Comparisons between antimicrobial pharmacodynamic indices and bacterial killing as described by using the Zhi model

Various suggestions have been made for empirical pharmacodynamic indices of antibiotic effectiveness, such as areas under the drug concentration-time curve in serum (AUC), AUC > MIC, AUC/MIC, area under the inhibitory curve (AUIC), AUC above MIC, and time above MIC (T > MIC). In addition, bacterial growth and killing models, such as the Zhi model, have been developed. The goal of the present study was to compare the empirical behavior of the Zhi model of bacterial growth and killing with the other empirical pharmacodynamic indices described above by using simulated clinical data analyzed with the USC*PACK PC clinical programs for adaptive control of drug therapy, with one model describing a concentration-dependent antibiotic (tobramycin) and another describing a concentration-independent antibiotic (ticarcillin). The computed relative number of CFU was plotted against each pharmacodynamic index, with each axis parameterized over time. We assumed that a good pharmacodynamic index should present a clear and continuous relationship between the time course of its values and the time course of the bacterial killing as seen with the Zhi model. Preliminary work showed that some pharmacodynamic indices were very similar. A good sensitivity to the change in the values of the MIC was shown for AUC/MIC and also for T > MIC. In addition, the time courses of some other pharmacodynamic indices were very similar. Since AUC/MIC is easily calculated and shows more sensitivity, it appeared to be the best of the indices mentioned above for the concentration-dependent drug, because it incorporated and used the MIC the best. T > MIC appeared to be the best index for a concentration-independent drug. We also propose a new composite index, weighted AUC (WAUC), which appears to be useful for both concentration-dependent and concentration-independent drugs.     

Double blind, randomised, placebo controlled study of oral vancomycin in prevention of necrotising enterocolitis in preterm, very low birthweight infants

AIMS: To evaluate the effectiveness of oral vancomycin in the prophylaxis of necrotising enterocolitis in preterm, very low birthweight infants. METHODS: A prospective, double blind, randomised, placebo controlled study in a tertiary referral centre of a university teaching hospital was conducted on 140 very low birthweight infants consecutively admitted to the neonatal unit. The babies were randomly allocated to receive oral vancomycin (15 mg/kg every 8 hours for 7 days) or an equivalent volume of placebo solution. Prophylaxis was started 24 hours before the start of oral feeds. All suspected cases of necrotising enterocolitis were investigated with a full sepsis screen and serial abdominal radiographs. Necrotising enterocolitis was diagnosed and staged according to modified Bell's criteria. RESULTS: Nine of 71 infants receiving oral vancomycin and 19 of 69 infants receiving the placebo solution developed necrotising enterocolitis (p = 0.035). Infants with necrotising enterocolitis were associated with a significant increase in mortality (p = 0.026) and longer duration of hospital stay (p = 0.002). CONCLUSIONS: Prophylactic oral vancomycin conferred protection against necrotising enterocolitis in preterm, very low birthweight infants and was associated with a 50% reduction in the incidence. However, widespread implementation of this preventive measure is not recommended, as it would only be effective in necrotising enterocolitis caused by Gram positive organisms and could increase the danger of the emergence of vancomycin resistant or dependent organisms. Its use should be restricted to a high prevalence nursery for a short and well defined period in a selected group of high risk patients.     

Mechanism of inhibition of tannic acid and related compounds on the growth of intestinal bacteria

Tannic acid, propyl gallate and methyl gallate, but not gallic acid, were found to be inhibitory to the growth of intestinal bacteria Bacteroides fragilis ATCC 25285, Clostridium clostridiiforme ATCC 25537, C. perfringens ATCC 13124, C. paraputrificum ATCC 25780, Escherichia coli ATCC 25922, Enterobacter cloacae ATCC 13047, Salmonella typhimurium TA98 and S. typhimurium YG1041 at 100-1000 microg/ml in culture broth. Neither Bifidobacterium infantis ATCC 15697 nor Lactobacillus acidophilus ATCC 4356 was inhibited by any of the above compounds up to 500 microg/ml. Tannic acid has a much greater relative binding efficiency to iron than propyl gallate, methyl gallate or gallic acid. The inhibitory effect of tannic acid to the growth of intestinal bacteria may be due to the strong iron binding capacity of tannic acid; whereas the effect of propyl gallate and methyl gallate probably occurs by a different mechanism. The growth of E. coli was restored by the addition of iron to the medium after the precipitate caused by tannic acid was removed. Neither B. infantis nor L. acidophilus require iron for growth. This probably contributes to their resistance to tannic acid. Because tannins are abundant in the human diet, tannins may affect the growth of some intestinal bacteria and thus may have an impact on human health.     

