Protection by Chinese Herbs Against Doxorubicin-Induced Focal and Segmental Glomerulosclerosis in Rats

The objective of this study was to evaluate the efficacy of Chinese herbs on Doxorubicin-induced focal and segmental glomerulosclerosis (FSGS) in rats. Twenty age-matched male Wistar rats were divided into two groups: group A (n = 10) given only water ad libitum served as the control group and group B (n = 10) was given Chinese herbs (40 ml/kg with drug concentration 1.75 g/ml) beginning at day zero. All rats were administered doxorubicin (7 mg/kg) intravenously. All the rats were placed in metabolic cages at day 0, 7, 14, 21, and 28, and daily proteinuria was measured. At day 28, the animals were killed by cervical dislocation, followed by immediate organ collection for histologic analysis of kidneys; blood was collected by tail vein and cardiac puncture (at day 28) for the measurement of serum albumin. Body weight (BW) and food intake were recorded. The rats in groups A and B demonstrated severe susceptibility to doxorubicin injection with the onset of proteinuria (80–100 mg/24h) at day 7. The rats in group B were partly resistant to doxorubicin nephropathy with decreasing proteinuria and increasing serum albumin compared with group A (p < 0.05). All 10 rats in group A developed at least 5% glomerulosclerosis with tubular casts at day 28. In contrast, the rats in group B developed less severe histologic renal disease. The difference in histologic scores between the two groups were significant at day 28 (12 in group B vs. 20 in group A, p = 0.002). Food intake of Group B animals progressively increased to reach 67–73% of those observed before the doxorubicin administration with 28–43% in Group A. After the 4-wk experimental period, BW in Group A decreased more significantly than that in Group B (?20 ± 3 and ?16 ± 1%, respectively, p = 0.035, paired T test). Chinese herbs seem to reduce proteinuria and attenuate renal histologic severity in rats with doxorubicin-induced FSGS and may offer an alternative to the treatment of FSGS.     

Effects of elastin-derived peptide on Achilles' tendon healing: An experimental study

Different matrix macromolecules modulate the tendon healing process. Elastin contains sequences which exhibit chemotactic activity both in vitro and in vivo. We analyzed the effects of synthetic elastin-derived peptide Val-Gly-Val-Ala-Pro-Gly suspended in a gel solution on the healing process of Achilles' tendon in a rat model. A total tenotomy at the middle 3rd was performed in 32 rats. During the suture repair the gel with (Group A) or without (Group B) the elastin-derived peptide was applied to the tendon stumps. Four animals for each period and group were killed at 10, 30, 60 and 90 days after surgery. The scar tissue was processed for histochemical, immuno-histochemical and morphometric analysis. An improved healing process with increase in cellularity and vascularity, especially at the early stage of the Achilles' tendon healing process was observed in Group A compared to Group B. The fiber alignment was also positively influenced by the factor. Immunolabeling with HAM 56 and lisozyme revealed a stronger reaction for the presence of monocyte/macrophage in Group A vs Group B especially in early stages. Chondral metaplasia and endochondral ossification occurred in the healed tissue of both group at 60 and 90 days.     

Surveillance cultures of tunneled cuffed catheter exit sites in chronic hemodialysis patients are of no benefit

Catheter-related infections are a major cause of morbidity and mortality in hemodialysis (HD) patients. This study evaluated the utility of surveillance swab cultures (Ssc) of tunneled cuffed catheter (TCC) exit sites as a prediction and prevention strategy for infection. A 6-month prospective-controlled trial with 94 chronic HD patients with a TCC who received monthly Ssc and were stratified by dialysis day into topical therapy based on Ssc results (Group A) or no therapy (Group B). Outcomes were exit site infection (ESI) and catheter-associated bacteremia (CAB). The overall monthly prevalence of positive Ssc was 14.9%. There was no difference in the number of positive Ssc (17.7% vs. 11.6%, p > 0.05) or ESI (19.6% vs.16.3%, p > 0.05) between Groups A and B, respectively. Catheter-associated bacteremia was higher in Group A (17.7% vs. 4.7%, p = 0.05). There were significantly more ESI in the patients treated for a positive Ssc. In Group A, the incidence of ESI was significantly higher in those treated for a positive vs. negative Ssc (55% vs. 12%, p = 0.009) and CAB rates trended higher with positive Ssc (22.2% vs. 16.7%, p > 0.05). The strategy of treating positive surveillance cultures is not beneficial. Positive Ssc do not predict the occurrence of catheter-related infection, and treatment of these cultures may lead to increased infection rates.     

