Optimized meropenem dosage regimens using a pharmacokinetic/pharmacodynamic population approach in patients undergoing continuous venovenous haemodiafiltration with high-adsorbent membrane.

BACKGROUND: The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane. OBJECTIVES: To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA. METHODS: A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC). RESULTS: The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required. CONCLUSIONS: We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.

[Bone graft reconstruction for posterior mandibular segment using the formwork technique]. / Greffes osseuses des secteurs mandibulaires postérieurs par technique de « coffrage ¼.

INTRODUCTION: Pre-implant bone graft in posterior mandibular segments is difficult because of masticatory and lingual mechanical constraints, because of the limited bone vascularization, and because of the difficulty to cover it with the mucosa. The formwork technique is especially well adapted to this topography. TECHNICAL NOTE: The recipient site is abraded with a drill. Grooves are created to receive and stabilize the grafts. The bone grafts were harvested from the ramus. The thinned cortices are assembled in a formwork and synthesized by mini-plates. The gaps are filled by bone powder collected during bone harvesting. DISCUSSION: The bone volume reconstructed with the formwork technique allows anchoring implants more than 8mm long. The proximity of the inferior alveolar nerve does not contra indicate this technique. The formwork size and its positioning on the alveolar crest can be adapted to prosthetic requirements by using osteosynthesis plates. The lateral implant walls are supported by the formwork cortices; the implant apex is anchored on the native alveolar crest. The primary stability of implants is high, and the torque is important. The ramus harvesting decreases operative risks.

Genomic full-length analysis of the B*08:79 allele suggests exon shuffling involving the B*08:01:01 and B*07:06 alleles.

B*08:79 is composed by partial B*08:01:01 and B*07:06 sequences because of a possible recombination event within intron 2.

Sequencing of a single HLA-B genotype including two rare alleles allows the detection of a new allele, B*44:130.

The novel HLA-B*44:130 allele was found in a Spanish donor. B*44:130 differs from B*44:40 by four nucleotide changes at codons 11, 12 and 24, producing three amino acid replacements, 11A>S, 12M>V and 24T>S.

Ochratoxin A levels in the plasma of healthy blood donors from Valencia and estimation of exposure degree: comparison with previous national Spanish data.

Blood plasma levels of ochratoxin A, a toxic secondary metabolite of several fungal species belonging to the genera Aspergillus and Penicillium, were determined in 168 blood donors from the population of Valencia (Spain) using LC-FLD. In conjunction with blood collection, detailed information on diet was obtained by using a questionnaire that encompassed a wide range of products potentially contaminated with the toxin. The investigation revealed a detection frequency of 100%. Mean level was 1.09 microg OTA/l of plasma and concentrations ranged between 0.15 and 5.71 microg OTA/l of plasma. Men's levels were slightly higher than levels observed in women. Results were analysed by Spearman rank correlation test and Gamma correlation statistic. There was no strong correlation between individual consumption of 26 food groups, described as possibly contaminated with OTA and plasma level of OTA. Multiple regression and factorial regression models were obtained explaining 14.9 and 64.4%, respectively, but they could not explain overall variability. Daily dietary intake of ochratoxin A was calculated on the basis of plasma toxin levels using the Breitholtz and Klassen formulae; for the overall population, mean values were 1.47 +/- 1.25 and 2.16 +/- 1.88 ng/kg bw/day, respectively. All results have been compared with other Spanish data.

Long-term storage in liquid nitrogen does not affect cell viability in cardiac valve allografts.

