Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients – the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125]

Background

The high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated.

Methods

CONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events.

Conclusion

The study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD.     

Effect of salinity on the distribution of Ponto-Caspian gammarids in a non-native area – environmental and experimental study

The native area of gammarids from the so-called ‘Caspian complex’, Pontogammarus robustoides (G.O. Sars, 1894), Obesogammarus crassus (G.O. Sars, 1894), Dikerogammarus haemobaphes (Eichwald, 1841) and D. villosus (Sowinsky, 1894), is associated with brackish waters. Over the last several decades they have colonized the European inland waters and part of the brackish Baltic Sea. It is believed that anthropogenic increase in the salinity of inland waters facilitated their expansion. However, the influence of salinity on the dispersal of gammarid species outside their native area is not fully understood. We tested the hypothesis that salinity was a major factor in determining distribution, based on the abundance of Gammaridae in three coastal areas of low salinity (brackish Baltic), i.e. 0.3, 3.4 and 7.3 PSU, successfully inhabited by them. Additionally, for the first time, the effect of water salinity on the osmoregulatory capacity of O. crassus was examined under laboratory conditions, for the salinities given above. The experiments showed that similarly as in the case of other Caspian complex species, salinity values of about 7 PSU create better conditions for osmoregulation in O. crassus than lower salinities (i.e. 0.3 and 3.4 PSU). In the environmental part of the study, we observed that only D. villosus achieved a significantly higher abundance in the area of 7.3 PSU. Thus, we concluded that in the range of 0.3–7.3 PSU, salinity is not a key factor governing the distribution of Ponto-Caspian gammarids.     

Trace element imbalances in patients undergoing chronic hemodialysis therapy – Report of an observational study in a cohort of Portuguese patients

IntroductionPatients with end-stage renal disease undergoing hemodialysis therapy are at risk of developing deficiencies of essential trace elements and/or overload of toxic trace elements, both of which may significantly affect their clinical status of. Those imbalances may result from the disease itself but also from the quality of the therapeutic process, namely the hemodialysis process, which has greatly evolved in the last decades. Thus, old observations that have been assumed as very well-proven have been recently questioned. In this case-control study we evaluate the current trace elements status in a group of Portuguese patients under hemodialysis therapy.Material and methodsSerum samples from patients (n = 93), collected for the routine periodic control of Al levels, were analyzed for a wide panel of trace elements (Li, Al, Mn, Co, Ni, Cu, Zn, Se, Rb, Sr, Mo, Cd, Ba, Pb) using inductively coupled plasma mass spectrometry technique (hemodialysis patients’ group). For comparison purposes, samples of individuals with no evidence of renal disease according to standard laboratory analytical criteria (n = 50) were also analyzed (control group).ResultsThe results showed significant differences between the two groups, with higher values in hemodialysis patients group for Al (14.6 vs. 9.5 μg/L), Co, Ni, Sr, Mo (4.5 vs. 1.4 μg/L), Cd (0.058 vs. 0.025 μg/L) and Pb (0.55 vs. 0.30 μg/L); and lower values in hemodialysis patients group for Li (4.0 vs. 75.8 μg/L), Mn, Cu (943.5 vs. 1038.5 μg/L), Zn (943.5 vs. 1038.5 μg/L), Se (71.5 vs. 103.8 μg/L), Rb (202.4 vs. 300.3 μg/L) and Ba (0.65 vs. 8.7 μg/L).ConclusionThis study confirms that hemodialysis patients tend to present significant trace elements imbalances, which may be related to the higher morbidity and mortality observed in this specific patients’ group.     