Extracellular Volume Changes and Blood Pressure Levels in Hemodialysis Patients

Background: Despite the use of highly efficient antihypertensive drugs (AHD), blood pressure (BP) is poorly controlled in the vast majority of hemodialysis (HD) patients. Many of them show no reduction in nocturnal BP, a finding that is associated with left ventricular hypertrophy. The aim of the study was to investigate the effect of the removal of a fluid overload on BP by monitoring the ambulatory BP during 48 hours in 16 hypertensive HD patients treated with AHD. Our aim was to obtain a gradual reduction in post‐HD body weight (BW) over a period of 3 to 4 months. Methods: During a period of 3–4 months, the postdialysis BW was reduced as the minimal tolerable BW was gradually achieved by slightly increasing the ultrafiltration volume. The Na concentration in the dialysate was reduced from 143–141 mmol/L to 139–138 mmol/L. Extracellular volume (ECV) was measured with a multiple‐frequency bioimpedance analyzer (Xitron 4000B, Xitron Technologies Inc., San Diego, CA, USA). Based on the change in ECV, the patients were subdivided into two groups: group 1 with a reduction in ECV (n = 10), and group 2 with no reduction (n = 6). At the start of the study, BW, BP, and AHD in group 1 and group 2 were virtually identical. Results: Group 1 showed a significant reduction during the entire 48‐hour period in systolic (156 ± 16 mmHg vs. 140 ± 14 mmHg, P = 0.030) and diastolic BP (97 ± 12 mmHg vs. 87 ± 9 mmHg, P = 0.026) as well as in mean arterial pressure (MAP, 117 ± 13 vs. 105 ± 10 mmHg, P = 0.027). This reduction was more marked during the night (systolic BP 156 ± 15 mmHg vs. 138 ± 14 mmHg, P = 0.007; diastolic BP 97 ± 12 mmHg vs. 85 ± 9 mmHg, P = 0.009) than during the day (157 ± 18 mmHg vs. 142 ± 15 mmHg, P = 0.067; diastolic BP 97 ± 13 mmHg vs. 90 ± 9 mmHg, P = 0.126). A significant reduction in systolic load also occurred during the entire 48‐hour period (76 ± 24% vs. 46 ± 28%, P = 0.043) as well as in night systolic load (75 ± 21% vs. 41 ± 30%, P = 0.015) and night diastolic load (67 ± 32% vs. 39 ± 31%, P = 0.030). AHD were stopped in eight and reduced in two patients. There were no significant reductions in BP and AHD in group 2. Conclusions: The removal of excess fluid is necessary for adequate BP control and especially for the reduction in elevated BP during the night.     

Equilibrium and kinetic adsorption study of Basic Yellow 28 and Basic Red 46 by a boron industry waste

In this study, the adsorption characteristics of Basic Yellow 28 (BY 28) and Basic Red 46 (BR 46) onto boron waste (BW), a waste produced from boron processing plant were investigated. The equilibrium adsorption isotherms and kinetics were investigated. The adsorption equilibrium data were analyzed by using various adsorption isotherm models and the results have shown that adsorption behavior of two dyes could be described reasonably well by a generalized isotherm. Kinetic studies indicated that the kinetics of the adsorption of BY 28 and BR 46 onto BW follows a pseudo-second-order model. The result showed that the BW exhibited high-adsorption capacity for basic dyes and the capacity slightly decreased with increasing temperature. The maximum adsorption capacities of BY 28 and BR 46 are reported at 75.00 and 74.73mgg(-1), respectively. The dye adsorption depended on the initial pH of the solution with maximum uptake occurring at about pH 9 and electrokinetic behavior of BW. Activation energy of 15.23kJ/mol for BY 28 and 18.15kJ/mol for BR 46 were determined confirming the nature of the physisorption onto BW. These results indicate that BW could be employed as low-cost material for the removal of the textile dyes from effluents.     