Liquid nitrogen is the most common medium used by tissue banks for the storage of cryopreserved heart valves. This study evaluates the effect of the length of storage on human cryopreserved heart valves. Human tissues (14 aortic and 13 pulmonary) were frozen in a controlled-rate freezer (1 degrees C/min) and stored in the liquid phase of a nitrogen tank for 9.1+/-1.6 years. The preservative solution was medium M199 containing 5% human serum albumin and 10% Me(2)SO. After thawing in a water bath at 42 degrees C, the cryoprotectant was removed. Then, fragments from vascular wall and leaflet were dissected. Explant cultures and histological studies were performed in order to assess cell viability and structural integrity. CD90 and CD31 expression was analysed in cultured cells using flow cytometry. Light microscopy, immunofluorescence staining and laser scanning confocal microscopy were used to evaluate cell viability and extracellular matrix components. Electron microscopy was used for ultrastructural study. Cell cultures could be obtained from all the specimens assayed. Cells grew from explants showing a fibroblastic phenotype. CD90 expression was common in cultured cells but a low percentage of cells expressed CD31. Histological results showed a good preservation estructure in both leaflets and vascular walls. Morphological features of cellular irreversible damage were very rare. No differences which could be due to length of allograft storage period were observed. We concluded that allografts stored in liquid nitrogen up to 13 years did not significantly undergo loss of cell viability other than that due to disinfection, freezing and thawing protocols.

Donor screening for hepatitis B virus infection in a cell and tissue bank.

BACKGROUND AND OBJECTIVES: Hepatitis B virus (HBV) has been transmitted by tissue transplantation. In order to reduce the risk of HBV transmission, testing for antibody to HBV core antigen (anti-HBc) is used in addition to testing for hepatitis B surface antigen (HBsAg) in many blood centers and tissue banks. DESIGN AND METHODS: We retrospectively analyzed the results of HBV assays in tissue donors. All tissue donors were tested for HBsAg and anti-HBc. All anti-HBc positive sera were tested for the antibody to HBsAg (anti-HBs). From July 2006, an HBV nucleic acid testing (NAT) assay was also performed. RESULTS: A total of 6855 tissue donors from January 1999 till July 2007 were tested for HBV assays: 4756 women and 2099 men. Positive HBsAg was found in 23 (0.36%) living donors, while no multiorgan or cord blood (CB) donor was found to be positive for HBsAg. Positive anti-HBc was found in 80 multiorgan donors (12.94%), 599 living donors (17.84%), and 103 CB donors (3.57%) (P<0.005), while isolated anti-HBc was found in 12 multiorgan (1.94%), in 126 living tissue donors (3.75%), and in 8 CB donors (0.28%). A total of 1310 donors were analyzed for single-sample DNA HBV NAT assay. DISCUSSION: We consider that anti-HBc and NAT assays must both still be performed in addition to HBsAg assay for HBV screening in tissue donors. All these tests will be useful in order to define an algorithm for safe and efficient management of the tissue bank.

[Optimising the quality of the unit dose dispensing process through the implementation of the semi-automated Kardex system]. / Optimización de la calidad del proceso de dispensación de medicamentos en dosis unitaria mediante la implantación del sistema semiautomático Kardex.

OBJECTIVE: To evaluate the effect of the incorporation of the semi-automated Kardex medication storage and dispensing system on the quality of the filling process of medicine trolleys in unit doses. METHOD: The speed of filling medicine trolleys in unit doses using the Kardex system was analysed retrospectively (n = 33,946 dispensings) and compared with the manual filling system (n = 5,284 dispensings); different filling procedures were used and compared. For each filling system and procedure, we obtained information for the number of dispensings and the time spent carrying this out. The speed of the process was calculated as the number of dispensings per hour. In addition, the drugs contained in the Kardex system were checked and the correspondence between both the actual and the theoretical content was assessed. RESULTS: The speed of the trolley filling process, expressed as the number of dispensings per hour, increased from 394 with the manual system (filling trolleys individually, n = 5,284 dispensings) to 417, 540 and 592 with the Kardex system when trolleys were filled individually (n = 16,530 dispensings), or grouped in two (n = 10,369 dispensings) or in three (n = 7,047 dispensings) respectively, at the start of the filling process. The check of the contents in the Kardex system detected 36% of trays with differences in quantity, one tray with out of date medication and three trays which should in theory have been empty and contained medication. CONCLUSIONS: The Kardex system optimises the speed of trolley filling with regard to the manual system, provided that the trolleys are grouped at the time of starting the preparation. The check of the cabinet contents shows that possibilities of error exist, related to its handling, which can be minimised by incorporating bar codes into the system s replenishment process.

