Synergy of Combining Methionine Restriction and Chemotherapy: The Disruptive Next Generation of Cancer Treatment.

All cancer cell types are methionine-addicted, which is termed the Hoffman effect. Cancer cells, unlike normal cells, cannot survive without large amount of methionine. In general, when methionine is depleted, both normal cells and cancer cells synthesize methionine from homocysteine, but cancer cells consume large amounts of methionine and they cannot survive without exogenous methionine. For this reason, methionine restriction has been shown to be effective against many cancers in vitro and in vivo. Methionine restriction arrests cancer cells in the S/G2-phase of the cell cycle. Cytotoxic agents that act in the S/G2-phase are highly effective when used in combination with methionine restriction due to the cancer cells being trapped in S/G2-phase, unlike normal cells which arrest in G1/G0-phase. Combining methionine restriction and chemotherapeutic drugs for cancer treatment is termed the Hoffman protocol. The efficacy of many cytotoxic agents and molecular-targeted drugs in combination with methionine restriction has been demonstrated. The most effective method of methionine restriction is the administration of recombinant methioninase (rMETase), which degrades methionine. The efficacy of rMETase has been reported in mice and human patients by oral administration. The present review describes studies on anticancer drugs that showed synergistic efficacy in combination with methionine restriction, including rMETase administration. It is proposed that the next disruptive generation of cancer chemotherapy should employ current therapy in combination with methionine restriction for all cancer types.

Public Performance Metrics: Driving Physician Motivation and Performance.

INTRODUCTION: As providers transition from "fee-for-service" to "pay-for-performance" models, focus has shifted to improving performance. This trend extends to the emergency department (ED) where visits continue to increase across the United States. Our objective was to determine whether displaying public performance metrics of physician triage data could drive intangible motivators and improve triage performance in the ED. METHODS: This is a single institution, time-series performance study on a physician-in-triage system. Individual physician baseline metrics-number of patients triaged and dispositioned per shift-were obtained and prominently displayed with identifiable labels during each quarterly physician group meeting. Physicians were informed that metrics would be collected and displayed quarterly and that there would be no bonuses, punishments, or required training; physicians were essentially free to do as they wished. It was made explicit that the goal was to increase the number triaged, and while the number dispositioned would also be displayed, it would not be a focus, thereby acting as this study's control. At the end of one year, we analyzed metrics. RESULTS: The group's average number of patients triaged per shift were as follows: Q1-29.2; Q2-31.9; Q3-34.4; Q4-36.5 (Q1 vs Q4, p < 0.00001). The average numbers of patients dispositioned per shift were Q1-16.4; Q2-17.8; Q3-16.9; Q4-15.3 (Q1 vs Q4, p = 0.14). The top 25% of Q1 performers increased their average numbers triaged from Q1-36.5 to Q4-40.3 (ie, a statistically insignificant increase of 3.8 patients per shift [p = 0.07]). The bottom 25% of Q1 performers, on the other hand, increased their averages from Q1-22.4 to Q4-34.5 (ie, a statistically significant increase of 12.2 patients per shift [p = 0.0013]). CONCLUSION: Public performance metrics can drive intangible motivators (eg, purpose, mastery, and peer pressure), which can be an effective, low-cost strategy to improve individual performance, achieve institutional goals, and thrive in the pay-for-performance era.

Design of a model to predict surge capacity bottlenecks for burn mass casualties at a large academic medical center.