Repair of experimental Achilles tenotomy with porcine renal capsule material in a rat model

Porcine small intestinal submucosa (SIS) is a collagenous acellular matrix which has found substantial utility as a tissue growth scaffold. In the present study, the utility of porcine renal capsule matrix (RCM) was compared to SIS in a rat Achilles tenotomy repair model. Groups of rats underwent surgical tenotomy followed by either no repair, repair with a SIS graft, or repair with a RCM graft. The weight-bearing ability of the manipulated limb was evaluated for 10 days following surgery using a subjective scale. Tenotomy sites sampled 28 days after surgery were numerically graded for degree of histologic change. There were no statistically significant differences between groups with respect to return to weight-bearing ability (p ≥ 0.05) or degree of histologic change (p ≥ 0.001); however, a non-significant trend suggested that rats treated with SIS or RCM experienced a faster return to limb function than untreated rats, and RCM-treated rats had slightly higher scores for degree of histologic change, suggesting a more rapid repair of the tenotomy site than in SIS-treated or untreated rats. The harvested tenotomy sites in all treatment groups were characterized by marked fibroplasia and presence of macrophages. Remnants of SIS surrounded by macrophages and multi-nucleated giant cells were still present in some rats, however remnants of RCM were not observed, suggesting more rapid incorporation of RCM. The results show that RCM is equivalent to SIS as a material for repair of Achilles tendon injury and merits further study in other tendon injury models.     

Impact of intradialytic exercise on arterial compliance and B-type natriuretic peptide levels in hemodialysis patients

Cardiovascular (CV) disease is the most common cause of mortality in end-stage kidney disease (ESKD), and arterial stiffness, measured by pulse wave velocity (PWV), is an independent predictor of all-cause and CV mortality. B-type natriuretic peptide (BNP) levels are high in patients with CV disease and ESKD, and increases in BNP may also be a marker of CV risk. Regular exercise has many benefits on quality of life and physical strength and may also improve CV risk, but few studies have addressed the impact of exercise on CV risk in ESKD. We performed a prospective cross-over trial in 19 hemodialysis (HD) patients to assess the impact of regular exercise on surrogate markers of CV risk-arterial compliance and BNP levels. Exercise involved the use of a bicycle ergometer for minimum 30 min at each HD session for 3 months, with a 1-month washout period. Group A (n=9) exercised for the first 3 months only, while group B (n=10) performed no intradialytic exercise initially and exercised for 3 months at cross-over (month 4). Pulse wave velocity was performed using a SphygmoCor device, with concurrent measurements of BNP and other serum markers, at the commencement of the study, at 3 months, and on completion. The mean PWV (A: 10.4+/-3.1 m/s, B: 9.8+/-3.8 at baseline) showed a trend toward improvement with exercise (A: 8.7+/-2.7, p=0.07), and no significant change without (B: 10.5+/-3.6, p=0.31). After cross-over, there was an increase in PWV in group A with cessation of exercise (9.75+/-2.4, p=0.01 vs. 3 months) and an improvement in group B with exercise (9.33+/-2.3, p=0.11 vs. 3 months). When comparing PWV after 3 months of exercise vs. 3 months of no exercise (paired t test), there was a significant difference in favor of exercise (9.04+/-0.59 vs. 10.16+/-0.74, p=0.008). The mean BNP levels following 3 months of exercise were also lower than those after 3 months of no exercise (504.4+/-101.2 vs. 809.4+/-196.1[N<100], p=0.047). There was an overall improvement in PWV, and to a lesser extent BNP levels, with 3 months of intradialytic exercise compared with no exercise, suggesting that regular exercise in ESKD may be associated with improvements in arterial compliance and a reduction in CV risk.     