Automated separation of cord blood units in top and bottom bags using the Compomat G4.

Cord blood (CB) has become a real alternative source of haematopoietic stem cells for bone marrow reconstitution in a variety of malignant disorders. As a response to this increasing activity, CB banks have been developed to guarantee the quality of processed CB units. Volume reduction of CB units maximizes storage space and also has other advantages. The aim of this study was to develop a program for the volume reduction of CB in the Compomat G4 device. We also compared two different top and bottom systems for CB fractionation (Compomat G4 and Optipress II). We empirically designed three different programs for volume reduction of CB with Compomat G4: two for final BC volume of 41 ml (CB1 and CB2) and the other one for buffy coat (BC) volume of 25 ml (CB3). Significantly worse recoveries were achieved for CB processed with program CB3. A RBC depletion of >or=50%, >or=60% and >or=70% were achieved for 67%, 39% and 9% of all units respectively. When comparing Compomat G4 and Optipress II, total nucleated cell recovery was similar for both methods, while lymphocytes recovery was significantly better for Optipress II.

Utility of bag segment and cryovial samples for quality control and confirmatory HLA typing in umbilical cord blood banking.

Many cord blood (CB) banks have been established worldwide as a response to the increasing number of CB transplantations. In this study, we describe a quality control program in which the utility of an integral bag segment and cryovial containing aliquots of cryopreserved product as haematopoietic content control and HLA typing confirmation for CB units has been evaluated. For this purpose, every month one stored CB unit and its satellite cryovials were thawed and washed. Nucleated cell counts, viability and clonogenic assays were performed from the bag and cryovial before washing. After washing, total nucleated cell, CD34+ counts, viability, and clonogenic assays were performed from the bag. In order to assure the ability of bag segments to confirm hematopoietic potential of CB units, clonogenic assays and viability were performed from attached segments of 10 CB units and the results were compared with those from bags and cryovials. When comparing all variables between thawed bag and cryovial samples, they showed similar results. Mean colony-forming unit (CFU) content of segment samples was 118.8 +/- 93.72 x 10(4) that resulted similar to bags and cryovials haematopoietic content. In conclusion, the quality control system described in this paper demonstrates that CB units are processed preserving the quantity and quality of the progenitor cells. The contiguous segment haematopoietic content is representative of the final product.

[Perioperative management of chronic medications not related with surgical procedures]. / Manejo perioperatorio de la medicación crónica no relacionada con la cirugía.

The correct management of chronic medications not related with surgical procedures in the perioperative period has a relevant place because each year millions of patients around the world undergo surgical procedures. For this reason the assistencial team should be aware of the importance of continuate or discontinuate determinate drugs during perioperative period because some of them are considered an important risk factor in the development of complications. The key is to differentiate necessary from unnecessary medication. This is a complex aspect, little studied, which difficult clinical decisions and favours the coexistence of several trends of clinical practice. The purpose of this review is to describe the factors that determinate the continuity or suspension of chronic medications which are not related with surgery in the perioperative period and to provide practice recommendations in lights of available publications.

[Caloric overload in critically ill patients treated with parenteral nutrition]. / Sobrecarga calórica en el paciente crítico tratado con nutrición parenteral.