Effect of dietary ghee – the anhydrous milk fat on lymphocytes in rats

Lymphocytes are important components of the immune system. Dietary lipids affect the functioning of the immune system. Changes in the lipid composition of the lymphocyte membrane is a case in point. Membrane structural changes are reflected in the altered function of the cell. Lymphocyte proliferation and lymphocyte rosetting are membrane associated phenomena. Ghee, is a clarified butter product, commonly used in the Indian diet. It is rich in saturated fatty acids and also contain oxysterols which are generated on prolonged heating of ghee. Male weanling rats were fed 2.5% (of the total fat levels) of fresh or thermally oxidized ghee for a period of 8 weeks. The control rats were fed groundnut oil. Lipid composition of lymphocytes in ghee fed rats showed changes. In vitro lipid peroxidation of lymphocyte membranes increased by 26% in oxidized ghee fed rats. Na⁺K⁺ ATPase activity was decreased in oxidized ghee fed rats (18%). Lymphocyte proliferation was reduced in ghee fed rats (32%), compared to the controls, irrespective of the mitogens used (ConA or PHA), or the tissue (splenocytes or peripheral blood lymphocytes). Oxysterols present in oxidized ghee are the likely agents inhibiting lymphoproliferation. Rosetting of lymphocytes decreased in the fresh ghee fed rats by 16% and in oxidized ghee fed rats by 25%. Membrane fluidity declined in the oxidized ghee fed rats. It is concluded that feeding ghee results in decreased proliferation of lymphocytes. Also, feeding oxidised ghee results in decreased proliferation of lymphocytes through alterations in the structure of the lymphocyte membranes in the rat.     

The efficacy of dexamethasone on reduction in the reoperation rate of chronic subdural hematoma – the DRESH study: straightforward study protocol for a randomized controlled trial

Background

Clinical studies are a necessity for new medications and therapies. Many studies, however, struggle to meet their recruitment numbers in time or have problems in meeting them at all. With increasing numbers of electronic health records (EHRs) in hospitals, huge databanks emerge that could be utilized to support research. The Innovative Medicine Initiative (IMI) funded project ‘Electronic Health Records for Clinical Research’ (EHR4CR) created a standardized and homogenous inventory of data elements to support research by utilizing EHRs. Our aim was to develop a Data Inventory that contains elements required for site feasibility analysis.

Methods

The Data Inventory was created in an iterative, consensus driven approach, by a group of up to 30 people consisting of pharmaceutical experts and informatics specialists. An initial list was subsequently expanded by data elements of simplified eligibility criteria from clinical trial protocols. Each element was manually reviewed by pharmaceutical experts and standard definitions were identified and added. To verify their availability, data exports of the source systems at eleven university hospitals throughout Europe were conducted and evaluated.

Results

The Data Inventory consists of 75 data elements that, on the one hand are frequently used in clinical studies, and on the other hand are available in European EHR systems. Rankings of data elements were created from the results of the data exports. In addition a sub-list was created with 21 data elements that were separated from the Data Inventory because of their low usage in routine documentation.

Conclusion

The data elements in the Data Inventory were identified with the knowledge of domain experts from pharmaceutical companies. Currently, not all information that is frequently used in site feasibility is documented in routine patient care.     

Effect of α-Ketoisocaproate and Leucine on the in Vivo Oxidation of Glutamate and Glutamine in the Rat Brain

Leucine and -ketoisocaproate (-KIC) were perfused at increasing concentrations into rat brain hippocampus by microdialysis to mimic the conditions of maple syrup urine disease. The effects of elevated leucine or -KIC on the oxidation of L-[U-¹⁴C]glutamate and L-[U-¹⁴C]glutamine in the brain were determined in the non-anesthetized rat. ¹⁴CO₂ generated by the metabolic oxidation of [^l4C]glutamate and [¹⁴C]glutamine in brain was measured following its diffusion into the eluant during the microdialysis. Leucine and -KIC exhibited differential effects on ¹⁴CO₂ generation from radioactive glutamate or glutamine. Infusion of 0.5 mM -KIC increased [^l4C]glutamate oxidation approximately 2-fold; higher concentrations of -KIC did not further stimulate [¹⁴C]glutamate oxidation. The enhanced oxidation of [¹⁴C]glutamate may be attributed to the function of -KIC as a nitrogen acceptor from [¹⁴C]glutamate yielding [¹⁴C]-ketoglutarate, an intermediate of the tricarboxylic acid cycle. [¹⁴C-]glutamine oxidation was not stimulated as much as [¹⁴C-]glutamate oxidation and only increased at 10 mM -KIC reflecting the extra metabolic step required for its oxidative metabolism. In contrast, leucine had no effect on the oxidation of either [¹⁴C]glutamate or [¹⁴C]glutamine. In maple syrup urine disease elevated -KIC may play a significant role in altered energy metabolism in brain while leucine may contribute to clinical manifestations of this disease in other ways.     