Resource settings have a major influence on the outcome of maintenance hemodialysis patients in South India

Chronic kidney disease is reaching epidemic proportions and the number of patients on renal replacement therapy (RRT) is increasing worldwide and also in developing countries. To meet the challenge of providing RRT, a few charity organizations provide hemodialysis units for underprivileged patients, as the private hospitals are unaffordable for the majority. There is a paucity of information on the outcome of dialysis in these patients. Here, we describe the outcome of hemodialysis patients comparing the middle‐ and upper‐class income group with the lower class income group. A retrospective analysis was carried out in 558 CKD patients initiated on maintenance hemodialysis in two different dialysis facilities. Group A (n=247) included those who belonged to the lowermost socioeconomic status and were undergoing dialysis in two nonprofit, charity (TANKER)‐run dialysis units, and Group B (n=311) was undergoing dialysis in a nonprofit hospital setting where no subsidy was given. Those patients of a low socioeconomic status, especially those who are diabetics, have a higher death rate (Group A‐38.1%, Group B‐4.2%) and loss to follow‐up (Group A‐25.9%, Group B‐0.3%) compared with those who are in the middle‐ and high‐income group. Higher EPO use and hence higher hemoglobin levels (Group A‐6.4±1.2, Group B‐8.9±1.5 P<0.001) were observed in those who were in the middle and the higher income group. Lower serum phosphorus level was observed in the low‐socioeconomic group (Group A‐4.7±1.5, Group B‐5.5±1.9, P<0.001). Patients belonging to the middle and higher socioeconomic group undergo more transplantations compared with the lower socioeconomic group (Group A‐2.4%, Group B‐65.6%).     

Clinical diagnostic indicators of renal and bone damage in rats intramuscularly injected with depleted uranium

The toxic effects and changes in biochemical markers related to kidney and bone in depleted uranium (DU)-injected rats were examined in order to clarify the relation between clinical biochemical markers and the degree of damage in these organs. Male Wistar rats received a single injection in the femoral muscles of 0.2, 1.0 or 2.0 mg kg(-1) of DU which was dissolved in nitric acid solution adjusted to pH 3.2, for comparison with the group injected with nitric acid solution, and the control group. Urine and faeces were collected periodically over a 24 h period. Thereafter, the rats were killed at 28 d after DU injection. The body weights of the DU-injected groups decreased dose-dependently for the first 3-7 d, and then began to increase. The DU concentrations in the urine and faeces decreased rapidly within 3-7 d after DU injection. Urinary N-acetyl-beta-D-glucosaminidase (NAG)/creatinine peaked at the third day after DU injection, with a high correlation to the injected DU doses. There were high correlations among the injected DU doses, DU concentrations in the kidney and urinary NAG/creatinine values that were obtained at 28 d, respectively. The blood urea nitrogen (BUN) and creatinine in the serum also showed a high correlation with the DU-injected doses. The results indicated that urinary NAG/creatinine, BUN and creatinine in serum were useful indicators to diagnose the renal damage by DU, as well as to estimate the DU intake and concentration in the kidney when the intake is >2 mg kg(-1) DU. The total bone mineral density of the proximal metaphysis of the tibia decreased in the 2 mg kg(-1) DU group. In addition, alterations of the trabecular bone structure by inhibiting bone formation and promoting bone resorption were observed by bone histomorphometery. The bone biochemical markers osteocalcin, tartrate-resistance acid phosphatase, pyridinoline and rat-parathyroid hormone increased in all the DU injected groups, indicating that these markers were useful as sensitive indicators for diagnosing bone damage, even if the DU dose injected is low.     

The effect of a change in epoetin alfa reimbursement policy on anemia outcomes in hemodialysis patients

