Systematic Design of a Magnetically Levitated Brushless DC Motor for a Reversible Rotary Intra-Aortic Blood Pump.

The IntraVAD is a miniature intra-aortic ventricular assist device (VAD) designed to work in series with the compromised left ventricle. A reverse-rotation control (RRc) mode has been developed to increase myocardial perfusion and reduce ventricular volume. The RRc mode includes forward rotation in systole and reverse rotation in diastole, which requires the IntraVAD to periodically reverse its rotational direction in synchrony with the cardiac cycle. This periodic reversal leads to changes in pressure force over the impeller, which makes the entire system less stable. To eliminate the mechanical wear of a contact bearing and provide active control over the axial position of the rotor, a miniature magnetically levitated bearing (i.e., the PM-Coil module) composed of two concentric permanent magnetic (PM) rings and a pair of coils-one on each side-was proposed to provide passive radial and active axial rotor stabilization. In the early design stage, the numerical finite element method (FEM) was used to optimize the geometry of the brushless DC (BLDC) motor and the maglev module, but constructing a new model each time certain design parameters were adjusted required substantial computation time. Because the design criteria for the module had to be modified to account for the magnetic force produced by the motor and for the hemodynamic changes associated with pump operation, a simplified analytic expression was derived for the expected magnetic forces. Suitable bearings could then be designed capable of overcoming these forces without repeating the complicated FEM simulation for the motor. Using this method at the initial design stage can inform the design of the miniature maglev BLDC motor for the proposed pulsatile axial-flow VAD.

Enhancing Opiorphin's Metabolic Stability and Preserving its Potent Analgesic Effect: A Systematic Review.

BACKGROUND: Opiorphin has been reported to show a stronger analgesic effect than morphine without causing side effects brought about by morphine-like drugs. Functional opiorphin analogs have been created to enhance its metabolic stability and preserve its potent analgesic effect. OBJECTIVE: We conducted a systematic review to summarize all opiorphin analogs and identify those with the strongest metabolic stability and antinociceptive effect. METHODS: From a total of 122 articles, 11 made it to the quantitative synthesis phase. The included articles were categorized into the type of modifications used to improve the metabolic stability of the peptide, metabolism and toxicity profile, drug absorption and in vitro cytotoxicity, anti-nociceptive effect, the opiorphin analogs' administration in animals or humans, and the type of the test used to test the antinociceptive effect. RESULTS: The substitution of natural amino acid with a non-natural amino acid, side-chain modifications, or D-aminoacid substitution were the most used type of peptide modification to create opiorphin analogs. STR-324 and PEGylated liposomes loaded with opiorphin showed the best metabolism and toxicity performance. [C]-[(CH2)6]-QRF-[S-O-(CH2)8]-R showed high stability in human plasma and stronger inhibitory potency. YQRFSR and PEGylated liposomes loaded with opiorphin showed a stronger antinociceptive effect than the parent opiorphin or morphine, with an analgesic effect of PEGylated liposomes lasting more than 50%. Intravenous administration was the preferred method of opiorphin analog administration, and different tests were used to test the antinociceptive effect. CONCLUSION: This paper presents the first systematic review discussing opiorphin and opiorphin analogs and identifies the most promising candidates for future research.

Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome.

STUDY OBJECTIVE: Incremental withdrawal of serotonin during wake to sleep transition is postulated as a key mechanism that renders the pharyngeal airway collapsible. While serotonin promotion with reuptake inhibitors have demonstrated modest beneficial effects during NREM sleep on obstructive sleep apnea (OSA), animal studies suggest a potential therapeutic role for selective serotonin receptor antagonists (5-HT3) in REM sleep. We aimed to test the hypothesis that a combination of ondansetron (Ond) and fluoxetine (Fl) may effectively reduce expression of disordered breathing during REM and NREM sleep in patients with OSA. DESIGN AND SETTING: A prospective, parallel-groups, single-center trial in patients with OSA. PARTICIPANTS: 35 adults with apnea hypopnea index (AHI) > 10; range 10-98. INTERVENTION: Subjects were randomized to placebo, n = 7; Ond (24 mg QD), n = 9; Fl (5 mg QD) + Ond (12 mg QD), n = 9; and Fl (10 mg QD) + Ond (24 mg QD), n = 10. MEASUREMENTS AND RESULTS: AHI was measured by in-lab polysomnography after a 7-day no-treatment period (Baseline) and on days 14 and 28 of treatment. The primary endpoint was AHI reduction at days 14 and 28. OND+FL resulted in approximately 40% reduction of baseline AHI at days 14 and 28 (unadjusted P < 0.03 for each) and improved oximetry trends. This treatment-associated relative reduction in AHI was also observed in REM and supine sleep. CONCLUSIONS: Combined treatment with OND+FL is well-tolerated and reduces AHI, yielding a potentially therapeutic response in some subjects with OSA.

Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-kappaB signaling pathways and involves a novel feed-forward regulatory mechanism.

The transcription factor NF-kappaB (nuclear factor kappaB) is a central mediator of inflammatory and apoptotic signaling in the cell. The protein kinase RIP-2 is a member of the CARD protein family (caspase activation and recruitment domain, also known as CARD3, Ripk2, CARDIAK, RICK, and CCK), and has been shown to be an activator of NF-kappaB. In this study, it was demonstrated by transcriptional profiling and protein expression analysis that the inflammatory cytokines TNF-alpha, IL-1 beta, and IFN-gamma induced RIP-2 transcription and translation in endothelial cells. Two mechanistically distinct inhibitors of NF-kappaB signaling, sulfasalazine (NF-kappaB inhibitor) and WY-14643 [PPAR alpha (peroxisome proliferator-activated receptor alpha) agonist] that interfere with the transcription factor RELA (p65), suppressed TNF-alpha induced RIP-2 gene expression, which indicated that NF-kappaB signaling was involved in the cytokine-induced transcriptional activation of RIP-2 gene expression. Consistent with these observations, multiple NF-kappaB response elements were found in the upstream regions of the human and mouse RIP-2 genes. NF-kappaB-mediated regulation of RIP-2 gene and protein expression suggests an additional step in the regulation of NF-kappaB function as RIP-2 has been shown to positively modulate NF-kappaB by binding IKK gamma (I kappaB kinase gamma), a component of the IKK complex. These findings support a positive feed-forward mechanism of NF-kappaB regulation that involves NF-kappaB-dependent induction of RIP-2 transcription and a subsequent increase in RIP-2 protein levels in response to inflammatory cytokines. Elevated RIP-2 protein levels are then available to promote NF-kappaB function via interaction with IKK gamma. RIP-2 is the first reported NF-kappaB-dependent protein kinase that positively regulates NF-kappaB activity.

A method for the analysis of tabun in multisol using gas chromatographic flame photometric detection.

Preparation and analysis of tabun (GA) solutions are necessary for the continued development of countermeasures to this nerve agent. GA solutions must be stable and compatible for use in the test systems chosen for study; however, GA is very unstable in saline solutions. In the past we have found GA in saline at 2 mg/mL to be stable for a month or less at -70 degrees C, whereas saline solutions of sarin (GB), soman (GD), and cyclosarin (GF) were stable for many months. Previous studies have shown that Multisol (48.5% H(2)O, 40% propylene glycol, 10% ethanol, and 1.5% benzyl alcohol) provides stable solutions of GA. We confirmed the stability of GA in Multisol with phosphorus nuclear magnetic resonance (P horizontal line NMR) and developed a method for the analysis of GA in Multisol using gas chromatographic flame photometric detection (GCFPD) in the phosphorus mode. The GC method used acetonitrile (CH(3)CN) for a dilution solvent because of its miscibility with GA in chloroform (CHCl(3)) standards and GA in Multisol samples at 1% (v/v). Furthermore, the dilutions with CH(3)CN made the phosphorus mode interference peak present in CHCl(3) analytically manageable, reduced the interferences of Multisol in the GC separation, and contributed to a safe and reliable analysis of GA at 20 mug/mL. We demonstrated the stability of GA in Multisol stored for more than a year at 70 degrees C. This method contributes a suitable technique for the preparation and analysis of reliable solutions of GA in nerve agent medical research and demonstrates the extended stability of GA in Multisol.

Nuclear magnetic resonance analysis of the solution and solvolysis of sulfur mustard in deuterium oxide.

