Dosage Individualization of Linezolid: Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity.

The high interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualized dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5 [±14.6] years) who underwent routine therapeutic drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-performance liquid chromatography. Population pharmacokinetic modeling was performed using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than the maximum licensed linezolid dose. The final PK model was then used to construct software for dosage individualization, and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespecified drug exposure targets. A further prospective study is needed to examine the potential clinical utility of individualized therapy.

Population Pharmacokinetics of Anidulafungin in Critically Ill Patients.

A two-compartment pharmacokinetic (PK) population model of anidulafungin was fitted to PK data from 23 critically ill patients (age, 65 years [range, 28 to 81 years]; total body weight [TBW], 75 kg [range, 54 to 168 kg]). TBW was associated with clearance and incorporated into a final population PK model. Simulations suggested that patients with higher TBWs had less-extensive MIC coverage. Dosage escalation may be warranted in patients with high TBWs to ensure optimal drug exposures for treatment of Candida albicans and Candida glabrata infections.

Influence of volumetric loading rate on aerobic sewage treatment for indigenous algal growth.

Many rural areas of Latin America and the Caribbean (LAC) region are economically depressed. Rural sewage treatment in most areas of LAC is deficient or non-existent. Consequently, the possibility of generating economic revenue from treated sewage is an attractive option for deprived areas of developing countries. Given its peculiar characteristics, rural sewage may be coupled with biological systems such as algae for nutrient cycling. Acceptable algae growth and nutrient elimination were obtained from rural sewage whose treatment may have fallen short of current disposal standards. In this study, aerobic systems working on an 8-month cycle at three different volumetric loading rates (Bv) were assessed in relation to the lifetime growth of three algae strains native to Ecuador. Results indicate Chlorella sp. M2 as the optimal algal strain, with the highest growth rate at Bv of 1 g COD L-1 d- 1 and a removal of organic-N (30%), PO4 3--P (87%) and NH4 +-N (95%). Concomitantly, the kinetic constants of the sewage resulted in a low biomass yield coefficient, making the proposed system highly suitable for developing countries. Finally, the proposed partial recovery stream method, combining nutrient recovery with economic resource generation, appears to contain great potential.

Effects of different strategies of mineral supplementation (marine algae alone or combined with rumen boluses) in organic dairy systems.

This study was designed to evaluate the effect of marine algae supplementation alone or in combination with a regular mineral supplement (rumen boluses) to improve the mineral status in organic dairy cattle and their effect on the milk mineral composition, milk production, composition (% of fat and protein) and quality (SCC). Thirty-two Holstein Friesian lactating cows were randomly selected and assigned to the algae (A), boluses (B), algae+boluses (AB) and control group (C). For the algae groups (A, AB), a supplement composed of Sea Lettuce (80%), Japanese Wireweed (17.5%) and Furbelows (2.5%) was formulated to be given to the cows at the rate of 100 g/animal per day (A1) for the length of 4 weeks. In the second half of the experiment (weeks 5-8), the algae mixture was reformulated and the proportion of Furbelows was increased from 2.5% to 5.0% with a subsequent decrease of Lettuce to 77.5% (A2). In the boluses group (B), each cow received 2 boluses after calving. Blood (serum) and milk samples were collected at 2 and 4 week intervals, respectively, and analysed for trace element concentrations by ICP-MS. Information related to the milk composition and SCC during a 305-day lactation for each animal were obtained from the Dairy Records Management System. The supplementation with algae, boluses or the combination of both treatments showed a statistically significant effect on the iodine (algae), selenium (boluses) and cobalt (algae+boluses) status of the animals. In milk, treatments had a statistical significant increase on iodine, and a tendency to increase selenium concentrations. The assayed algae mixture combined with another source of selenium could be an effective tool to improve the mineral status in serum and milk.

Brain Pathology in Adult Rats Treated With Domoic Acid.