In 1997, the Health Care Financing Administration Hematocrit Measurement Audit (HMA) program initiated use of a 3-month rolling average hematocrit (Hct) level for reimbursement of epoetin claims in hemodialysis patients, with denial of payment when this value exceeded 36.5%. This study evaluated the impact of the HMA program on anemia-related outcomes in hemodialysis patients. An observational, retrospective study of 987 hemodialysis patients from 11 dialysis centers in the United States was performed, collecting data between October 1996 and December 1997. Centers were selected from a pool of nearly all facilities in the United States, which during May 1997 satisfied one of two criteria: greater than 75% of patients at the facility had mean Hct level of > or =33% (Group A) or fewer than 50% of patients at the facility had mean Hct level of > or =33% (Group B). Each facility maintained its own anemia management practices without specific anemia management interventions as part of this study. Hct level, hemoglobin (Hb) level, and epoetin dose were analyzed to compare the pre-HMA period (October 1996 to May 1997) to the HMA period (June to December 1997) and/or for each of the five quarters of the study period. The primary study endpoint was the percentage of patients with Hct levels of > or =33% during each study quarter. The mean Hct level at baseline was 34% in Group A and 33.4% in Group B (p = 0.01). Hct levels, which were increasing before implementation of the HMA program, decreased during the HMA period (p < 0.001 and p = 0.013 in Groups A and B, respectively). The percentage of patients in Groups A and B with mean quarterly Hct levels of > or =33% decreased during the last quarter of the HMA implementation period compared to the quarter immediately preceding the start of the HMA program (p < 0.001 for both comparisons). Changes in Hb levels were similar to those seen in Hct levels. The mean epoetin dose administered decreased from 13,090 U/week at the start of the study to 11,884 U/week immediately before the HMA program took effect (p < 0.05). The HMA program adversely affected anemia treatment outcomes, regardless of whether dialysis units before HMA implementation had <50% of patients with a Hct level of > or =33% or had >75% of patients with a Hct level of > or =33%. The decline in mean weekly dose of epoetin was likely a result of withholding doses out of concern among providers about risk of reimbursement denial.     

The amnion muscle combined graft (AMCG) conduits in nerves repair: an anatomical and experimental study on a rat model

The amnion muscle combined graft (AMCG) conduits showed good clinical results in peripheral nerves gap repair. It combines the human amniotic membrane with autologous skeletal muscle fibres. These results seem attributable to the biological characteristics of human amniotic membrane: Pluripotency, anti-inflammatory and low immunogenicity.We here evaluate the final outcome of nerve regeneration morphologically and functionally, across the AMCG compared to nerve autograft. Fourteen Wistar rats were divided into two groups: In Group A, including 6 rats, the left forelimb was treated performing a 1.5?cm length gap on median nerve that was then reconstructed with a reverse autograft. In Group B, including 8 rats, the gap was reconstructed with AMCG. Functional results were evaluated at 30, 60 and 90 days performing grasping tests. Morphological and stereological analyses were performed at T90 using high-resolution light microscopy and design-based stereology. The AMCG conduits revealed nerve fibres regeneration and functional recovery. Functional recovery was observed in both groups with AMCG conduits group showing lower values and a regeneration of median nerves with more myelinated fibres with the same axon size, but thinner myelin than the autograft group. Though the autograft remains the gold standard to restore wide nerve gaps, the AMCG conduit has proved to be effective in enabling nerve regeneration through a critical rat’s nerve gap of 15?mm. These findings empirically support the great clinical results obtained using AMCG conduit to restore traumatic nerve’s gap from 3 to 6?cm of mixed forearm nerves.

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Ethanol combined with heparin as a locking solution for the prevention of catheter related blood stream infections in hemodialysis patients: A prospective randomized study

Introduction: Ethanol lock solution has been mainly administered in paediatric and home parenteral nutrition patients in order to prevent catheter related blood stream infections (CRBSI). Its utility in hemodialysis (HD) patients with non‐tunneled‐uncuffed catheter (NTC) has been poorly explored. Methods: We conducted a prospective randomized study in chronic HD patients requiring a newly inserted NTC‐while awaiting for the maturation of an already established arteriovenous fistula (AVF) or arteriovenous graft (AVG) or tunneled‐cuffed catheter insertion. Patients were randomized in two groups: Group A, where the lock solution was ethanol 70% + unfractionated heparin 2000 U/mL and group B, that received only unfractionated heparin 2000 U/mL. Primary end point was CRBSIs whereas exit site infections, thrombotic and bleeding episodes were the secondary end points. Findings: One hundred three HD patients were enrolled in the study (group A, n = 52; group B, n = 51). The median number of catheter days was 32 for group A (range: 23–39) and 34 (range: 27–40) for group B with no statistically significant difference between the two groups. Group A (ethanol + heparin) demonstrated 4/52 episodes (7.69%) of CRBSI whereas Group B (heparin) 11/51 episodes (21.57%) (P = 0.04). CRBSI rates per 1000 catheter days were 2.53/1000 catheter days for group A and 6.7/1000 catheter days for group B (P = 0.04). Mean cumulative infection‐free catheter survival in the ethanol group did not differ significantly compared to the heparin group (log‐rank test = 2.99, P = 0.08). Thrombotic episodes did not differ between the two groups. Discussion: Locking of NTCs in HD patients with ethanol 70% + unfractionated heparin reduces CRBSI rates without increasing the thrombotic episodes.     