Effect of chronic desipramine treatment on neurotransmitter-thyrotropin releasing hormone—thyrotropin interactions in the rat

Long-term administration of the antidepressant drug, desipramine (20 mg/kg/day, orally for 28 days), decreased the stimulatory effect of the ₂-adrenoceptor agonist, clonidine (250 g/kg, i.p.) on thyrotropin (TSH) secretion in the rat, but did not alter basal TSH secretion. -Adrenoceptor-mediated inhibition of TSH secretion by isoproterenol (1 mg/ kg, i.p.) was unaffected by chronic desipramine treatment, as were the stimulatory effect of TSH-releasing hormone (TRH, 5 g/kg, i.v.) on TSH release and its inhibition by the -adrenoceptor antagonist, phentolamine (2 mg/kg, i.p.). These findings suggest that chronic desipramine treatment induces subsensitivity of ₂-adrenoceptors which modulate TSH secretion in the rat while not affecting -adrenoceptor-mediated inhibition of TSH release. These findings suggest that pituitary TRH receptors are unchanged but that changes occurred at the hypothalamic level in ₂-adrenoceptor-mediated stimulation of TRH release. Although cerebral -adrenoceptors have been shown convincingly to be down-regulated after chronic desipramine treatment, their function in the hypothalamic TRH system after 28 days of treatment with desipramine appears to be unimpaired.     

Effect of sealing on the incorporation of pyrene in goat erythrocyte ghosts — A fluorescence study

The incorporation of pyrene within the membrane interior of goat erythrocyte ghost has been estimated from its fluorescence spectrum. The excimer to monomer fluorescence intensity ratio of embedded pyrene is a function of the fluidity of its environment and the magnitude of its incorporation. Our study shows that this ratio is considerably less (30%) in a pre-sealed ghost than in the non-sealed ghost revealing that the site of incorporation of the probe is indeed the hydrophobic interior of the membrane; as in the later case, the probe has access to the membrane interior from both sides of the membrane. Our study on kinetics of molecular exchange indicates a very fast (of the order of seconds) transfer rate of pyrene from probed to unprobed erythrocyte ghosts through the aqueous phase rather than actual fusion of the membranes.     

Effect of Dephosphorylation on the Self-association and the Precipitation of β-Casein

The pyrolyzate of the nondialyzable melanoidin prepared from glucose-ammonia reaction system (kept in pH 5.3~6.0 during the reaction) was fractionated to volatile fraction and nonvolatile fraction. Among the volatile components, two pyridines and four alkylpyrazines were identified. On the other hand, one imidazole compound and two β-hydroxypyridines isolated from the nonvolatile fraction were identified as 4(5)-methylimidazole, 3-hydroxypyridine and 2-methyl-5-hydroxypyridine, respectively. It is inferred that these compounds are not produced by the fission of the main skeleton in the melanoidin molecule, but formed by pyrolysis of the heterocyclic compounds present as a small moiety in the melanoidin.     