Our laboratory performs in vitro experiments in which cell cultures are exposed to sulfur mustard (HD) to investigate the toxicity of this agent of chemical warfare. To perform these experiments, it is important to know the rate of hydrolysis of HD in order to calculate the concentrations of HD and its hydrolysis products during the experiment. Researchers have previously investigated the kinetics and mechanism of the hydrolysis of HD using a variety of methods. In the present study, we used nuclear magnetic resonance (NMR) spectroscopy and gas chromatography/mass spectrometry (GC/MS) to investigate HD's dissolution and solvolysis in deuterium oxide (D 2 O) at 2 mM. We followed activity in proton spectrums and determined the half-life (t 1/2) of HD to be 7.0 +/- 0.5 min in four experiments performed at 22 degrees C. In addition, we determined the t 1/2 of HD in D 2 O containing 0.17 M sodium chloride to be 24 +/- 1 min in three experiments performed at 22 degrees C. As further proof of the existence of HD dissolved into D 2 O, deutero-hexane was used to extract the D 2 O HD solution. The resulting deutero-hexane solution was studied by 1 H NMR and GC/MS. The results obtained match those received from a standard deutero-hexane HD solution. These results demonstrate that HD can be identified in D 2 O with proton NMR and that proton NMR data can be used to monitor the subsequent solvolysis of HD.

Application and detection of (14)c-hd in two mouse models.

The CD1-haired mouse and the SKH-hairless mouse are two animal models that have been used to evaluate sulfur mustard (HD) exposure and protection in our laboratory. In a recent study we observed that a substance P inhibitor protected the haired mouse ear against an HD solution, but the same drug was not successful in protecting the hairless mouse against HD vapor. This experiment prompted us to compare HD exposures between these models. We determined the (14)C content in the skin after exposures to HD containing (14)C-HD. Rate curves were generated for applications of (1) HD in methylene chloride to the haired mouse ear; (2) HD in methylene chloride to the hairless mouse dorsal skin; and (3) saturated HD vapor to the hairless mouse dorsal skin for 6 min. The curves showed a reduction in (14)C disintegrations per min in animals euthanized 0 to 2 h postexposure. The largest percentage of decrease of (14)C content in skin occurred within 30 min of HD challenge for all exposures. An 8-mm skin-punch biopsy and a 14-mm annular skin section surrounding the region of the 8-mm skin punch were taken from the hairless mouse dorsal skin exposed to HD in methylene chloride. The ratio of the (14)C content in the 8-mm skin punch to that in the surrounding 14-mm annular skin section was 7.3, demonstrating that the HD application spreads beyond the initially biopsied site. A concentration/time value of 6.3 mug/cm(2)/min was determined by counting skin (14)C disintegrations per minute in animals euthanized immediately after exposure to saturated HD vapor. Determinations of the amount of HD showed that similar quantities of HD, 0.4 mg, were detected on each model. These results contribute to a better quantitative understanding of HD application in the haired and hairless mouse models.

Methods of advanced wound management for care of combined traumatic and chemical warfare injuries.

OBJECTIVE: Chemical warfare agents are potential threats to military personnel and civilians. The potential for associated traumatic injuries is significant. Damage control surgery could expose medical personnel to agents contaminating the wounds. The objectives of this study were to demonstrate efficacy of surgical decontamination and assess exposure risk to attending personnel. METHODS: Weanling pigs were randomly assigned to 2 of 4 debridement tools (scalpel, Bovie knife, Fugo Blade, and Versajet Hydrosurgery System). Penetrating traumatic wounds were created over the shoulder and thigh and then exposed to liquid sulfur mustard (HD) for 60 minutes. Excisional debridement of the injuries was performed while vapors over each site were collected. Gas chromatography was used to measure HD in samples of collected vapors. Unbound HD was quantified in presurgical wound swabs, excised tissues, and peripheral tissue biopsies following solvent extraction. RESULTS: Excisional debridement produced agent-free wound beds (surgical decontamination). A significant amount of HD vapor was detected above the surgical fields with each tool. Apart from the Versajet producing significantly lower levels of HD detected over thigh wounds compared with those treated using the scalpel, there were no differences in the amount of agent detected among the tools. All measured levels significantly exceeded established safety limits. Vesicating levels of unbound HD were extracted from excised tissue. There was no measured lateral spreading of HD beyond the surgical margins. CONCLUSIONS: There is significant occupational exposure risk to HD during surgical procedures designed to stabilize agent-contaminated wounds. If appropriate protective measures are taken, surgical decontamination is both effective and safe.