Effect of hydroxyapatite porosity on growth and differentiation of human osteoblast-like cells

To study whether hydroxyapatite (HA) porosity can influence its osteoconductive properties, cell adhesion, proliferation and differentiation were compared in human osteoblast-like cells grown on HA disks of different porosity (A = 20%, B = 40%, C = 60%). Human osteoblast-like cells were isolated and characterized. Proliferation rate and alkaline phosphatase (ALP) activity were assessed at 3, 7, 15, 21, and 28 days. Type I collagen and osteonectin production were demonstrated with fluorescence microscopy and osteoblast adhesion studied at 7 and 21 days by scanning electron microscopic analysis. Cell growth on HA was three- to six-fold lower than on polystyrene control disks. At 28 days, 2141 (±350) cells/well grew on the most porous disks (Group C), with highly significant differences from controls (p < 0.005). The ALP production was 2–3 fold lower on HA than on plastic. In the Group C the mean ALP activity was of 2.95 (±0.07) UI/well after 28 days, higher than in the other two groups. At 21 and 28 days, proliferation rate and ALP activity on the three HA cultures were significantly different (p < 0.05). A decrease in cell population and increased ALP activity were observed on the most porous material, and high proliferation and poor differentiation rates on the less porous disks.     

Urinary benzo[a]pyrene and its metabolites as molecular biomarkers of asphalt fume exposure characterized by microflow LC coupled to hybrid quadrupole time-of-flight mass spectrometry

As a step to study the health effects of asphalt fume exposure, an analytical method was developed to characterize benzo[a]pyrene and its hydroxy metabolites in the urine of asphalt fume-exposed rats. This method is based on microflow liquid chromatography (LC) coupled to hybrid quadrupole orthogonal acceleration time-of-flight mass spectrometry (Q-TOFMS). Twenty-four female Sprague-Dawley rats were used in the experiment, with 8 as controls and 16 exposed to asphalt fumes in a whole-body inhalation chamber for 10 days (4 h/day). Generated at 150 degrees C, the asphalt fume concentration in the animal exposure chamber ranged 76-117 mg/m(3). In the urine of the asphalt fume-exposed rats, benzo[a]pyrene and its metabolites of 3-hydroxybenzo[a]pyrene, benzo[a]pyrene-7,8-dihydrodiol(+/-), and benzo[a]pyrene-7,8,9,10-tetrahydrotetrol(+/-) were identified, and their concentrations were determined at 2.19 +/- 0.49, 16.17 +/- 0.3, 6.28 +/- 0.36, and 29.35 +/- 0.26 ng/100 mL, respectively. The metabolite concentrations from the controlled group, however, were either under the detection limits or at a relatively very low level (0.19 +/- 0.41 ng/100 mL for benzo[a]pyrene-7,8,9,10-tetrahydrotetrol metabolite). The results clearly indicate that the benzo[a]pyrene and its hydroxy metabolites were significantly elevated (p < 0.001) in the urine of asphalt fume-exposed rats relative to controls. The study also demonstrated that the combination of microflow LC separation and collision-induced dissociation leading to a characteristic fragmentation pattern by hybrid Q-TOFMS offers a distinct advantage for the identifications and characterizations of the benzo[a]pyrene metabolites.     