OBJECTIVE: To assess the degree of hypernutrition of critically-ill patients under treatment with parenteral nutrition (PN) in a multi-purpose intensive care unit (ICU). SCOPE: Patients under treatment with parenteral nutrition in a multi-purpose intensive care unit. Prospective study lasting four months. INTERVENTION: The amounts of the daily dose of glucose, lipids and nitrogen were calculated in PN, enteral nutrition (EN), dextrose solution (DS) and propofol. The daily dose of glucose and lipid administered intravenously (i.v.) was assessed with respect to the recommended value (4-5 mg/kg/min and 1.5 g/kg/day, respectively) and with respect to the dose prescribed in the PN regime The total daily calorie intake (i.v. plus EN) was assessed with respect to the recommended value (25-35 kcal/kg/day). RESULTS: The study involved 30 patients totalling 488 days with PN. The total daily dose of i.v. lipids (PN plus propofol) exceeded the recommended value on 23.2% of the days with propofol (13 of 56) and on 3.7% of the days without propofol (16 of 432). The total daily dose of i.v. dextrose did not exceed any day the maximum metabolization threshold. On 28.2% of the days with EN and 39.6% of the days without EN, the total daily dose of i.v. dextrose exceeded the PN regimen. Similarly, on 41% of the days with propofol, the total daily dose of i.v. lipids exceeded the PN regimen. The total calorie intake (i.v. plus EN) exceeded the recommended value on 46.9% of the days with EN (51 of 109) and on 5% of the days without EN (19 of 379). CONCLUSION: The glucose of dextrose solution and the propofol lipid are not routinely discounted from the PN regime. A trend towards hypernutrition of the critically-ill patient is shown, especially on days with simultaneous treatment with PN and EN.

Nonalcoholic components in wine reduce low density lipoprotein cholesterol in normocholesterolemic rats.

Using an experimental model that enables the effects of alcohol to be distinguished from the effects of the nonalcoholic components present in wine, we determined whether wine has effects other than those of alcohol on the metabolism of cholesterol. Male rats were fed a standard diet and had free access to water and either wine or an equivalent alcohol solution for 45 d or 6 mon. Alcohol intake was similar in the two groups of animals. Consumption of the alcohol solution or wine did not influence plasma cholesterol or high density lipoprotein-cholesterol. At 45 d, the consumption both of wine and of alcohol solution reduced low density lipoprotein (LDL)-cholesterol and very low density lipoprotein cholesterol. At 6 mon, only the rats that consumed wine had reduced LDL-cholesterol. After 45 d of consuming alcohol solution, total cholesterol in the aorta was significantly increased mainly as a result of the rise in free cholesterol. In the aorta, the effect of wine consumption was similar to the effect of alcohol solution consumption, although it was less intense. The only clear effect that could be ascribed to the nonalcoholic components in wine was that the LDL-cholesterol was reduced in the long term, although aortic cholesterol was not.

[Quality of the home parenteral nutrition program: 14 years of experience at a general university hospital]. / Calidad del programa de nutrición parenteral a domicilio: 14 años de experiencia en un hospital general universitario.

The quality of home parenteral nutrition (NPD in its Spanish acronym) depends on the frequency and type of complication associated with NPD treatment and the likelihood of survival. The present study assesses the quality of the NPD programme in place in our hospital in terms of survival, infections and mechanical complications. A retrospective study was carried out into the clinical follow-up data of all the patients (n = 24) included in our NPD programme since its start in 1985 until 1998 (14 years). An estimate is made for: a) the annual index of infectious complications (IAC in its Spanish acronym), b) the annual index of mechanical complications (MAC in its Spanish acronym) and c) the likelihood of survival by means of the Kaplan-Meier method. The quality specifications adopted are those of the literature reflecting the current provision of NPD programmes and the survival values of patients undergoing dialysis for chronic kidney failure. The most frequent pathology in our context is benign (70.8%), distributed as follows: small bowel syndrome of ischaemic origin (45.8%), small bowel syndrome of non-ischaemic origin (12.5%) and idiopathic intestinal pseudo-obstruction (12.5%). The patients with benign pathologies present a higher survival rate than patients with neoplastic disease (95% in the fifth year of treatment versus 45% at twenty months), with a statistically significant difference. The annual index of infectious complications is 0.6 (median value of the 14 years studied). Similarly, the annual indices of obstructions and thromboses are 0.11 and 0.0095, respectively. In our opinion, the quality of the NPD programme in place at our hospital is highly satisfactory because both the survival rate and the annual indices of mechanical and infectious complications are acceptable with regard to the programmes in place in the international sphere. In addition, in terms of survival, NPD seems slightly more effective than dialysis for chronic kidney disease.