Domoic acid (DA) is a neurotoxin reported to produce damage to the hippocampus, which plays an important role in memory. The authors inoculated rats intraperitoneally with an effective toxic dose of DA to study the distribution of the toxin in major internal organs by using immunohistochemistry, as well as to evaluate the induced pathology by means of histopathologic and immunohistochemical methods at different time points after toxin administration (6, 10, and 24 hours; 5 and 54 days). DA was detected by immunohistochemistry exclusively in pyramidal neurons of the hippocampus at 6 and 10 hours after dosing. Lesions induced by DA were prominent at 5 days following treatment in selected regions of the brain: hippocampus, amygdala, piriform and perirhinal cortices, olfactory tubercle, septal nuclei, and thalamus. The authors found 2 types of lesions: delayed death of selective neurons and large areas of necrosis, both accompanied by astrocytosis and microgliosis. At 54 days after DA exposure, the pathology was characterized by still-distinguishable dying neurons, calcified lesions in the thalamus, persistent astrocytosis, and pronounced microgliosis. The expression of nitric oxide synthases suggests a role for nitric oxide in the pathogenesis of neuronal degeneration and chronic inflammation induced by DA in the brain.

Effects of Enteromyxum scophthalmi experimental infection on the neuroendocrine system of turbot, Scophthalmus maximus (L.).

Enteromyxum scophthalmi is an intestinal myxosporean parasite responsible for serious outbreaks in turbot Scophthalmus maximus (L.) culture, in North-western Spain. The disease affects the digestive tract, provokes severe catarrhal enteritis, emaciation and high rates of mortality. The digestive parasitization triggers a response with the coordinate participation of immune and neuroendocrine systems through the action of peptides released by enteroendocrine cells and present in nervous elements, acting as neuro-immune modulators. The present study was designed to assess the response of the turbot neuroendocrine system against E. scophthalmi infection. Immunohistochemical tests were applied to sections of the gastrointestinal tract of uninfected and E. scophthalmi-infected turbot to characterize the presence of bombesin (BOM), glucagon (GLUC), somatostatin (SOM), leu-enkephalin (LEU) and met-enkephalin (MET). The occurrence of E. scophthalmi in the turbot gastrointestinal tract increased the number of enteroendocrine cells immunoreactive to SOM, LEU and MET. On the other hand, BOM and GLUC immunoreactive cells were less numerous in the gastrointestinal tract of the parasitized turbot. Scarce immunoreactivity to BOM, GLUC and SOM was observed in nerve fibres and neurons of the myenteric plexus of control and infected fish. The results indicate that E. scophthalmi infection in turbot induced changes in the neuroendocrine system, with the diminution of the anorexigenic peptides BOM and GLUC; the increase of enkephalins, related to pro-inflammatory processes; and the increase of SOM, which may cause inhibitory effects on the immune response, constituting a compensatory mechanism to the exacerbated response observed in E. scophthalmi-infected turbot.

Study of the distribution of active caspase-3-positive cells in turbot, Scophthalmus maximus (L.), enteromyxosis.

Enteromyxosis caused by Enteromyxum scophthalmi is one of the parasitizations with a higher economic impact on turbot, Scophthalmus maximus (L.), aquaculture. This myxosporean produces severe catarrhal enteritis with abundant inflammatory infiltrates in the lamina propria-submucosa (LP), epithelial detachment and leucocyte depletion of the lymphohaematopoietic organs. Some advances made on the pathogenesis pointed to a role of apoptosis in the enteromyxosis. Therefore, the main aim of this work was to employ the TUNEL assay and the anti-(active caspase-3) immunohistochemical assay to detect apoptotic cells in both healthy and E. scophthalmi-infected turbot in order to establish the presence and distribution of apoptotic cells during development of the disease. More apoptotic cells located within the gastrointestinal epithelium were observed in the initial stages of the infection in E. scophthalmi-infected turbot compared with non-infected turbot. As the infection progressed, a higher degree of apoptosis occurred in the epithelium of folds heavily parasitized. In the severely infected turbot, apoptosis was also found among the leucocytes of the intestinal inflammatory infiltrates. Moreover, the number of active caspase-3-positive cells in the lymphohaematopoietic organs tended to increase with disease severity. In view of the results, increased apoptosis in the epithelium may favour the scaling that occurs during enteromyxosis and cell death of leucocytes in the intestinal LP, contributing to leucocyte depletion in severe cases.