Arterial Hypertension Is Associated with Increased Serum Lipoprotein(a) Levels in End‐Stage Renal Disease Patients

In addition to disorders in lipoprotein metabolism, several other factors are involved in the development of atherosclerotic changes in end‐stage renal disease (ESRD) patients. One of these is arterial hypertension. We evaluated serum lipids—total cholesterol (TC), triglycerides (TG), apolipoproteins (A_I , A _II , B, E), lipoprotein(a) [Lp(a)]—in 109 ESRD patients on dialysis [46 on hemodialysis (HD); 63 on continuous ambulatory peritoneal dialysis (CAPD)] and in 45 hyperlipidemic patients without renal failure (HL group). Dialysis patients were divided in two groups. Group A included 42 hypertensive patients (mean age: 62.3 ± 15.5 years) whose blood pressure (BP) was satisfactorily controlled with anti‐hypertensive medications. Group B included 67 non hypertensive patients (mean age: 66.6 ± 11.9 years). Levels of Lp(a) were significantly higher in both the HD (p = 0.001) and the CAPD (p < 0.05) patients as compared with the HL group. When the HD and CAPD groups were divided into hypertensive and non hypertensive patients, Lp(a) levels were significantly higher in the hypertensive patients; this difference was not observed among non renal failure patients. These results indicate that arterial hypertension is associated with elevated Lp(a) serum levels in ESRD patients undergoing either HD or CAPD.     

Inhibitory effect of resveratrol on the pharmacokinetic of ibrutinib by UPLC–MS/MS

Objective: To investigate the impact of resveratrol on the metabolism of ibrutinib in vitro and in vivo.

Methods: In vitro, rat liver microsomes (RLM) and human liver microsomes (HLM) were used to study. In vivo, 18 male SD rats were randomly divided into three groups (n?=?6): ibrutinib and the multiple dose of 100?mg/kg resveratrol for consecutive 7 days (Group A), ibrutinib and the single dose of 100?mg/kg resveratrol (Group B), ibrutinib (Group C). Processed samples were analyzed by UPLC–MS/MS.

Results: Resveratrol showed inhibition on RLM and HLM in vitro. The IC₅₀ of resveratrol was 8.745?µM in RLM and 7.789?µM in HLM. Furthermore, Groups A and B both increased the AUC and reduced the CLz/F. The C_max of Group A and the MRT_(0–t) of Group B were significantly improved.

Conclusions: Resveratrol inhibits the pharmacokinetic of ibrutinib in vitro and in vivo. It is necessary to pay more attention to adjust the dose of the drug when resveratrol is used in combination with ibrutinib.     

Superior neuroprotective effects of cerebrolysin in heat stroke following chronic intoxication of Cu or Ag engineered nanoparticles. A comparative study with other neuroprotective agents using biochemical and morphological approaches in the rat

The possibility that cerebrolysin, a mixture of several active fragments of neurotrophic factors and peptides induces neuroprotection following nanoparticles induced exacerbation of brain damage in heat stroke was examined in a rat model. For this purpose, the therapeutic efficacy of Cerebrolysin (2.5 or 5 ml/kg) recommended for stroke treatment was used in comparison with other drugs in standard doses recommended for such therapy in clinical situations e.g., levetiracetam (44 mg/kg), pregabalin (200 mg/kg), topiramate (40 mg/kg,i.p.) and valproate (400 mg/kg). Rats subjected to 4 h heat stress in a biological oxygen demand (BOD) incubator at 38 degrees C (Rel Humid 45-47%; Wind vel 22.4 to 25.6 cm/sec) developed profound behavioral symptoms of heat stroke e.g., hyperthermia, profuse salivation, prostration and gastric ulcerations in the stomach. These rats also exhibited marked brain pathology at this time. Thus, breakdown of the blood-brain barrier (BBB) to proteins associated with brain edema formation could be seen in these heat stressed rats as compared to control groups. The edematous brain areas showed profound neuronal damage and/or distortion in large areas of the neuropil. These pathological symptoms were further exacerbated in Cu or Ag nanoparticles treated group (50-60 nm particle size, 50 mg/kg, i.p./day for 7 days) after identical heat stress on the 8th day. Pretreatment with cerebrolysin (2.5 ml/kg, i.v.) daily for 3 days in normal rats before heat stress significantly reduced the behavioral stress symptoms and the breakdown of the BBB function, edema formation and neuronal injuries. However, the magnitude and intensity of these neuroprotective effects were much less intense in all other drug treated rats after similar heat stress. On the other hand, almost double dose of cerebrolysin (5 ml/kg) was needed to achieve comparable neuroprotection in nanoparticles treated animals after heat stress. Whereas, double dose of all other compounds was much less effective in inducing neuroprotection in nanoparticles treated heat-exposed animals. These observations are the first to show that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal and in nanoparticles treated group. Furthermore, cerebrolysin in double dose was the most effective in inducing neuroprotection in nanoparticles treated heat exposed rats on brain pathology as compared to double doses of other drugs. Taken together, our results show that cerebrolysin has the most superior neuroprotective effects on brain pathology in heat stroke in both normal and nanoparticles treated rats as compared to other contemporary neuroprotective agents, not reported earlier.     