Effect of cervus and cucumis polypeptide combined with zoledronic acid on bone metabolic biochemical markers in glucocorticoids – Induced osteoporosis patients

ObjectiveTo investigate the effect of cervus and cucumis polypeptide combined with zoledronic acid on bone metabolic biochemical markers in glucocorticoids - induced osteoporosis patients.MethodsA total of 100 patients with glucocorticoids - induced osteoporosis admitted to our hospital from January 2015 to June 2017 were enrolled in this study. Patients were divided into observation group and control group by random number table method, 50 cases in each group. Patients in the observation group were treated with deer melon polypeptide in combination with zoledronic acid, and patients in the control group were treated with zoledronic acid alone. The patients in both groups were treated for 2 months. The changes of bone mineral density (BMD) and biochemical markers of bone metabolism in lumbar vertebrae L1-4, left femoral neck and large trochanter were analyzed before and after treatment.ResultsThe pre- BMD at lumbar spine L_1-4, left femoral neck and great trochanter had no statistic difference (P > 0.05), the BMD at each sites improved after treatment, and the difference were statistical before and after treatment (P < 0.05). BMD at above sites of two groups after treatment had statistical difference (P < 0.05), and the BMD at lumbar spine L_1-4, left femoral neck and great trochanter in the observation group was higher than that of the control group. There were no significant differences in PTH, 25-(OH)D3, TRACP, β-CTX and BGP levels between the two groups before treatment (P > 0.05). The levels of 25-(OH)D3, TRACP, β-CTX and BGP in the two groups were significantly improved after treatment (P < 0.05), and the levels of PTH, TRACP and β-CTX in the observation group were significantly lower than those in the control group. The levels of 25-(OH) D3 and BGP were significantly higher than those of the control group (P < 0.05).ConclusionThe cervus and cucumis polypeptide combined with zoledronic acid can improve the BMD at lumbar spine L_1-4, left femoral neck and great trochanter, and ameliorate the bone metabolic biochemical markers for patients with glucocorticoids - induced osteoporosis.     

Effects of midazolam on the contraction and relaxation of segments of thoracic aorta stripped of endothelium and stimulated by adrenaline – experimental study in rabbits

To evaluate the effects of midazolam on the angiokinesis of segments of rabbits' thoracic aorta stripped of endothelium and stimulated by adrenaline.Two groups of aortic rings removed from albinic rabbits anesthetized with thiopental were used (Group I – 6 animals; Group II – 12 animals), stripped of endothelium, studied in an organ chamber, perfused by Krebs-Henseleit solution. The groups were stimulated by adrenaline, recording the maximum contraction and dT/dt at 12, 36, 60 and 120. When the plateau phase was reached, the vessel was washed with perfusion solution, recording relaxation at 2, 4 and 6. When the base values were reached, Group I underwent a new adrenergic stimulus; and Group II was stimulated with midazolam and then with adrenaline, and the same values were recorded. T test was applied as a statistical analysis when two variables were studied. When studying more than two variables the Anova test was used, supplemented by the Tuckey test.Group I did not show any significant difference between the two stimuli. Group II – the midazolam significantly reduced the maximum contraction induced by adrenaline (83.01 ± 4.11%) (p < 0.01). The dT/dt was reduced at 12 (57.06 ± 8.47%), and also at 36 (70.59 ± 5.26%). There was no significance at 60 and 120 (p < 0.01).The relaxation increased significantly at all measurements – at 2-adrenaline 39.31 ± 9.60%; adrenaline/midazolam: 44.06 ± 9.62% (p < 0.05). At 4-adrenaline: 53.08 ± 8.3%; adrenaline/midazolam: 61.68 ± 8.50% (p < 0.01). At 6-adrenaline: 76.26 ± 5.45%; adrenaline/midazolam: 84.20 ± 7.96% (p < 0.01).Midazolam significantly reduced the maximum contraction obtained by the adrenergic stimulus as well as the dT/dt in the initial phases of contraction. The relaxation speed also increased.     

