Evaluation of the RIDA(®)QUICK immunochromatographic norovirus detection assay using specimens from Australian gastroenteritis incidents

A range of laboratory methods is now available for the detection of norovirus, a major cause of gastroenteritis. Recently, a commercial immunochromatographic assay for norovirus detection, the RIDA^®QUICK assay, has become available, but there is still only limited information on its efficacy. This study examined the sensitivity and specificity of the RIDA^®QUICK assay, using faecal material received for testing in a major diagnostic/reference laboratory in Australia. The sensitivity of the assay was found to be 83% and the specificity was 100%. No false positive norovirus results were found and the assay did not cross-react with common faecal viruses such as rotavirus, astrovirus, sapovirus and adenovirus. The assay was less reliable for genogroup I (GI) noroviruses than for genogroup II (GII) noroviruses. Genotypes detected by the assay included GII.1, GII.2, GII.3, GII.4, GII.6 and GII.7. The assay failed to detect any GI specimens in the test group. Genotypes not detected included GI.4 and GI.6. The assay was simple and quick to perform. It is valuable in a point-of-care situation or as a backup in a laboratory where a rapid initial norovirus result is required.     

Clustering of metabolic abnormalities among obese patients and mortality after percutaneous coronary intervention

Although current literature demonstrates metabolic abnormalities are associated with mortality, obese patients who tend to have more metabolic abnormalities paradoxically have lower overall mortality rates compared to their normal-weight counterparts. In this study, we examined the prevalence of metabolic abnormality clustering and its relation to mortality in obese and normal-weight patients after percutaneous coronary intervention (PCI). Patients (n = 9,673) undergoing elective PCI from October 2003 through December 2006 at a single urban hospital were categorized by body mass index (BMI) levels of 18.5 to 24.9, 25.0 to 29.9, 30.0 to 34.9, and ≥35 kg/m(2) and by number of metabolic abnormalities possessed (hypertension, impaired fasting glucose/diabetes, triglycerides ≥150 mg/dl, high-density lipoprotein cholesterol < 40 mg/dl, and C-reactive protein ≥2.0 mg/L). All-cause mortality was assessed through June 30, 2007. Mean age of patients was 65.9 years and 66% were men. Prevalences of 4 or 5 metabolic abnormalities were 12%, 18%, 24%, and 31% in patients with BMI levels of 18.5 to 24.9, 25.0 to 29.9, 30 to 34.9, and ≥35 kg/m(2), respectively. In patients with BMI of 30.0 to 34.9 kg/m(2), hazard ratios (95% confidence intervals) for mortality associated with 2, 3, and 4 to 5 metabolic abnormalities versus 0 to 1 metabolic abnormality were 1.31 (0.79 to 2.17), 1.42 (0.83 to 2.43), and 2.39 (1.24 to 4.59), respectively. Analogous hazard ratios for patients with BMI ≥35 kg/m(2) were 1.94 (0.90 to 4.20), 1.44 (0.63 to 3.28), and 2.17 (0.91 to 5.18). All-cause mortality rates per 1,000 person-years were 55.5, 33.7, 28.3, and 33.8 in patients with BMI levels of 18.5 to 24.9, 25 to 29.9, 30 to 34.9, and ≥35 kg/m(2), respectively. In conclusion, BMI levels of 25.0 to 29.9 and 30 to 34.9 kg/m(2) were associated with lower all-cause mortality after PCI. However, an increased number of metabolic abnormalities translated into increased all-cause mortality.     

Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo

We report the analysis of CPI-613, the first member of a large set of analogs of lipoic acid (lipoate) we have investigated as potential anticancer agents. CPI-613 strongly disrupts mitochondrial metabolism, with selectivity for tumor cells in culture. This mitochondrial disruption includes activation of the well-characterized, lipoate-responsive regulatory phosphorylation of the E1?? pyruvate dehydrogenase (PDH) subunit. This phosphorylation inactivates flux of glycolysis-derived carbon through this enzyme complex and implicates the PDH regulatory kinases (PDKs) as a possible drug target. Supporting this hypothesis, RNAi knockdown of the PDK protein levels substantially attenuates CPI-613 cancer cell killing. In both cell culture and in vivo tumor environments, the observed strong mitochondrial metabolic disruption is expected to significantly compromise cell survival. Consistent with this prediction, CPI-613 disruption of tumor mitochondrial metabolism is followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines. Further, CPI-613 shows strong antitumor activity in vivo against human non-small cell lung and pancreatic cancers in xenograft models with low side-effect toxicity.     