OBJECTIVES: To design and test a model to predict surge capacity bottlenecks at a large academic medical center in response to a mass-casualty incident (MCI) involving multiple burn victims. METHODS: Using the simulation software ProModel, a model of patient flow and anticipated resource use, according to principles of disaster management, was developed based upon historical data from the University Hospital of the University of Michigan Health System. Model inputs included: (a) age and weight distribution for casualties, and distribution of size and depth of burns; (b) rate of arrival of casualties to the hospital, and triage to ward or critical care settings; (c) eligibility for early discharge of non-MCI inpatients at time of MCI; (d) baseline occupancy of intensive care unit (ICU), surgical step-down, and ward; (e) staff availability-number of physicians, nurses, and respiratory therapists, and the expected ratio of each group to patients; (f) floor and operating room resources-anticipating the need for mechanical ventilators, burn care and surgical resources, blood products, and intravenous fluids; (g) average hospital length of stay and mortality rate for patients with inhalation injury and different size burns; and (h) average number of times that different size burns undergo surgery. Key model outputs include time to bottleneck for each limiting resource and average waiting time to hospital bed availability. RESULTS: Given base-case model assumptions (including 100 mass casualties with an inter-arrival rate to the hospital of one patient every three minutes), hospital utilization is constrained within the first 120 minutes to 21 casualties, due to the limited number of beds. The first bottleneck is attributable to exhausting critical care beds, followed by floor beds. Given this limitation in number of patients, the temporal order of the ensuing bottlenecks is as follows: Lactated Ringer's solution (4 h), silver sulfadiazine/Silvadene (6 h), albumin (48 h), thrombin topical (72 h), type AB packed red blood cells (76 h), silver dressing/Acticoat (100 h), bismuth tribromophenate/Xeroform (102 h), and gauze bandage rolls/Kerlix (168 h). The following items do not precipitate a bottleneck: ventilators, topical epinephrine, staplers, foams, antimicrobial non-adherent dressing/Telfa types A, B, or O blood. Nurse, respiratory therapist, and physician staffing does not induce bottlenecks. CONCLUSIONS: This model, and similar models for non-burn-related MCIs, can serve as a real-time estimation and management tool for hospital capacity in the setting of MCIs, and can inform supply decision support for disaster management.

A survey of emergency physicians' fear of malpractice and its association with the decision to order computed tomography scans for children with minor head trauma.

OBJECTIVE: The objective of the study was to determine whether fear of malpractice is associated with emergency physicians' decision to order head computed tomography (CT) in 3 age-specific scenarios of pediatric minor head trauma. We hypothesized that physicians with higher fear of malpractice scores will be more likely to order head CT scans. METHODS: Board-eligible/board-certified members of the Michigan College of Emergency Physicians were sent a 2-part survey consisting of case scenarios and demographic questions. Effect of fear of malpractice on the decision to order a CT scan was evaluated using a cumulative logit model. RESULTS: Two hundred forty-six members (36.5%) completed the surveys. In scenario 1 (infant), being a male and working in a university setting were associated with reduced odds of ordering a CT scan (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.18-0.88; and OR, 0.35; 95% CI, 0.13-0.96, respectively). In scenario 2 (toddler), working for 15 years or more, at multiple hospitals, and for a private group were associated with reduced odds of ordering a CT scan (OR, 0.46; 95% CI, 0.26-0.79; OR, 0.36; 95% CI, 0.16-0.80; and OR, 0.51; 95% CI, 0.27-0.94, respectively). No demographic variables were significantly associated with ordering a CT scan in scenario 3 (teen). Overall, the fear of malpractice was not significantly associated with ordering a CT scan (OR, 1.28; 95% CI, 0.73-2.26; and OR, 1.70; 95% CI, 0.97-3.0). Only in scenario 2 was high fear significantly associated with increased odds of ordering a CT scan (OR, 2.09; 95% CI, 1.08-4.05). CONCLUSIONS: Members of Michigan College of Emergency Physicians with a higher fear of malpractice score tended to order more head CT scans in pediatric minor head trauma. However, this trend was shown to be statistically significant only in 1 case and not overall.

FLPe functions in zebrafish embryos.

