle intervention, provides a feasible scheme in preventing type 2 diabetes, which could be implemented in the primary health care system.

Texture strengthening in warm-rolled cadmium-1% silver alloy

The variation in the tensile properties at 77 K and 300 K in warm-rolled (300 K) Cd-1% Ag alloy with deformation has been studied in longitudinal as well as transverse specimens. The low-temperature yield strength increases with warm rolling without much loss in ductility. The strength at 300 K, however, decreases with heavy warm deformation. From microstructural studies and X-ray investigations, it was observed that changes in grain size and texture occur during warm rolling. Both these changes are found to be important in deciding the tensile properties. The longitudinal and transverse strengths at 77 K vary linearly with l-frac12, where l is the average grain diameter, and thus they obey the Hall-Petch relation. The Hall-Petch slope, k, is lower in specimens with favourable lcub1013rcub texture while the intercept σo is higher when the lcub0002rcub texture is less favourable.

Zinc, cadmium and lead resistance mechanisms in bacteria and their contribution to biosensing

In bacteria resistance to heavy metals is mainly achieved through active efflux, but also sequestration with proteins or as insoluble compounds is used. Although numerous studies have dealt with zinc, cadmium and lead resistance mechanisms in bacteria, it has still remained unclear how different transporters are integrated into an effective homeostasis/resistance network and whether specific mechanisms for lead sequestration exist. Furthermore, since metals are toxic not only to bacteria but to higher organisms as well, it is important to be able to estimate possible biological effects of heavy metals in the environment. This could be done by determining the bioavailable amount of the metals in the environment with bacterial bioreporters. That is, one can employ bacteria that respond to metal contamination by a measurable signal to assess the property of metals to cross biological membranes and to cause harmful effects in a possibly polluted environment. In this thesis a new lead resistance mechanism is described, interplay between CBA transporters and P-type ATPases in zinc and cadmium resistance is presented and finally the acquired knowledge is used to construct bacterial bioreporters for heavy metals with increased sensitivity and specificity. The new lead resistance model employs a P-type ATPase that removes Pb2+ ions from the cytoplasm and a phosphatase that produces inorganic phosphate for lead sequestration in the periplasm. This was the first study where the molecular mechanism of lead sequestration has been described. Characterization of two P-type ATPases and two CBA transporters showed that resistance mechanisms for Zn2+ and Cd2+ are somewhat different than for Pb2+ as these metals cannot be sequestered as insoluble compounds as easily. Resistance to Zn2+ was conferred merely by the CBA transporter that could export both cytoplasmic and periplasmic ions; whereas, full resistance to Cd2+ required interplay of a P-type ATPase that exported cytoplasmic ions to periplasm and a CBA transporter that further exported periplasmic ions to the outside. The knowledge on functionality of the transporters and metal-inducible promoters was exploited in bioreporter technology. A transporter-deficient bioreporter strain that lacked exporters for Zn2+/Cd2+/Pb2+ could detect up to 45-fold lower metal concentrations than its wild type counterpart due to the accumulation of metals in the cell. The broad specificity issue of bioreporters was overcome by using Zn-specific promoter as a sensor element, thus achieving Zn-specific bioreporter.

Dietary modulation of β-catenin signalling in an experimental model of colon cancer

Colorectal cancer is among the major cancers and one of the leading causes of cancer-related deaths in Western societies. Its occurrence is strongly affected by environmental factors such as diet. Thus, for preventative strategies it is vitally important to understand the mechanisms that stimulate adenoma growth and development towards accelerated malignancy or, in contrast, attenuate them to remain in quiescence for periods as long as decades. The main objective of this study was to investigate whether diet is able to modulate β-catenin signalling related to the promotion or prevention of intestinal tumourigenesis in an animal model of colon cancer, the Min/+ mouse. A series of dietary experiments with Min/+ mice were performed where fructo-oligosaccharide inulin was used for tumour promotion and four berries, bilberry (Vaccinium myrtillus), lingonberry (Vaccinium vitis-idaea), cloudberry (Rubus chamaemorus) and white currant (Ribes x pallidum), were used for tumour prevention. The adenomas (Apc-/-) and surrounding normal-appearing mucosa (Apc+/-) were investigated separately due to their mutational and functional differences. Tumour promotive and preventive diets had opposite effects on β-catenin signalling in the adenomas that was related to the different adenoma growth effects of dietary inulin and berries. The levels of nuclear β-catenin and cyclin D1 combined with size of the adenomas in the treatment groups suggests that diets induced differences in the cancerous process. Adenomas progressing to malignant carcinomas are most likely found in the sub-groups having the highest levels of β-catenin. On the other hand, adenomas staying quiescent for a long period of time are most probably found in the cloudberry or white currant diet groups. The levels of membranous E-cadherin and β-catenin increased as the adenomas in the inulin diet group grew, which could be a result of the overall increase in the protein levels of the cell. Therefore, the increasing levels of membranous β-catenin in Min/+ mice adenomas would be undesirable, due to the simultaneous increase in oncogenic nuclear β-catenin. We propose that the decreased amount of membranous β-catenin in benign adenomas of berry groups also means a decrease in the nuclear pool of β-catenin. Tumour promotion, but not the tumour prevention, influenced β-catenin signalling already in the normal appearing mucosa. Inulin-induced tumour promotion was related to β-catenin signalling in Min/+ mice, and in WT mice changes were also visible. The preventative effects of berries in the initiation phase were not mediated by β-catenin signalling. Our results suggest that, in addition to the number, size, and growth rate of adenomatous polyps, the signalling pattern of the adenomas should be considered when evaluating preventative dietary strategies.

