Do distribution volumes and clearances relate to tissue volumes and blood flows? A computer simulation

BACKGROUND: Kinetics of inhaled agents are often described by physiological models. However, many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (F(A)) generated by the physiological uptake and distribution models used by the Gas Man(® )program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows. METHODS: Gas Man(® )was used to generate F(A )vs. time curves during the wash-in and wash-out period of 115 min each with a high fresh gas flow (8 L.min(-1)), a constant alveolar minute ventilation (4 L.min(-1)), and a constant inspired concentration (F(I)) of halothane (0.75%), isoflurane (1.15%), sevoflurane (2%), or desflurane (6%). With each of these F(I), simulations were ran for a 70 kg patient with 5 different cardiac outputs (CO) (2, 3, 5, 8 and 10 L.min(-1)) and for 5 patients with different weights (40, 55, 70, 85, and 100 kg) but the same CO (5 L.min(-1)). Two and three compartmental models were fitted to F(A )of the individual 9 runs using NONMEM. After testing for parsimony, goodness of fit was evaluated using median prediction error (MDPE) and median absolute prediction error (MDAPE). The model was tested prospectively for a virtual 62 kg patient with a cardiac output of 4.5 L.min(-1 )for three different durations (wash-in and wash-out period of 10, 60, and 180 min each) with an F(I )of 1.5% halothane, 1.5% isoflurane, sevoflurane 4%, or desflurane 12%. RESULTS: A three-compartment model fitted the data best (MDPE = 0% and MDAPE ≤ 0.074%) and performed equally well when tested prospectively (MDPE ≤ 0.51% and MDAPE ≤ 1.51%). The relationship between CO and body weight and the distribution volumes and clearances is complex. CONCLUSION: The kinetics of anesthetic gases can be adequately described e by a mammilary compartmental model. Therefore, concepts that are traditionally thought of as being applicable to the kinetics of intravenous agents can be equally well applied to anesthetic gases. Distribution volumes and clearances cannot be equated to tissue volumes and blood flows respectively

H5N1 Vaccine-Specific B Cell Responses in Ferrets Primed with Live Attenuated Seasonal Influenza Vaccines

Live attenuated influenza H5N1 vaccines have been produced and evaluated in mice and ferrets that were never exposed to influenza A virus infection (Suguitan et al., Plos Medicine, e360:1541, 2006). However, the preexisting influenza heterosubtypic immunity on live attenuated H5N1 vaccine induced immune response has not been evaluated.Primary and recall B cell responses to live attenuated H5N1 vaccine viruses were examined using a sensitive antigen-specific B cell ELISpot assay to investigate the effect of preexisting heterosubtypic influenza immunity on the development of H5N1-specific B cell immune responses in ferrets. Live attenuated H5N1 A/Hong Kong/213/03 and A/Vietnam/1203/04 vaccine viruses induced measurable H5-specific IgM and IgG secreting B cells after intranasal vaccination. However, H5-specific IgG secreting cells were detected significantly earlier and at a greater frequency after H5N1 inoculation in ferrets previously primed with trivalent live attenuated influenza (H1N1, H3N2 and B) vaccine. Priming studies further revealed that the more rapid B cell responses to H5 resulted from cross-reactive B cell immunity to the hemagglutinin H1 protein. Moreover, vaccination with the H1N1 vaccine virus was able to induce protective responses capable of limiting replication of the H5N1 vaccine virus to a level comparable with prior vaccination with the H5N1 vaccine virus without affecting H5N1 vaccine virus induced antibody response. vaccine and the heterosubtypic immunity may be beneficial for pandemic preparedness

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

Effects of Hepatocyte CD14 Upregulation during Cholestasis on Endotoxin Sensitivity

Cholestasis is frequently related to endotoxemia and inflammatory response. Our previous investigation revealed a significant increase in plasma endotoxin and CD14 levels during biliary atresia. We therefore propose that lipopolysacharides (LPS) may stimulate CD14 production in liver cells and promote the removal of endotoxins. The aims of this study are to test the hypothesis that CD14 is upregulated by LPS and investigate the pathophysiological role of CD14 production during cholestasis. Using Western blotting, qRT-PCR, and promoter activity assay, we demonstrated that LPS was associated with a significant increase in CD14 and MD2 protein and mRNA expression and CD14 promoter activity in C9 rat hepatocytes but not in the HSC-T6 hepatic stellate cell line in vitro. To correlate CD14 expression and endotoxin sensitivity, in vivo biliary LPS administration was performed on rats two weeks after they were subjected to bile duct ligation (BDL) or a sham operation. CD14 expression and endotoxin levels were found to significantly increase after LPS administration in BDL rats. These returned to basal levels after 24 h. In contrast, although endotoxin levels were increased in sham-operated rats given LPS, no increase in CD14 expression was observed. However, mortality within 24 h was more frequent in the BDL animals than in the sham-operated group. In conclusion, cholestasis and LPS stimulation were here found to upregulate hepatic CD14 expression, which may have led to increased endotoxin sensitivity and host proinflammatory reactions, causing organ failure and death in BDL rats

Experimental Meningococcal Sepsis in Congenic Transgenic Mice Expressing Human Transferrin