Effect of pH and Glucose on the Stability of α-lactalbumin

The objective of this study is to understand the influence of pH and effect of cosolvent (glucose) on the stabilization of bovine α-lactalbumin by using ultrasonic techniques. Values of density, ultrasonic velocity and viscosity were measured for bovine α-lactalbumin (5 mg/ml) dissolved in phosphate buffer (pH 2, 5, 7, 9 and 12) solutions mixed with and without the cosolvent at 30 °C. These measurements were used to calculate few thermo-acoustical parameters such as adiabatic compressibility, intermolecular free length, acoustic impedance, relaxation time, relative association constant, the partial apparent specific volume and the partial apparent specific adiabatic compressibility for the said systems. The obtained results revealed a strong comparison between the effects of acidic and alkaline pH values on protein denaturation, i.e., the acidic pH are instantaneous and are of less magnitude whereas alkaline pH are slower but sharper. Further the present study supports the fact that the presence of glucose stabilizes α-lactalbumin against denaturation due to pH variation, which may be due to the strengthening of non-covalent interactions and the steric exclusion effect.     

Influence of aluminium on the immune system – an experimental study on volunteers

The purpose of this study was to examine whether oral exposure to aluminum (Al) can affect the human immune system. Eighteen healthy volunteers (mean age 42, 28–57 yr) were divided into a test group (9 females, 4 males) and a referent group (3 females, 2 males). Over 6 weeks, the test subjects ingested 10 ml of antacid (aluminum hydroxide, 59 mg Al/ml) three times daily. Aluminum was analyzed in urine before and during the exposure period (ICP-MS). Blood samples were used for analysis of lymphocyte subpopulations, mitogen-induced lymphocyte proliferation and in vitro production and circulating plasma concentrations of immunoglobulin (Ig) A, IgG, IgM, interleukin (IL) -2 and IL-4. Urinary Al concentration in the test subjects was approximately 10- to 20-fold higher than in the referent group during exposure. This indicates that ingestion of an Al-containing antacid is associated with an Al absorption far above that originating from food and drinking water. In both referents and test subjects the lymphocyte subpopulations, lymphocyte proliferation and the in vitro Ig and IL production showed similar, time-dependent changes before as well as during the exposure period. No major differences were seen between the referent and test groups regarding the immune parameters, except for a slightly smaller CD8+CD45R0+ population (primed cytotoxic T-cells), in the exposed individuals as compared to the referents. The results also show that subjects on antacid therapy may constitute a suitable population for studying biological effects of high-dose oral exposure to Al.     

Effect of ultraviolet B (302 nm) irradiation on viability, metabolic and detoxification functions of goat hepatocytes – in vitro study

The object of the present study was to investigate the effect(s) of UV-B irradiation on the functional integrity, metabolic and detoxifying capacity of the isolated goat hepatocytes. Isolated goat hepatocytes were subjected to UV-B irradiation invitro for 0, 250, 500, 1250, 2500 and 7500 Joules/m² which correspond to the irradiation time of 0, 1, 2, 5, 10 and 30 min. Cells were then analysed for Viability (Trypan blue exclusion test [TBE], 3-[4,5-dimethylthiozol-2yl]-2,5-diphenyltetrazolium bromide [MTT] assay, Membrane integrity (Lactate dehydrogenase [LDH] leakage, Lipid peroxidation) Detoxification (Ureagenesis, Cytochrome P450 activity [CYP450, Diazepam metabolism] and Glutathione-S-Transferase [GST] activity. The results show that there was no difference in functional, metabolic as well as detoxifying parameters of the hepatocytes when irradiated from 0–1250 Joules/m², whereas a significant alteration was appreciable in the parameters such as LDH leakage, lipid peroxidation, and CYP450 activity when irradiated beyond 1250 Joules/m². Our present findings suggest that the biologically compatible and feasible dose of UV-B irradiation for xenotransplantation appears to be 1250 Joules/m².     