Moderate red wine consumption protects the rat against oxidation in vivo.

The effect of the moderate consumption of red wine on the antioxidant system in rat liver, kidney and plasma has been evaluated. Wistar rats were treated in separate groups as follows: control; red wine for 45 days or 6 months; and 13.5% ethanol for 45 days or 6 months. The consumption of alcoholic beverages was free because the rat could always choose between the alcoholic beverage and the water. In liver, red wine ingestion resulted in higher hepatic superoxide dismutase and glutathione peroxidase activities after 45 days of treatment. The data indicate that wine and ethanol ingestion resulted in lower hepatic malondialdehyde and enhanced hepatic catalase activity in both of the periods studied. In kidney, the reduced glutathione/oxidized glutathione ratio was higher after 45 days of wine consumption, and the malondialdehyde was lower after 6 months of wine consumption. In plasma, malondialdehyde was lower after 6 months of both treatments, but plasmatic vitamin E was higher after red wine consumption while it was lower after ethanol consumption for this period of time. The present study shows that the moderate and prolonged consumption of red wine is consistent with higher protection against oxidation in vivo.

Model for voluntary wine and alcohol consumption in rats.

It has been suggested that moderate consumption of ethanol and wine has a protective effect on human health. Animal models used to date for alcohol consumption can not mimic real situations in humans because the consumption is forced and/or excessive. The present study proposes to determine the effects of a voluntary and ad lib consumption model more similar to that of human behavior. Male Wistar rats had free access to either standard diet and water or the same diet plus red wine, sweet wine, or a solution equivalent to red wine (13.5% ethanol) or to sweet wine (20% ethanol + 130 g/L sucrose) for 30 days or 6 months. Daily wine consumption was 15.8 +/- 0.9 and 2.0 +/- 0.2 ml/day for sweet and red wines, respectively. The consumption of each of the alcoholic solutions was similar to that of the wine they were simulating. Drinking wine or ethanol did not affect food and water intakes or growth rate. Plasma metabolites were not substantially affected by consumption of wine or ethanol. Although moderate and high wine consumption did not change the activity of plasma marker enzymes of tissue damage, the consumption of the 2 alcoholic solutions caused a long-term increase in the activity of aspartate aminotransferase. It seems that wine consumption protects the organism from hepatic lesions induced by ethanol alone.

Regulation of ammonia-metabolizing enzymes expression in the liver of obese rats: differences between genetic and nutritional obesities.

OBJECTIVE: To determine the expression of carbamoylphosphate synthetase (CPS) and glutamine synthetase (GS) in two different models of obese rats: genetically obese rats and diet obese rats. SUBJECTS: Lean and genetically obese (fa/fa) Zucker rats were used. DESIGN: Lean animals (30-60 d old) were fed for 30 d with standard chow pellets or with a hypercaloric cafeteria diet. Genetically obese rats were fed with standard chow pellets. MEASUREMENTS: Enzyme activity, protein (Western blot) and mRNA (Northern blot) contents of CPS and GS were measured in liver homogenates. RESULTS: In genetically obese animals CPS mRNA content was higher, and GS mRNA content was lower than in control animals; CPS protein content did not change and CPS activity was lower than in control rats. Diet-obese rats had higher levels of CPS and GS mRNAs than control animals; GS protein content and activity was higher than in the control group and at the same time, CPS activity was very low. CONCLUSIONS: In the genetically obese animals the expression of CPS and GS is mainly regulated at the pre-translational level, whereas in the diet obese rats there is a noticeable post-translational component. A reciprocal regulation between CPS and GS can be established at pre-translational levels, whereas at post-transcriptional levels it cannot. It can be concluded that in diet-obese animals the mechanisms involved in retaining nitrogen (low CPS activity) are modulated at the post-translational level.