Analysis of procedure-related costs and proposed benefits of using patient-specific approach in total knee arthroplasty

Recently, patient-specific approaches to total knee arthroplasty (TKA) have been introduced that utilize preoperative magnetic resonance imaging data to manufacture custom cutting jigs specific to a patient's bony anatomy. These approaches intend to provide the benefits of accurate implant alignment while overcoming some of the proposed disadvantages of current computer navigation systems. In this study, a cost and benefit assessment of implementing the patient-specific approach compared to conventional and computer-navigated TKA was conducted at a large academic medical center. Fixed and time-dependent operating room (OR) costs were determined and compared, as well as the cost for processing operative equipment and additional procedure-related expenditures. Overall, patient-specific TKA was not cost saving in this model on a per-case basis compared to conventional methods, although it was less costly overall to the institution compared to implementing intraoperative navigation. However, the patient-specific approach provides the institution with an additional 28 minutes of available OR time per intervention based on reduction in preparation and operative times compared to conventional methods and an additional 67 minutes compared to computer navigation based on this model. This time savings is likely to provide a greater economic impact to the health care system than implant-related cost savings.     

Mitochondrial oxygen tension within the heart

By using a newly developed optical technique which enables non-invasive measurement of mitochondrial oxygenation (mitoPO₂) in the intact heart, we addressed three long-standing oxygenation questions in cardiac physiology: 1) what is mitoPO₂ within the in vivo heart?, 2) is mitoPO₂ heterogeneously distributed?, and 3) how does mitoPO₂ of the isolated Langendorff-perfused heart compare with that in the in vivo working heart? Following calibration and validation studies of the optical technique in isolated cardiomyocytes, mitochondria and intact hearts, we show that in the in vivo condition mean mitoPO₂ was 35 ± 5 mm Hg. The mitoPO₂ was highly heterogeneous, with the largest fraction (26%) of mitochondria having a mitoPO₂ between 10 and 20 mm Hg, and 10% between 0 and 10 mm Hg. Hypoxic ventilation (10% oxygen) increased the fraction of mitochondria in the 0–10 mm Hg range to 45%, whereas hyperoxic ventilation (100% oxygen) had no major effect on mitoPO₂. For Langendorff-perfused rat hearts, mean mitoPO₂ was 29 ± 5 mm Hg with the largest fraction of mitochondria (30%) having a mitoPO₂ between 0 and 10 mm Hg. Only in the maximally vasodilated condition, did the isolated heart compare with the in vivo heart (11% of mitochondria between 0 and 10 mm Hg). These data indicate 1) that the mean oxygen tension at the level of the mitochondria within the heart in vivo is higher than generally considered, 2) that mitoPO₂ is considerably heterogeneous, and 3) that mitoPO₂ of the classic buffer-perfused Langendorff heart is shifted to lower values as compared to the in vivo heart.     

The rapid hydrolysis of chlordiazepoxide to demoxepam may affect the outcome of chronic osmotic minipump studies

Background

In chronic studies, the classical benzodiazepine chlordiazepoxide (CDP) is often the preferred drug because, unlike other benzodiazepines, it is soluble in water. However, rapid CDP hydrolysis in solution has been described. This would diminish plasma levels in chronic minipump studies and introduce the corelease of active compounds.

Methods

Therefore, the present study aimed to explore the putative hydrolysis of CDP in aqueous solution over time and to identify the hydrolysis products. Moreover, we aimed to characterize the hydrolysis products for their in vitro (³H-flunitrazepam binding and oocyte electrophysiology) and in vivo (stress-induced hyperthermia paradigm) GABA_A receptor potency.

Results

CDP in solution hydrolyzed to the ketone structure demoxepam which was confirmed using mass spectrometry. The hydrolysis was concentration dependent (first-order kinetics) and temperature dependent. CDP exerted greater potency compared to demoxepam in vitro (increased activity at GABA_A receptors containing α₁ subunits) and in vivo (stress-induced hyperthermia), although ³H-flunitrazepam binding was comparable.

Conclusions

The classical benzodiazepine CDP is rapidly hydrolyzed in solution to the active compound demoxepam which possesses a reduced activity at the GABA_A receptor. Chronic studies that use CDP in aqueous solution should thus be interpreted with caution. It is therefore important to consider drug stability in chronic minipump applications.     

Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs

OBJECTIVES: A volunteer trial was performed to compare the pharmacokinetics of 5 drugs--warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin--when administered at a microdose or pharmacologic dose. Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was or is likely to be problematic. METHODS: In a crossover design volunteers received (1) 1 of the 5 compounds as a microdose labeled with radioactive carbon (carbon 14) (100 microg), (2) the corresponding (14)C-labeled therapeutic dose on a separate occasion, and (3) simultaneous administration of an intravenous (14)C-labeled microdose and an oral therapeutic dose for ZK253, midazolam, and erythromycin. Analysis of (14)C-labeled drugs in plasma was done by use of HPLC followed by accelerator mass spectrometry. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of ZK253, midazolam, and erythromycin at therapeutic concentrations, whereas HPLC-accelerator mass spectrometry was used to measure warfarin and diazepam concentrations. RESULTS: Good concordance between microdose and therapeutic dose pharmacokinetics was observed for diazepam (half-life [t((1/2))] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 microg and t((1/2)) of 35.7 hours, CL of 1.3 L/h, and V of 123 L for 10 mg), midazolam (t((1/2)) of 4.87 hours, CL of 21.2 L/h, V of 145 L, and oral bioavailability [F] of 0.23 for 100 microg and t((1/2)) of 3.31 hours, CL of 20.4 L/h, V of 75 L, and F of 0.22 for 7.5 mg), and development compound ZK253 (F = <1% for both 100 microg and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 microg and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 microg and 17.9 L for 5 mg) was probably a result of high-affinity, low-capacity tissue binding. The oral microdose of erythromycin failed to provide detectable plasma levels as a result of possible acid lability in the stomach. Absolute bioavailability for the 3 compounds examined yielded excellent concordance with data from the literature or data generated in house. CONCLUSION: Overall, when used appropriately, microdosing offers the potential to aid in early drug candidate selection.     