Effects of dietary phosphorus and calcium-to-phosphorus ratio on calcium and bone metabolism in healthy 20- to 43-year-old Finnish women

Dietary habits have changed during the past decades towards an increasing consumption of processed foods, which has notably increased not only total dietary phosphorus (P) intake, but also intake of P from phosphate additives. While the intake of calcium (Ca) in many Western countries remains below recommended levels (800 mg/d), the usual daily P intake in a typical Western diet exceeds by 2- to 3-fold the dietary guidelines (600 mg/d). The effects of high P intake in healthy humans have been investigated seldom. In this thesis healthy 20- to 43-year-old women were studied. In the first controlled study (n = 14), we examined the effects of P doses, and in a cross-sectional study (n = 147) the associations of habitual P intakes with Ca and bone metabolism. In this same cross-sectional study, we also investigated whether differences exist between dietary P originating from natural P sources and phosphate additives. The second controlled study (n = 12) investigated whether by increasing the Ca intake, the effects of a high P intake could be reduced. The associations of habitual dietary calcium-to-phosphorus ratios (Ca:P ratio) with Ca and bone metabolism were determined in a cross-sectional study design (n = 147). In the controlled study, the oral intake of P doses (495, 745, 1245 and 1995 mg/d) with a low Ca intake (250 mg/d) increased serum parathyroid hormone (S-PTH) concentration in a dose-dependent manner. In addition, the highest P dose decreased serum ionized calcium (S-iCa) concentration and bone formation and increased bone resorption. In the second controlled study with a dietary P intake of 1850 mg/d, by increasing the Ca intake from 480 mg/d to 1080 mg/d and then to 1680 mg/d, the S-PTH concentration decreased, the S-iCa concentration increased and bone resorption decreased dose-dependently. However, not even the highest Ca intake could counteract the effect of high dietary P on bone formation, as indicated by unchanged bone formation activity. In the cross-sectional studies, a higher habitual dietary P intake (>1650 mg/d) was associated with lower S-iCa and higher S-PTH concentrations. The consumption of phosphate additive-containing foods was associated with a higher S-PTH concentration. Moreover, habitual low dietary Ca:P ratios (≤0.50, molar ratio) were associated with higher S-PTH concentrations and 24-h urinary Ca excretions, suggesting that low dietary Ca:P ratios may interfere with homeostasis of Ca metabolism and increase bone resorption. In summary, excessive dietary P intake in healthy Finnish women seems to be detrimental to Ca and bone metabolism, especially when dietary Ca intake is low. The results indicate that by increasing dietary Ca intake to the recommended level, the negative effects of high P intake could be diminished, but not totally prevented. These findings imply that phosphate additives may be more harmful than natural P. Thus, reduction of an excessively high dietary P intake is also beneficial for healthy individuals.

On the orientation of grain boundaries in cadmium recrystallized during hot deformatio

The authors are grateful to Professor K. P. Abraham for the provision of facilities and encouragement. One of us (PRR) acknowledges the award of a National Associateship by the UGC which facilitated a short-time visit to the Indian Institute of Science.