Immunohistochemical diagnosis of tenacibaculosis in paraffin-embedded tissues of Senegalese sole Solea senegalensis Kaup, 1858.

A sensitive and specific immunohistochemical technique was developed to improve the diagnosis of tenacibaculosis and to better understand its pathogenesis. Senegalese sole Solea senegalensis Kaup, 1858 were inoculated subcutaneously with a bacterial suspension of Tenacibaculum maritimum, and samples were taken at different hours post-inoculation. Sections from different organs were used as positive controls. In addition, a total of 128 field samples from different organs collected from tenacibaculosis outbreaks were used. Tenacibaculum maritimum antigens were detected in several organs of experimentally infected Senegalese sole and in at least one of the tissues from fish suffering from natural tenacibaculosis previously confirmed by culture and PCR-based methods. In fish collected during outbreaks, a strong positive reaction was detected in ulcerative skin areas. Moreover, bacterial antigen was identified inside scale pockets and in sites of the skin with mild lesion. In kidney and spleen, evident immunostaining of bacterial antigen was detected in both naturally and experimentally infected fish. Besides, the presence of T. maritimum in the intestinal tract without associated histological changes suggests that this organ may act as a reservoir for T. maritimum. The results of this study confirm the usefulness of IHC for the diagnosis of tenacibaculosis in paraffin-embedded tissues.

Quantitative and qualitative evaluation of iNOS expression in turbot (Psetta maxima) infected with Enteromyxum scophthalmi.

Enteromyxum scophthalmi is the causative agent of turbot enteromyxosis, an intestinal parasitisation that produces severe desquamative enteritis leading to a cachectic syndrome and eventually the death. It is well known the importance of the innate immune response against parasites in fish, with the release of antimicrobial substances such as reactive oxygen and nitrogen species, produced by the inducible nitric oxide synthase (iNOS). This enzyme is mainly found in phagocytes, but also in structural cells from the intestinal mucosa. The aim of this study was to characterize iNOS in intestine and lymphohaematopoietic organs (spleen and anterior kidney) of turbot by means of immunohistochemistry in order to assess the possible changes of this enzyme through the infection. The presence of the enzyme was evaluated in control and E. scophthalmi-infected turbot. The results showed immunoreactivity in the apical border of enterocytes and mild staining of goblet cells in both control and infected turbot although it was more evident and widespread in infected turbot compared to control. Moderate numbers of iNOS+ cells were present in the lamina propria-submucosa of fish which presented moderate and severe inflammatory infiltrates at this level. In spleen and kidney, iNOS+ cells were scattered through the parenchyma and, in severely infected fish, tended to be allocated near the vascular structures and melano-macrophage centres. The number of positive cells at the lymphohaematopoietic organs was significantly higher in infected turbot and increased as infection progressed. The increase in the expression of iNOS in the tissues of E. scophthalmi-infected turbot was more evident in individuals with severer lesions. The measurement of the levels of iNOS during turbot enteromyxosis reveals a possibly delayed response that would not able to eliminate the parasites but would exacerbate mucosal injury.

Morphopathological features of a severe ulcerative disease outbreak associated with Tenacibaculum maritimum in cultivated sole, Solea senegalensis (L.).

This study describes morphopathologic changes in naturally infected farmed Senegalese sole affected by tenacibaculosis caused by Tenacibaculum maritimum. Macroscopic observation, in addition to light microscopy and scanning electron microscopy, was used to study the lesions. Main lesions were characterized by complete loss of epidermis and dermis, as well as extensive necrosis of muscle layers. Mild-to-moderate inflammatory response with the presence of macrophages was noted around hyaline degenerated muscle cells. Gram-negative filamentous bacteria could be detected only at the dermis. Under scanning electron microscopy, filamentous bacteria located over the scales without epithelium could be observed. These findings together with the isolation and PCR detection of the bacteria in kidney and skin tissues suggest that once the bacteria reach the dermis, probably through eroded epidermis, they are able to proliferate and produce enzymes that are responsible for the damage in the underlying tissues.

