Thrombolytic therapy for treatment of pulmonary embolism in the postoperative period: Case report and review of the literature

A patient with morbid obesity and insulin-dependent diabetes was admitted to the surgical intensive care unit, four days status postsurgical repair of an umbilical hernia. A pulmonary embolus (PE) was diagnosed by ventilation/perfusion scan and confirmed by transthoracic echocardiogram. A right ventricular ejection fraction/volumetric/oximetry pulmonary artery catheter revealed a very low ejection fraction and cardiac index. Systemic urokinase therapy was initiated and the patient improved considerably over the ensuing 12 hours. Anesthesiologists must be able to diagnose the signs and symptoms of PE and should be familiar with treatment modalities to reverse right ventricular dysfunction. Review of the literature regarding thrombolytic therapy in the perioperative period indicates potential benefit in select patients.     

Identification of monoclonal antibodies capable of differentiating antigenic varieties of eastern equine encephalitis viruses

We have isolated and characterized 3 monoclonal antibody (Mab) reagents useful in the serological identification of varieties of eastern equine encephalitis (EEE) viruses. These antibodies were specific for the E1 glycoprotein of their homologous viruses. One Mab, 1B5C-3, reacted specifically with all North American (NA) EEE viruses isolated over a 50 year period. This antigenic stability of NA isolates was genetically confirmed by oligonucleotide fingerprinting. Evolutionary stability is a unique feature among alphaviruses. The Mab, 1C1J-4 reacted specifically with 1 South American isolate of EEE virus. A third Mab, 1B1C-4, was EEE virus complex reactive. While none of these antibodies had virus neutralizing activity, the identified reactivities could be demonstrated in the more rapid serological tests of enzyme-linked immunosorbent assay and indirect immunofluorescence.     

Auditing the Representation of Female Versus Male Athletes in Sports Science and Sports Medicine Research: Evidence-Based Performance Supplements

Although sports nutrition guidelines promote evidence-based practice, it is unclear whether women have been adequately included in the underpinning research. In view of the high usage rates of performance supplements by female athletes, we conducted a standardised audit of the literature supporting evidence-based products: β-alanine, caffeine, creatine, glycerol, nitrate/beetroot juice and sodium bicarbonate. Within 1826 studies totalling 34,889 participants, just 23% of participants were women, although 34% of studies included at least one woman. Across different supplements, 0–8% of studies investigated women exclusively, while fewer (0–2%) were specifically designed to compare sex-based responses. The annual publication of female-specific studies was ~8 times fewer than those investigating exclusively male cohorts. Interestingly, 15% of the female participants were classified as international/world-class athletes, compared with 7% of men. Most studies investigated performance outcomes but displayed poorer representation of women (16% of participants), whereas health-focussed studies had the greatest proportion of female participants (35%). Only 14% of studies including women attempted to define menstrual status, with only three studies (~0.5%) implementing best practice methodologies to assess menstrual status. New research should target the efficacy of performance supplements in female athletes, and future sports nutrition recommendations should specifically consider how well female athletes have contributed to the evidence-base.     

Riding with the sharks: Serious leisure cyclist's perceptions of sharing the road with motorists

As serious leisure cyclists increase their presence on Australian public roads, there have been reports within the popular and mainstream literature of a growing tension between these cyclists and other road users. Until now, there has been limited research exploring the relationship between serious leisure cyclists and other road users as it pertains to issues of safety and motivations to cycle for leisure. This mixed methods research provides insights into a particular cohort of serious leisure cyclists and their experiences of sharing the roads with motorists. Analysis reveals a range of concerns amongst this sub-group, mediated by factors such as age, experience and environment. The paper calls for a differential focus on sub-groups of cyclists when considering policy formation, regulation and safe provision for cyclists on roads.     

Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15A1)-targeted prodrug (1S,2S,5R,6S)-2-[(2'S)-(2-amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid (LY544344) in rats and dogs: assessment of first-pass bioactivation and dose linearity.

The peptidyl prodrug (1S,2S,5R,6S)-2-[(2'S)-(2-Amino)propionyl]a-minobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid, also known as LY544344, was discovered to improve the oral bioavailability of the parent drug (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a potent group II metabotropic glutamate receptor agonist. This prodrug has been shown to deliver high plasma concentrations of the active drug via intestinal peptide transporter 1 (SLC15A1) (PepT1)-mediated intestinal transport and presystemic hydrolysis in preclinical species. The current data describe the pharmacokinetic behavior of LY544344 and LY354740, with a specific focus on the first-pass activation processes and dose linearity in rats and dogs. The PepT1 transporter makes an attractive prodrug target because of its high capacity and relatively broad substrate specificity. This was demonstrated by the wide dose proportionality observed in both species (up to 1000 mg/kg in rats and 140 mg/kg in dogs). After oral administration of LY544344, absorption and bioactivation were extensive and rapid, with greater than 97% of prodrug hydrolysis occurring before its appearance in the hepatic portal vein. Systemic activation was likewise extensive, with 100% conversion of a 7-mg/kg intravenous dose in dogs. Radiolabeled studies confirmed that hydrolysis to LY354740 was the only metabolic pathway and that the excretion pattern of the active drug was not altered by administration of the prodrug. These results demonstrate the nearly ideal prodrug properties of LY544344 and further validate the utility of the peptide transporter-directed approach to prodrug design.     