The role of platelets during reproduction

The availability of mice with defined defects within the hemostatic system enabled researchers to identify a role the coagulation system for embryonic and placental development. However, the role of platelets during development has only recently been experimentally addressed, giving some insight into potential functions of platelets during development. Thus, a quantitative embryonic platelet defect (severe thrombopenia secondary to NF-E2 deficiency) is associated with an embryonic growth retardation and reduced vascularisation of the placenta. Maternal platelet deficiency is associated with placental hemorrhage, which, however, does not impair embryonic or maternal survival. In vitro studies established that platelets or platelet conditioned medium regulate the invasive properties of human extravillous trophoblast cells and induce a phenotypical switch of trophoblast cells. These data imply that platelets are of relevance during placentation. Conversely, platelets and the formation of platelet-fibrin aggregates are dispensable for the development of the embryo proper, establishing that the lethal phenotypes observed in some embryo slacking coagulation regulators does not result from an inability to form platelet-fibrin aggregates, but likely reflects altered protease dependent signaling during vascular development.     

Serotonin and the neurobiology of the ejaculatory threshold

Disorders of the ejaculatory threshold, such as lifelong premature ejaculation, are fairly common in humans and can have a great impact on the quality of life. Research in humans and rats have indicated that increased serotonin levels in the central nervous system elevate the ejaculatory threshold, probably via 5-HT(1B) and 5-HT(2C) receptors, whereas depletion of serotonin decreases the ejaculatory threshold. 5-HT(1A) receptor activation strongly lowers the ejaculatory threshold, probably mediated by both the reduction of serotonin levels via presynaptic 5-HT(1A) receptors and yet unknown effects of postsynaptic 5-HT(1A) receptors. The present review attempts to integrate psychopharmacological data on serotonergic control over ejaculation with the knowledge of the neuroanatomical substrate of ejaculation, indicating the importance of the lumbosacral spinal cord, the nucleus paragigantocellularis, the lateral hypothalamic area and several other supraspinal areas. In addition, the gaps in our understanding of the role of serotonin in the ejaculatory threshold are discussed. Filling in those gaps might help to design specific drugs that alter the ejaculatory threshold, thereby alleviating ejaculatory disorders.     

Measurement of alcohol hangover severity: development of the Alcohol Hangover Severity Scale (AHSS)

Objective

This study aims to develop a new alcohol hangover symptom severity scale and compare its effectiveness with the Hangover Symptoms Scale (HSS), the Acute Hangover Scale (AHS), and a one-item hangover score.

Methods

Data from 1,410 Dutch students (Penning et al., Alcohol Alcohol 47:248-252, 2012) on the severity of 47 hangover symptoms were re-analyzed to develop the Alcohol Hangover Severity Scale (AHSS). The psychometric properties of the AHSS were compared with those of the HSS and the AHS. A survey among 1,000 students compared the AHSS and HSS with a one-item hangover severity score. The AHSS was further tested in a naturalistic hangover experiment.

Results

The 12 items of the AHSS were fatigue, clumsiness, dizziness, apathy, sweating, shivering, nausea, heart pounding, confusion, stomach pain, concentration problems, and thirst. The Penning et al. (Alcohol Alcohol 47:248–252, 2012) data revealed that the predictive validity of the AHSS (92.4 %) for the overall hangover score was significantly higher than that of the HSS (81.5 %) and the AHS (71.0 %). The survey data (N?=?966) showed that scores on the AHSS (39.7 %) and the HSS (47.6 %) only moderately predicted the one-item hangover score. A total of 119 subjects completed the naturalistic study. On average, they consumed 9.7 alcoholic consumptions, yielding a mean estimated blood alcohol concentration (BAC) of 0.16 %. During hangover, the AHSS score correlated significantly with the number of alcoholic consumptions (r?=?0.38, p?<?0.0001) and estimated BAC (r?=?0.40, p?<?0.0001).

Conclusions

The AHS, HSS, and AHSS all seem appropriate for application in hangover research. The use of a one-item hangover scale is not recommended.     

Coevolution of gene families in prokaryotes

We study gene family coevolution on a tree of life based on a large-scale ancestral gene content reconstruction, which includes gene duplication and deletion events. The insights obtained from this study are threefold: (1) Global properties, such as the distribution of coevolution partners and the formation of disconnected clusters of coevolving families, can be an inevitable consequence of evolution along a tree. (2) Concerted family expansion (gene duplication) and contraction (gene deletion) reflect functional constraints and therefore lead to better function prediction. (3) "Long-range" coevolutionary relationships, caused mostly by large family expansions or contractions, reveal high-level evolutionary organization of cellular processes in prokaryotes.