First description of an olfactory neuroblastoma in goldfish Carassius auratus: a case report.

An external pinkish growing mass that emerged from the right nostril of an adult goldfish Carassius auratus L. was evaluated by means of light microscopy and immunohistochemistry. The neoplasm presented a well-developed fibrovascular stroma associated with solid cell nests and a large number of Flexner-Wintersteiner rosettes. Myelinated fibres were observed around them. Neoplastic cells showed a prominent degree of nuclear atypia and low mitotic activity. The latter was in agreement with the low reactivity of tumour cells to anti-proliferating cell nuclear antigen antibody. Immunohistochemistry also revealed anti-neuronal nitric oxide synthase, anti-S100 protein, antineuropeptide Y, and anti-cytokeratin immunoreactivity in tumour cells as well as in normal olfactory epithelium of goldfish control sections. Histopathological and immunohistochemical findings strongly suggest a diagnosis of an olfactory neuroblastoma (ONB). To our knowledge this is the first description of ONB in goldfish.

Mucosal CD3ε+ cell proliferation and gut epithelial apoptosis: implications in rainbow trout gastroenteritis (RTGE).

Rainbow trout gastroenteritis (RTGE) is an emerging disease that has acquired new relevance in European rainbow trout, Oncorhynchus mykiss (Walbaum), culture, because of the economic losses it causes. Disease aetiology and pathogenesis remain unclear. The lesions appear restricted to the gastrointestinal tract where extensive mucosal detachment associated with high numbers of segmented filamentous bacteria (SFB) can be detected. In this study, an RTGE outbreak in north-western Spain was investigated, and findings observed in diseased trout were compared with control fish. PAS stain and immunohistochemical assays with anti-CD3ε and anti-active caspase-3 antibodies were performed. The results showed that CD3ε+ inflammatory infiltrates were present in the intestine of diseased trout both in the lamina propria-submucosa and within the epithelium. Moreover, an increased number of caspase-3+ cells in the intestinal mucosa and also strong anti-caspase-3 immunoreactivity in desquamated cells in the gut lumen were observed. Changes in the number of goblet cells were also found, resulting in an increase or depletion of mucous cells depending on the severity of the intestinal lesions. These findings suggest that T cells and apoptosis play an important role in the development and pathogenesis of RTGE.

Effect of fat level on physicochemical and sensory properties of dry-cured duck sausages.

The effect of fat content (20, 30, and 40%) on chemical composition, color, texture parameters, and sensory properties of dry-cured duck sausages was studied. Protein content showed significant differences (P < 0.001) among batches (19.3, 22.1, and 27.5% for high, medium, and low fat, respectively). Fat level affected the lightness (P < 0.05), redness, and yellowness (P < 0.001) of dry-cured duck sausages. Shear force increased with decreased fat content (1.45, 2.37, and 3.81 kg/cm(2) for high, medium, and low fat, respectively). The sensory properties of fat level, cohesiveness, fat odor, hardness, and juiciness were significantly different with respect to fat level. Duck sausages with 20% fat content obtained higher scores for sensory traits compared with sausages of 30 and 40% fat content.

Physicochemical and nutritional composition of dry-cured duck breast.

A total of 80 dry-cured duck breasts were used in this study. The gross composition, color and textural parameters, fatty acid and amino acid profiles, macro- and micromineral content, and sensory properties were analyzed. In comparison with other dry-cured meat products made from cuts of whole meat, dry-cured duck breast is characterized by low moisture and a higher protein content. Saturated, monounsaturated, and polyunsaturated fatty acid contents in intramuscular fat were approximately 35, 57, and 8% of the total fatty acid methyl esters, respectively. The main essential amino acids present in dry-cured duck breast were lysine and leucine, followed by valine, threonine, and isoleucine, with aspartic and glutamic acids being the most important in the nonessential fraction. Dry-cured duck breast proved to be a valuable source of iron, zinc, copper, and manganese (7.57, 4.66, 0.84, and 0.87 mg/100 g of edible portion, respectively), providing approximately 57, 45.2, 93, and 43.7% of the recommended daily allowances, respectively.