Pilot study: alleviation of pain in burning mouth syndrome with topical sucralose

Burning mouth syndrome affects 1-3% of the population The exact mechanism is unknown. Bartoshuk has demonstrated sweet hypogeusia in those with burning mouth syndrome. Intensification of sweet taste may compensate for this deficit and reduce the pain.     

Aminoindoles, a novel scaffold with potent activity against Plasmodium falciparum

This study characterizes aminoindole molecules that are analogs of Genz-644442. Genz-644442 was identified as a hit in a screen of ∼70,000 compounds in the Broad Institute''s small-molecule library and the ICCB-L compound collection at Harvard Medical School. Genz-644442 is a potent inhibitor of Plasmodium falciparum in vitro (50% inhibitory concentrations [IC₅₀s], 200 to 285 nM) and inhibits P. berghei in vivo with an efficacy of >99% in an adapted version of Peters'' 4-day suppressive test (W. Peters, Ann. Trop. Med. Parasitol. 69:155–171, 1975). Genz-644442 became the focus of medicinal chemistry optimization; 321 analogs were synthesized and were tested for in vitro potency against P. falciparum and for in vitro absorption, distribution, metabolism, and excretion (ADME) properties. This yielded compounds with IC₅₀s of approximately 30 nM. The lead compound, Genz-668764, has been characterized in more detail. It is a single enantiomer with IC₅₀s of 28 to 65 nM against P. falciparum in vitro. In the 4-day P. berghei model, when it was dosed at 100 mg/kg of body weight/day, no parasites were detected on day 4 postinfection. However, parasites recrudesced by day 9. Dosing at 200 mg/kg/day twice a day resulted in cures of 3/5 animals. The compound had comparable activity against P. falciparum blood stages in a human-engrafted NOD-scid mouse model. Genz-668764 had a terminal half-life of 2.8 h and plasma trough levels of 41 ng/ml when it was dosed twice a day orally at 55 mg/kg/day. Seven-day rat safety studies showed a no-observable-adverse-effect level (NOAEL) at 200 mg/kg/day; the compound was not mutagenic in Ames tests, did not inhibit the hERG channel, and did not have potent activity against a broad panel of receptors and enzymes. Employing allometric scaling and using in vitro ADME data, the predicted human minimum efficacious dose of Genz-668764 in a 3-day once-daily dosing regimen was 421 mg/day/70 kg, which would maintain plasma trough levels above the IC₉₀ against P. falciparum for at least 96 h after the last dose. The predicted human therapeutic index was approximately 3, on the basis of the exposure in rats at the NOAEL. We were unable to select for parasites with >2-fold decreased sensitivity to the parent compound, Genz-644442, over 270 days of in vitro culture under drug pressure. These characteristics make Genz-668764 a good candidate for preclinical development.     

Extracorporeal life support systems: alternative vs. conventional circuits

Emerging technologies and practices for pediatric and neonatal extracorporeal life support (ECLS) are promising. This experiment sought to compare the Medtronic 0800 silicon rubber membrane oxygenator to the Quadrox-iD Pediatric oxygenator in the conventional roller pump circuit, as well as comparing the conventional circuit to an alternative circuit. Three circuits were set up in the experiment. Two conventional roller pump circuits were used to compare the two oxygenators and an alternative circuit consisting of the Quadrox-iD Pediatric oxygenator and Maquet Rotaflow centrifugal pump system was used to identify differences between circuits. All three circuits were primed with Lactated Ringers' solution and human blood, with an hematocrit of 40%. Testing occurred at flow rates of 250, 500, and 750 ml/ min at 37°C for mean arterial line pressures of 60, 80, and 100 mmHg. The results of the experiment showed lower pressure drops and greater retention of total hemodynamic energy (THE) across the Quadrox-iD Pediatric oxygenator compared to the Medtronic 0800 oxygenator. Furthermore, the centrifugal pump used in the alternative circuit showed no back flow at flow rates as low as 250 ml/min while, on the other hand, rpm levels were kept below 2200 for flow rates as high as 750 ml/min. Findings support the usage of the Quadrox-iD Pediatric oxygenator in a circuit utilizing the Maquet Rotaflow centrifugal pump system due to lower pressure drops and greater percentage of THE retained across the circuit. Additional advantages of the alternative circuit include rapid set-up time, easy transport, lower priming volumes, and no gravity-dependent venous drainage system so that it can be situated in close proximity to and at the level of the patient.