Effect of Omacor on HRV parameters in patients with recent uncomplicated myocardial infarction – A randomized, parallel group, double-blind, placebo-controlled trial: study design [ISRCTN75358739]

Background

A large body of data derived from animal, epidemiological and clinical studies indicate that n-3 polyunsaturated fatty acids have a favourable effect on the prognosis of patients with cardiovascular disease in general, and on reducing sudden death in particular. Depressed heart rate variability (HRV), an indicator of impairment of the autonomic nervous system, has been shown to be a powerful predictor of subsequent mortality in patients surviving an acute myocardial infarction. A multitude of studies have demonstrated this strong association, suggesting that the imbalance in the sympathic/parasympathetic system may facilitate emergence of ventricular arrhythmias. Heart rate variability parameters will be assessed in the present study, with the primary objective of evaluating the possible superiority of Omacor (a highly refined, concentrated omega-3 fatty acid) versus placebo in improving HRV from baseline to endpoint in patients with recent uncomplicated myocardial infarction. Both groups will receive optimal conventional treatment. The study will also explore and quantify improvement in time domain HRV indices and will assess the safety of administering Omacor to optimally treated post-infarction patients (conventional treatment).

Methods

This multi-centre study will evaluate the effect of Omacor 1 g, o.d. on time-domain HRV parameters in comparison to placebo o.d. in patients with recent uncomplicated transmural myocardial infarction. Patients will be screened during the first few days after the acute event as appropriate for the patient's condition, and after obtaining informed consent. Based on inclusion/exclusion criteria, a first 24-hour Holter recording will be performed. Two to five days later, screened patients still eligible for the study will undergo a second 24-hour Holter recording. After the second Holter recording, all patients will be randomly allocated to treatment with Omacor 1 g, o.d. or placebo o.d. One hundred patients will be followed in double-blind fashion for a six-month period after randomization. Visits, including 24-hour Holter recording and assessment of adverse events, will take place at one-month intervals ± five days after randomization, i.e., six times in all.     

Effects on the prostate of environmental cadmium exposure – A cross-sectional population study in China

To explore possible effects of environmental cadmium exposure on prostate in humans, and the possible relationship of serum sex hormones to occurrence of clinic signs of tissue changes in the prostate, a case-control study was undertaken in the southeast part of China in 1998. A total of 297 male volunteers from a control area and two cadmium-polluted areas were included as subjects in this study. All the subjects were required to answer a questionnaire and to undergo a complete physical examination including digital-rectal examination (DRE). Blood and urine samples were collected. Serum total prostate specific antigen (PSA), total serum testosterone (T), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay and enzymeimmunoassay method, respectively. The data of urinary cadmium (U-Cd) and blood cadmium (B-Cd) were obtained by atomic absorption spectrometry (AAS) as an indicator of cadmium body burden. Statistical analysis was applied to investigate a possible relation between cadmium exposure and prostate pathological changes. The results show that there is a clear dose-response relationship between cadmium exposure and the prevalence of cases with abnormal PSA. The blood cadmium content in cases with positive DRE was significantly higher than that of subjects with negative DRE (P<0.05). Significant differences in the level of FSH between cases with positive DRE and the normal subjects were also noted (P<0.05). These results indicate that chronic environmental cadmium exposure is associated with injuries to human prostate. A possible relationship to changes in circulating sex hormones needs further investigation.     

Effect of α-p-chlorophenoxyisobutyrate on the metabolism of isoprenoid compounds in the rat

1. Feeding of alpha-p-chlorophenoxyisobutyrate (CPIB) to rats increased ubiquinone concentration in the liver but not in other tissues. The increase was progressive with the time of feeding and related to the concentration of CPIB in the diet. 2. Incorporation of [1-(14)C]acetate, but not of [2-(14)C]mevalonate, into sterols in the liver in vivo or by liver slices in vitro was decreased on feeding the rats with CPIB. However, incorporation of mevalonate into ubiquinone increased. 3. CPIB, when added in low concentrations to liver slices, had no effect on isoprene synthesis from acetate; higher concentrations, however, were inhibitory. 4. No activation of ubiquinone synthesis from mevalonate was observed when CPIB was added to the liver slices synthesizing ubiquinone. 5. The increase in ubiquinone in CPIB-fed animals appears to be due to increased synthesis in the initial stages and to decreased catabolism in the later stages. 6. An inverse relationship was found between the concentration of ubiquinone in the liver and the serum sterol concentration in CPIB-fed rats.