Assessing infant exposure to persistent organic pollutants via dietary intake in Australia

Persistent organic pollutants (POPs) including polybrominated diphenyl ethers (PBDEs); organochlorine pesticides (OCPs); and polychlorinated biphenyls (PCBs) persist in the environment, bioaccumulate, and pose a risk of causing adverse human health effects. Typically, exposure assessments undertaken by modeling existing intake data underestimate the concentrations of these chemicals in infants. This study aimed to determine concentrations of POPs in infant foods, assess exposure via dietary intake and compare this to historical exposure. Fruit purees, meat and vegetables, dairy desserts, cereals and jelly foods (n = 33) purchased in 2013 in Brisbane, Australia were analyzed. For OCPs and PCBs, concentrations ranged up to 95 pg/g fw and for PBDEs up to 32 pg/g fw with most analytes below the limit of detection. Daily intake is dependent on type and quantity of foods consumed. Consumption of a 140 g meal would result in intake ranging from 0 to 4.2 ng/day, 4.4 ng/day and 13.3 ng/day, for OCPs, PBDEs and PCBs, respectively. PBDEs were detected in 3/33 samples, OCPs in 9/33 samples and PCBs in 13/33 samples. Results from this study indicate exposure for infants via dietary (in contrast to dust and breast milk) intake in Australia contribute only a minor component to total exposure.

Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise

Dietary nitrate (NO3−) supplementation with beetroot juice (BR) over 4–6 days has been shown to reduce the O2 cost of submaximal exercise and to improve exercise tolerance. However, it is not known whether shorter (or longer) periods of supplementation have similar (or greater) effects. We therefore investigated the effects of acute and chronic NO3− supplementation on resting blood pressure (BP) and the physiological responses to moderate-intensity exercise and ramp incremental cycle exercise in eight healthy subjects. Following baseline tests, the subjects were assigned in a balanced crossover design to receive BR (0.5 l/day; 5.2 mmol of NO3−/day) and placebo (PL; 0.5 l/day low-calorie juice cordial) treatments. The exercise protocol (two moderate-intensity step tests followed by a ramp test) was repeated 2.5 h following first ingestion (0.5 liter) and after 5 and 15 days of BR and PL. Plasma nitrite concentration (baseline: 454 ± 81 nM) was significantly elevated (+39% at 2.5 h postingestion; +25% at 5 days; +46% at 15 days; P < 0.05) and systolic and diastolic BP (baseline: 127 ± 6 and 72 ± 5 mmHg, respectively) were reduced by ∼4% throughout the BR supplementation period (P < 0.05). Compared with PL, the steady-state V̇o2 during moderate exercise was reduced by ∼4% after 2.5 h and remained similarly reduced after 5 and 15 days of BR (P < 0.05). The ramp test peak power and the work rate at the gas exchange threshold (baseline: 322 ± 67 W and 89 ± 15 W, respectively) were elevated after 15 days of BR (331 ± 68 W and 105 ± 28 W; P < 0.05) but not PL (323 ± 68 W and 84 ± 18 W). These results indicate that dietary NO3− supplementation acutely reduces BP and the O2 cost of submaximal exercise and that these effects are maintained for at least 15 days if supplementation is continued.

Chronic disease risks and use of a smartphone application during a physical activity and dietary intervention in Australian truck drivers

- Objective This study examined chronic disease risks and the use of a smartphone activity tracking application during an intervention in Australian truck drivers (April-October 2014). - Methods Forty-four men (mean age=47.5 [SD 9.8] years) completed baseline health measures, and were subsequently offered access to a free wrist-worn activity tracker and smartphone application (Jawbone UP) to monitor step counts and dietary choices during a 20-week intervention. Chronic disease risks were evaluated against guidelines; weekly step count and dietary logs registered by drivers in the application were analysed to evaluate use of the Jawbone UP. - Results Chronic disease risks were high (e.g. 97% high waist circumference [≥94 cm]). Eighteen drivers (41%) did not start the intervention; smartphone technical barriers were the main reason for drop out. Across 20-weeks, drivers who used the Jawbone UP logged step counts for an average of 6 [SD 1] days/week; mean step counts remained consistent across the intervention (weeks 1–4=8,743[SD 2,867] steps/day; weeks 17–20=8,994[SD 3,478] steps/day). The median number of dietary logs significantly decreased from start (17 [IQR 38] logs/weeks) to end of the intervention (0 [IQR 23] logs/week; p<0.01); the median proportion of healthy diet choices relative to total diet choices logged increased across the intervention (weeks 1–4=38[IQR 21]%; weeks 17–20=58[IQR 18]%). - Conclusions Step counts were more successfully monitored than dietary choices in those drivers who used the Jawbone UP. - Implications Smartphone technology facilitated active living and healthy dietary choices, but also prohibited intervention engagement in a number of these high-risk Australian truck drivers.