External and internal calibration of the MHC class I-specific receptor Ly49A on murine natural killer cells

Expression of the H-2Dd-specific inhibitory receptor Ly49A on murine NK cells is subject to MHC class I-dependent modulation in vivo. As a result, NK cells in H-2Dd-transgenic mice express low cell surface levels of Ly49A, whereas NK cells from nontransgenic C57BL/6 (B6) mice express high levels. The purpose of this study was to assess the role of MHC class I molecules on the NK cell itself vs those on surrounding cells in this calibration and to test whether the Ly49A levels are subject to regulation in mature NK cells also. Analysis of transgenic mice with mosaic expression of an H-2Dd/Ld transgene showed that MHC class I molecules on surrounding cells (external ligands) and on the NK cell itself (internal ligands) played distinct roles in the determination of Ly49A levels. External ligands were involved in down-regulation of Ly49A levels in vivo, whereas internal ligands kept the down-regulated levels of Ly49A low upon NK cell activation in vitro. Furthermore, in an experimental system based on adoptive transfer of spleen cells, receptor down-regulation of Ly49A occurred as a rapid adaptation process in mature NK cells after interaction with the H-2Dd ligand in vivo. This suggests that Ly49 levels are not fixed but can be changed in mature NK cells when they are exposed to a changed MHC class I environment.     

Treatment of Styrene-Contaminated Airstream in Biotrickling Filter Packed with Slags

This paper reports the result of studies using a biotrickling filter with blast-furnace slag packings (sizes = 2–4 cm and specific surface area = 120 m2∕m3) for treatment of styrene in an airstream. The effects of volumetric styrene loading L, superficial gas velocity U0 and liquid recirculation rate VL on the styrene elimination capacity K, and the removal efficiency K∕L were tested. Variations of styrene concentration with packing height as well as rates of nutrient utilization were also tested. The results show that for L< 30 g∕m3?h, K∕L was nearly independent of U0 in the range of 29–67 m∕h and was independent of VL in the range of 3.84–9.60 m∕h. In this range, the rate of styrene removal was both reaction and diffusion limited and the reaction was of zero-order kinetics. For higher loadings, K∕L decreased with increasing U0 and increased with increasing VL and the system approached the condition of reaction limitation.     

Determination of the epitope of an inhibitory antibody to proliferating cell nuclear antigen

We identified an expansion of the CAG trinucleotide repeat in the coding region of the Machado-Joseph disease gene in 7 of 24 American families diagnosed with autosomal dominant ataxia. All affected individuals were heterozygous for an expanded allele that ranged from 67 to more than 200 CAG repeats, whereas the normal allele had 14 to 33 repeats. In contrast to the Azorean-Portuguese origins of Machado-Joseph disease, the two largest American families were of German and Dutch-African descent. Clinical, pathologic, and genetic evaluations suggest that American families with spinocerebellar ataxia type 3 differ from those with Machado-Joseph disease by their ethnic origins, predominant spinopontine atrophy, lack of dystonic features, and larger CAG repeat expansion.     

The simplified two-pipette technique is more efficient than the conventional three-pipette method for blastomere biopsy in human embryos

Kell and Kx are two quantitatively minor proteins from the human erythrocyte membrane which carry blood groups antigens and are thought to be a metalloprotease and a membrane transporter, respectively. In the red cell membrane, these proteins form a complex stabilized by disulfide bond(s). Phosphorylation status of these proteins was studied, in the presence or absence of effectors of several kinases, either on intact cells incubated with [32P]-orthophosphate or on ghosts incubated with [gamma-32P]ATP. Purification of Kell-Kx complex, by immunochromatography on an immobilized human monoclonal antibody of Kell blood group specificity allowed to establish that (i) neither protein is phosphorylated on tyrosine; (ii) the Kell protein is a putative substrate for Casein Kinase II (CKII) and Casein Kinase I (CKI) but not for protein kinase C (PKC), whereas Kx protein is phosphorylated by CKII and PKC but not by CKI; (iii) Protein Kinase A neither phosphorylates the Kell nor the Kx proteins.     

An optimal instruction scheduler for superscalar processor

Performance in superscalar processing strongly depends on the compiler's ability to generate codes that can be executed by hardware in an optimal or near optimal order. Generating optimal code is an NP-complete problem. However, there is a need for highly optimized code, such as in superscalar or real-time systems. In this paper, an instruction scheduling scheme for optimizing a program trace is proposed. Optimized code can be arrived at without much redundant work, if some important features in code are well explored and utilized in scheduling. To formalize the task, two abstract models, one for a superscalar processor and the other for a program trace, are given. These two models reflect most of the characteristics of the scheduling problem. The interrelations between instructions and partial schedules are thoroughly studied, and dominance and equivalence relations on them are defined. These relations are then used to reduce the solution space and eventually help to produce optimal schedules. The results of experiments that show the promise of the proposed scheme are also presented