Diabetes aggravates nanoparticles induced breakdown of the blood-brain barrier permeability, brain edema formation, alterations in cerebral blood flow and neuronal injury. An experimental study using physiological and morphological investigations in the rat

The possibility that diabetes aggravates nanoparticles induced blood-brain barrier (BBB) breakdown, edema formation and brain pathology was examined in a rat model. Engineered nanoparticles from metals Ag and Cu (50-60 mn) were administered (50 mg/kg, i.p.) once daily for 7 days in normal and streptozotocine induced diabetic rats. On the 8th day, BBB permeability to Evans blue and radioactive iodine (131I-sodium) was examined in 16 brain regions. In these brain regions alterations in regional CBF was also evaluated using radiolabelled (125I) carbonized microspheres (o.d. 15 +/- 6 microm). Regional brain edema and Na+, K+ and Cl- ion analysis were done in 8 selected brain regions. Histopathology was used to detect neuronal damage employing Nissl staining. Nanoparticles treatment in diabetic rats showed much more profound disruption of the BBB to Evans blue albumin (EBA) and radioiodine in almost all the 16 regions examined as compared to the normal animals. In these diabetic animals reduction in regional cerebral blood flow (CBF) was more pronounced than in normal rats. Edema development as seen using water content and increase in Na+ and a decrease in K+ ion were most marked in diabetic rats as compared to normal rats after nanoparticles treatment. Cell changes in the regions of BBB disruptions were also exacerbated in diabetic rats compared to normal group after nanoparticles treatment. Taken together, these observations are the first to show that diabetic rats are more susceptible to nanoparticles induced cerebrovascular reactions in the brain and neuronal damage. The possible mechanisms and significance of the present findings are discussed.     

Screening of biomedical polymer biocompatibility in NMRI-mice peritoneal cavity: A comparison between ultra-high-molecular-weight polyethylene (UHMW-PE) and polyethyleneterephthalate (PET)

The peritoneal resident cell population is influenced by various inflammatory and immunogenic stimuli. The influence of intraperitoneal application of polyethyleneterephthalate (PET) (group A) and ultra-high-molecular-weight polyethylene (UHMW-PE) (group B) powders on peritoneal cell count and macrophage activity was investigated. Powders were tested to mimic wear particles from solid implant devices as these particles often cause chronic granulomatous inflammation. The results were compared with the inflammatory response following an abdominal midline incision (group C) and untreated animals (group D). On days 1, 7, 14 and 30 peritoneal cells were quantified and the number of active macrophages was assessed. Groups A and C mice showed a significant loss of macrophages in the peritoneal lavage at day 1 but this returned to normal values (group D) on day 7. In contrast, group B animals remained at low peritoneal cell counts but showed the highest number of active macrophages. Only in this latter group was adhesion formation and granulomatous clustering of polymer powder observed. Applying the parameters macrophage count and the number of active macrophages it can be concluded that PET elicits a weaker inflammatory reaction than UHMW-PE in mice peritoneal cavity. Thus this animal model may be used as a screening test for biomedical materials, especially their wear products.