Severe meningococcal sepsis is still of high morbidity and mortality. Its management may be improved by an experimental model allowing better understanding of its pathophysiology. We developed an animal model of meningococcal sepsis in transgenic BALB/c mice expressing human transferrin. We studied experimental meningococcal sepsis in congenic transgenic BALB/c mice expressing human transferrin by transcriptional profiling using microarray analysis of blood and brain samples. Genes encoding acute phase proteins, chemokines and cytokines constituted the largest strongly regulated groups. Dynamic bioluminescence imaging further showed high blood bacterial loads that were further enhanced after a primary viral infection by influenza A virus. Moreover, IL-1 receptor–associated kinase–3 (IRAK-3) was induced in infected mice. IRAK-3 is a negative regulator of Toll-dependant signaling and its induction may impair innate immunity and hence result in an immunocompromised state allowing bacterial survival and systemic spread during sepsis. This new approach should enable detailed analysis of the pathophysiology of meningococcal sepsis and its relationships with flu infection

Macular thickness measurements in healthy Norwegian volunteers: an optical coherence tomography study

<p>Abstract</p> <p>Background</p> <p>Ethnic, intersubject, interoperator and intermachine differences in measured macular thickness seem to exist. Our purpose was to collect normative macular thickness data in Norwegians and to evaluate the association between macular thickness and age, gender, parity, and contraception status.</p> <p>Methods</p> <p>Retinal thickness was measured by Stratus Optical Coherence Tomography in healthy subjects. Mean macular thickness (MMT) was analyzed by repeated measures ANOVA with three dependent regional MMT-variables for interaction with age, gender, parity and oral contraception use. Exploratory correlation with age by the Pearson correlation test, both before and after stratification by gender was performed. Differences in MMT between older and younger subjects, between oral contraception users and non-users, as well as parous and nulliparous women were studied by post-hoc Student's t-tests.</p> <p>Results</p> <p>Central MMT in Norwegians was similar to values earlier reported in whites. MMT in central areas of 1 and 2.25 mm in diameter were higher in males than in females. In younger subjects (≤43 years) differences in MMT between genders were larger than in the mixed age group, whereas in older subjects (>43 years) the small differences did not reach the set significance level. No differences were found in minimal foveolar thickness (MMFT) between the genders in any age group.</p> <p>Mean foveal thickness (1 mm in diameter) was positively associated with age in females (r = 0.28, p = 0.03). MMFT was positively associated with age in all groups and reached significance both in females and in mixed gender group (r = 0.20, p = 0.041 and r = 0.26, p = 0.044 respectively).</p> <p>Mean foveal thickness and MMFT were significantly higher in parous than in nulliparous women, and age-adjusted ANOVA for MMFT revealed a borderline effect of parity.</p> <p>Conclusions</p> <p>Age and gender should be taken into consideration when establishing normal ranges for MMT in younger subjects. The gender difference in retinal thickness in young, but not older adults suggests a gonadal hormonal influence. The possible association between parity and retinal structure and its clinical relevance, should be studied further.</p

Atorvastatin Improves Survival in Septic Rats: Effect on Tissue Inflammatory Pathway and on Insulin Signaling

The aim of the present study was to investigate whether the survival-improving effect of atorvastatin in sepsis is accompanied by a reduction in tissue activation of inflammatory pathways and, in parallel, an improvement in tissue insulin signaling in rats. Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Serum glucose and inflammatory cytokines levels were assessed 24 h after CLP. The effect of atorvastatin on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle and adipose tissue. Atorvastatin improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity, characterized by an increase in glucose disappearance rate during the insulin tolerance test. Sepsis induced an increase in the expression/activation of TLR4 and its downstream signaling JNK and IKK/NF-κB activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin reversed all these alterations in parallel with a decrease in circulating levels of TNF-α and IL-6. In summary, this study demonstrates that atorvastatin treatment increased survival, with a significant effect upon insulin sensitivity, improving insulin signaling in peripheral tissues of rats during peritoneal-induced sepsis. The effect of atorvastatin on the suppression of the TLR-dependent inflammatory pathway may play a central role in regulation of insulin signaling and survival in sepsis insult

Value of hospital antimicrobial stewardship programs [ASPs]:a systematic review

Abstract Background Hospital antimicrobial stewardship programs (ASPs) aim to promote judicious use of antimicrobials to combat antimicrobial resistance. For ASPs to be developed, adopted, and implemented, an economic value assessment is essential. Few studies demonstrate the cost-effectiveness of ASPs. This systematic review aimed to evaluate the economic and clinical impact of ASPs. Methods An update to the Dik et al. systematic review (2000–2014) was conducted on EMBASE and Medline using PRISMA guidelines. The updated search was limited to primary research studies in English (30 September 2014–31 December 2017) that evaluated patient and/or economic outcomes after implementation of hospital ASPs including length of stay (LOS), antimicrobial use, and total (including operational and implementation) costs. Results One hundred forty-six studies meeting inclusion criteria were included. The majority of these studies were conducted within the last 5 years in North America (49%), Europe (25%), and Asia (14%), with few studies conducted in Africa (3%), South America (3%), and Australia (3%). Most studies were conducted in hospitals with 500–1000 beds and evaluated LOS and change in antibiotic expenditure, the majority of which showed a decrease in LOS (85%) and antibiotic expenditure (92%). The mean cost-savings varied by hospital size and region after implementation of ASPs. Average cost savings in US studies were $732 per patient (range:$2.50 to $2640), with similar trends exhibited in European studies. The key driver of cost savings was from reduction in LOS. Savings were higher among hospitals with comprehensive ASPs which included therapy review and antibiotic restrictions. Conclusions Our data indicates that hospital ASPs have significant value with beneficial clinical and economic impacts. More robust published data is required in terms of implementation, LOS, and overall costs so that decision-makers can make a stronger case for investing in ASPs, considering competing priorities. Such data on ASPs in lower- and middle-income countries is limited and requires urgent attention