Bayesian analysis of quantitative antimicrobial assays

Quantitative antimicrobial assays are used to assess the efficacy of chemical germicides. Standard methods for statistical analysis use log reduction (LR), the difference on the log scale between average surviving microbes for control and test carriers, as an efficacy measure. These methods have several deficiencies. The LR parameter is not on the original response scale, which complicates its interpretation. The presence of two different definitions of LR makes the statistical inference even more difficult. Current statistical methods for antimicrobial assay analysis rely on asymptotic normal theory, which might not work well for small samples. In addition, they do not appropriately incorporate censored ('too numerous to be counted') observations in the analysis. To overcome those problems, a new Bayesian approach is introduced here. It has also the advantages of more flexible statistical inference, and incorporated prior information in the model.     

Economics of one-stage versus two-stage bilateral total knee arthroplasties

Patients requiring bilateral total knee arthroplasties may have both joints replaced simultaneously during one hospitalization (one-stage) or during two separate hospitalizations (two-stage). The goals of the current study were to retrospectively analyze discharge patterns for 91 patients who had one-stage bilateral total knee arthroplasties and 32 patients who had two-stage surgeries, and to quantify their in-hospital costs and their costs if the patients were discharged from the hospital to an inpatient unit. Patients having one-stage and two-stage surgery were similar in age, gender, severity of illness (as measured by the American Society of Anesthesiologists Physical Status score), principal diagnosis, and ethnicity. Using a microcosting approach, the authors found that the average in-hospital costs for one-stage total knee arthroplasty (27,468 US dollars) were significantly lower (by 24%) than for two-stage total knee arthroplasty. However, 38% of patients who had the one-stage bilateral total knee arthroplasties were admitted to an acute rehabilitation unit, which had a mean cost of 6469 US dollars and length of stay of 9 days. In contrast, none of the patients who had the two-stage procedure required acute rehabilitation. Patients who had the two-stage procedure were discharged directly home (or with home health services) 42% of the time, versus 21% for patients who had the one-stage procedure. Patients from both groups were discharged to a skilled nursing facility approximately (1/2) of the time, accruing similar costs. Economic analyses of the one-stage procedure need to consider that these patients will require increased use of acute inpatient rehabilitation after hospital discharge.     

Fatty metastatic lesions in 2 patients with renal clear-cell carcinoma

This is a case report of 2 patients with previously resected renal cell carcinoma who present with unusual fatty lesions that proved to be metastases.     

Neuronal overexpression of COX-2 results in dominant production of PGE2 and altered fever response

Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE(2) over other prostaglandins, followed by more modest inductions of PGI(2), and relatively smaller increases in PGF(2alpha),PGD(2), and TxB(2). We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1 2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response.     

Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer

Current epidemiological evidence supports a pathogenetic model of gastric cancer involving intermediate stages that include chronic gastritis and intestinal metaplasia. This study explores the molecular features of gastric cancer and premalignant stages using DNA microarray-based gene expression profiling and relates these findings to clinical, pathological, and ethnic parameters. A total of 124 tumor and adjacent mucosa samples were analyzed using spotted cDNA microarrays containing 9381 nonredundant gene elements. Tumor specimens were diffuse, intestinal, or mixed gastric cancer and adjacent mucosa, which generally displayed signs of chronic gastritis or intestinal metaplasia. Expression patterns could be discerned that readily defined premalignant and tumor subtypes. Chronic gastritis exhibits a pronounced mitochondrial gene expression signature, which may be linked to Helicobacter pylori pathogenesis. Intestinal metaplasia was associated with increased expression of many intestinal differentiation genes, many of which were not overexpressed in tumors. Samples were obtained from 91 Australian and 33 Chinese patients to explore potential variation in gene expression between these populations. Despite differences in the incidence, and potentially the etiology, of gastric cancer between these ethnic groups, we found the tumors to be molecularly similar. The identification of molecular signatures that are characteristic of subtypes of gastric cancer and associated premalignant changes should enable further analysis of the steps involved in the initiation and progression of this disease.     

First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling

The first cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor is reported. The inhibitor was obtained by rational modification of a high throughput screening lead with the aid of a S. pneumoniae FabH homology model. This homology model was used to design analogues that would have both high affinity for the enzyme and appropriate aqueous solubility to facilitate cocrystallization studies.     

Early onset of rejection in concordant hamster xeno hearts display signs of necrosis, but not apoptosis, correlating to the phosphocreatine concentration

BACKGROUND: The importance of apoptosis contra necrosis for ischemia/reperfusion (RP) and acute rejection in concordant rodent xenotransplantation is largely unknown. We explored this question by comparing rodent allo and concordant xenotransplants with different morphological methods to detect apoptosis and biochemical data on the levels of high-energy phosphates obtained with in vitro 31Phosphorous Magnetic Resonance Spectroscopy (31P MRS). More specifically, we applied a hitherto unused method in transplantation research, apoptosis specific biotin labeled oligonucleotides designed with a 10 base pair stem region and a 20 nucleotides large loop that form a hairpin like shape. The results obtained with this method were compared to results obtained with the more widely used in situ 3'-end labeling of DNA (TUNEL) assay and extraction and gel electrophoresis of labeled DNA (DNA laddering). METHODS: Cervical heart transplantations were performed between inbred Lewis (L) (RT1l) to L, L to DA (RT1a) rats, hamster (H) to H and H to L (X) (n=5 for all groups except for X, n=9). All hearts were subjected to 30 min of cold ischemia (+4 degrees C) and 6 h of RP before explantation. In vitro 31P MRS was used to determine the phosphocreatine (PCr), beta-adenosine triphosphate (beta-ATP) concentrations and the PCr/beta-ATP ratio of the transplants. We correlated the biochemical data to haematoxylin and eosin (H & E) stained tissue slides scored for rejection, infiltration of antibodies and complement depositions, DNA extraction and gel electrophoresis of labeled DNA (DNA laddering), in situ 3'-end labeling of DNA (TUNEL) and the apoptosis specific hairpin probe assays scoring. RESULTS: The rejection score of the xeno grafts differed significantly compared to their syngeneic hamster to hamster controls (2.40 +/- 0.25 vs. 1.20 +/- 0.20; P=0.005) and they had a significantly higher TUNEL score, 228 +/- 15 vs. 2.44 +/- 0.32 (P=0.009), that correlated to changes in PCr concentration (P<0.001) and to the PCr/beta-ATP ratio (P=0.01). The uptake was mainly (90-95%) located to 1-2 microm large extra cellular 'granule'. A picture resembling early necrosis was seen on the H & E stainings and reflected in the Billingham rejection score above. CONCLUSIONS: After 6 h of RP the onset of acute rejection in the concordant hamster xeno hearts displayed features of early, possibly mitochondrial, necrosis, but not apoptosis, which correlated to changes in the PCr concentration and the PCr/beta-ATP ratio. The mechanism for the early rejection observed is unclear and might be caused by other factors in the sera apart from cellular components, antibodies and complement factors. Identification of the underlying mechanisms could enable us to design rational therapies that prevent activation of the recipient's innate immune response.