Computational and experimental analyses of mammalian arylamine N-acetyltransferase structure and function.

Arylamine N-acetyltransferases (NATs) play an important role in the metabolism of arylamine and hydrazine drugs and many arylamine procarcinogens. The two human N-acetyltransferases, NAT1 and NAT2, are widely distributed in human tissues and are highly polymorphic. Although many xenobiotic procarcinogens and drugs are known mammalian NAT substrates, it is unclear what physiological roles these enzymes might play, what endogenous substrates they primarily act upon, or the mechanisms underlying the functional effects of specific NAT gene coding region single-nucleotide polymorphisms. Analyses of mammalian NAT protein structures can greatly help to answer these questions. Homology modeling techniques can be used to approximate mammalian NAT structures using known bacterial NAT crystal structures as templates. In comparison to the bacterial template NATs used for homology modeling, mammalian NATs have a 17-residue insert of unknown structure and function. Homology modeling analyses yielded two different alignments (Modeler 8v1 or 3DCoffee algorithms) that placed this insert in two likely alternative locations. Secondary structure prediction techniques and experimental analyses of a series of human NAT2 mutants with artificial deletions/replacements of the insert region distinguished one of these alternatives as the most likely insert location and provided a better understanding of its structure and function. This study demonstrates both the utility and limitations of computational structural modeling with proteins that differ as much as the mammalian and bacterial NATs.     

Two-generation reproductive toxicity evaluation of dietary 17beta-estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) mice.

No information exists on reproductive/developmental effects in mice exposed to dietary 17beta-estradiol (E2) over multiple generations. Therefore, under OECD Test Guideline 416 with enhancements, CD-1 mice (F0 generation, 25 mice/sex/group) were exposed to dietary E2 at 0, 0.001, 0.005, 0.05, 0.15, or 0.5 ppm ( approximately 0, 0.2, 1, 10, 30, or 100 mug E2/kg body weight/day) for 8 weeks prebreed, 2 weeks mating, approximately 3 weeks gestation, and 3 weeks lactation. At weaning, selected F1 offspring (F1 parents; 25/sex/group) and extra retained F1 males (one per litter) were exposed to the same dietary concentrations and durations as the F0 generation; study termination occurred at F2 weaning; F1/F2 weanlings (up to three per sex per litter) were necropsied with organs weighed. At 0.5 ppm, effects were increased F1/F2 perinatal loss, prolonged F0/F1 gestational length, reduced numbers of F2 (but not F1) litters/group, reduced F1/F2 litter sizes, accelerated vaginal patency (VP) and delayed preputial separation (PPS), increased uterus + cervix + vagina weights (UCVW) in F0/F1 adults and F1/F2 weanlings, and decreased testes and epididymides weights (TEW) in F1/F2 weanlings. At 0.15 ppm, effects were increased UCVW in F0/F1 adults and F1/F2 weanlings, accelerated VP, delayed PPS, and reduced TEW in F1/F2 weanlings. At 0.05 ppm, UCVW were increased in F1/F2 weanlings, and PPS was delayed only in extra retained F1 males. There were no biologically significant or treatment-related effects on F0/F1 parental body weights, feed consumption, or clinical observations, or on F0/F1 estrous cyclicity, F0/F1 andrology, or F1/F2 anogenital distance at any dose. The no observable effect level was 0.005 ppm E2 ( approximately 1 mug/kg/day). Therefore, the mouse model is sensitive to E2 by oral administration, with effects on reproductive development at doses of 10- 100 mug/kg/day.     

The genetics of cutaneous melanoma

Although germline mutations in CDKN2A are present in approximately 25% of large multicase melanoma families, germline mutations are much rarer in the smaller melanoma families that make up most individuals reporting a family history of this disease. In addition, only three families worldwide have been reported with germline mutations in a gene other than CDKN2A (i.e., CDK4). Accordingly, current genomewide scans underway at the National Human Genome Research Institute hope to reveal linkage to one or more chromosomal regions, and ultimately lead to the identification of novel genes involved in melanoma predisposition. Both CDKN2A and PTEN have been identified as genes involved in sporadic melanoma development; however, mutations are more common in cell lines than uncultured tumors. A combination of cytogenetic, molecular, and functional studies suggests that additional genes involved in melanoma development are located to chromosomal regions 1p, 6q, 7p, 11q, and possibly also 9p and 10q. With the near completion of the human genome sequencing effort, combined with the advent of high throughput mutation analyses and new techniques including cDNA and tissue microarrays, the identification and characterization of additional genes involved in melanoma pathogenesis seem likely in the near future.