To assay the efficiency of the FLP/FRT site-specific recombination system in Danio rerio, a construct consisting of a muscle-specific promoter driving EGFP flanked by FRT sites was developed. FLPe capped RNA was microinjected into transgenic single cell stage zebrafish embryos obtained by crossing hemizygous transgenic males with wild-type females. By 48 h post fertilization (hpf), the proportion of embryos displaying green fluorescence following FLPe RNA microinjection was significantly lower (7.7%; P < 0.001) than would be expected from a cross in the absence of the recombinase (50%). Embryos that retained fluorescence displayed marked mosaicism. Inheritance of the excised transgene in non-fluorescent, transgenic embryos was verified by PCR analysis and FLPe-mediated recombination was confirmed by DNA sequencing. Sperm derived from confirmed transgenic males in these experiments was used to fertilize wild-type eggs to determine whether germline excision of the transgene had occurred. Clutches sired by FLPe-microinjected males contained 0-4% fluorescent embryos. Transgenic males that were phenotypically wild-type produced no fluorescent progeny, demonstrating complete excision of the transgene from their germline. FLPe microinjected males that retained some fluorescent muscle expression produced a small proportion of fluorescent offspring, suggesting that in mosaic males not all germline cells had undergone FLPe-mediated transgene excision. Our results show that FLPe, which is derived from Saccharomyces cerevisiae, is an efficient recombinase in zebrafish maintained at 28.5°C.

Importance of volume and concentration for ropivacaine interscalene block in preventing recovery room pain and minimizing motor block after shoulder surgery.

BACKGROUND: This three-staged study estimated the volume and concentration of interscalene ropivacaine that would prevent recovery room pain after shoulder surgery under general anesthesia. METHODS: Stages 1/2: Interscalene catheter administration of ropivacaine was by a 10% incremental up-down sequential manner depending on the presence of recovery room pain in the previous patient. Stage 1: Ropivacaine (0.5% volume) was varied from 30 ml. Stage 2: Ropivacaine (20 ml, the ED(volume)95 estimate from stage 1) concentration was varied from 0.45%. Stage 3: Subjects were randomly assigned to receive 30 ml of ropivacaine, 0.5% ("conventional dose"), or 20 ml of ropivacaine, 0.375% (the estimated ED(volume+concentration)95 from stages 1/2). A postoperative elastomeric infusion of 0.2% ropivacaine (2 ml/h) was administered. Grip strength was measured in the recovery room and time to first pain at 24 h. RESULTS: Stage 1 (n = 34): Ropivacaine 0.5% ED(volume)50/ED(volume)95 (95% CI) estimates were 2.7/20.5 ml (2.4-9.5/17.3-25.8). Stage 2 (n = 29): Ropivacaine 20 ml ED(concentration)50/ED(concentration)95 (95% CI) estimates were 0.15/0.34% (0.13-0.30/0.29-0.43). The ED(dose)50 was similar for stages 1/2 (13.5 vs. 30 mg), but the ED(dose)95 was higher for stage 1 (102.5 vs. 68 mg). Stage 3 (n = 40): Satisfaction (0-10) was modestly higher for the new/lower dose (median [interquartile range] = 10 [10-10] versus 9 [8-10], P = 0.007). Pooled data regression analysis showed that increasing ropivacaine concentration increased grip weakness but not block duration. CONCLUSIONS: Ropivacaine interscalene block requires a threshold volume and concentration, with concentration primarily determining motor block. When combined with continuous blockade, suprathreshold ropivacaine doses do not significantly prolong primary block duration but may compromise patient satisfaction.

Laparoscopic liver resection for hepatocellular carcinoma.

OBJECTIVE: To provide an updated review on the clinical experience in laparoscopic liver resection, specifically for hepatocellular carcinoma. METHODS: A comprehensive literature search in MEDLINE was conducted for all English papers up to May 2010 on laparoscopic liver resection for hepatocellular carcinoma. Patient characteristics, perioperative results, and oncologic outcomes were compared and analysed. RESULTS: We analysed 11 clinical studies involving 466 hepatocellular carcinoma patients treated with laparoscopic hepatectomy. Thirty-seven (9%) patients underwent major resection. Cirrhosis occurred in 62%. The mean operative time was 189.5 min, and the mean blood loss was 315.6 mL. Blood transfusion was required in 14.6% of patients. There were two operative deaths. Postoperative complications included bile leakage (1%), bleeding (2.9%), liver failure (5.1%), and ascites (6%). The 1-year, 3-year, and 5-year disease-free survival rates ranged from 60% to 90%, 50% to 64%, and 31% to 50%, respectively, and the corresponding overall survival rates ranged from 85% to 100%, 67% to 100%, and 50% to 97% respectively. CONCLUSION: Laparoscopic liver resection for hepatocellular carcinoma appears to be safe and to achieve acceptable oncologic outcomes even in cirrhotic livers, but whether it is comparable to conventional open surgery needs to be evaluated in a randomized, controlled trial setting.

SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.

Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.

Gonadotropin hormone and receptor sequences from model teleost species.

Fish offer some advantages for the study of vertebrate reproductive physiology. Only a few of the genes encoding the components of the hypothalamic-pituitary-gonadal axis have been identified from model teleosts. This study describes a combination of database searching and molecular approaches to identify the FSH and LH gonadotropin beta-subunits (fshb and lhb, respectively), and the LH receptor (lhr) from two model teleost species: zebrafish (Danio rerio) and Fugu (Takifugu rubripes). Sequence and phylogenetic analyses were used to examine the relationships that exist between gonadotropins and their receptors from species representing several piscine orders. The gonadotropin alpha-subunit (Cga) is highly conserved among teleosts and tetrapods. The presence of a genomic pseudogene (cgap) was also noted in zebrafish. Generally, teleostean FSHbeta protein sequences share less identity with each other than do LHbeta protein sequences, supporting the hypothesis that FSHbeta diverged more rapidly during teleost evolution. Interestingly, and uniquely, zebrafish Fshb lacked two highly conserved cysteine residues in the "determinant loop" which is thought to contribute towards receptor binding and specificity. Teleost gonadotropin receptor sequences clearly diverged into two distinct groups, FSHR and LHR. As has been seen with mammalian gonadotropin receptor transcripts, splice variants of zebrafish lhr were also observed.

Histology-based screen for zebrafish mutants with abnormal cell differentiation.

The power of histology to define states of cell differentiation was used as the basis of a mutagenesis screen in zebrafish. In this screen, 7-day-old parthenogenetic half-tetrad larvae from potential carrier females were screened for mutations affecting cell differentiation in hematoxylin and eosin-stained tissue sections. Seven, noncomplementing, recessive mutations were found. Two mutations affect only the retina: segmented photoreceptors (spr) show a discontinuous photoreceptor cell layer; vestigial outer segments (vos) has fewer photoreceptor cells and degenerated outer segments within this cell layer. Three mutants have gut-specific defects: the epithelial cells of kirby (kby) are replaced by ballooned cells; the intestines of stuffy (sfy) and stuffed (sfd) contain increased luminal mucus. Two mutations affect multiple organs: disordered neural retina (dnr) has disrupted retinal layering and mild nuclear abnormalities in the gut and liver; and in huli hutu (hht), the retinal cell layers are disorganized and multiple organs have mild to severe nuclear abnormalities that are reminiscent of the atypia of human neoplasia. Each mutation appears to be homozygous lethal. This screen is proof of principle for the feasibility of histologic screens to yield novel mutations, including potential models of human disease. The throughput for this type of screen may be enhanced by automation.

Segmental hemodynamics during partial liquid ventilation in isolated rat lungs.

UNLABELLED: Partial liquid ventilation (PLV) is a means of ventilatory support in which gas ventilation is carried out in a lung partially filled with a perfluorocarbon liquid capable of supporting gas exchange. Recently, this technique has been proposed as an adjunctive therapy for cardiac arrest, during which PLV with cold perfluorocarbons might rapidly cool the intrathoracic contents and promote cerebral protective hypothermia while not interfering with gas exchange. A concern during such therapy will be the effect of PLV on pulmonary hemodynamics during very low blood flow conditions. In the current study, segmental (i.e. precapillary, capillary, and postcapillary) hemodynamics were studied in the rat lung using a standard isolated lung perfusion system at a flow rate of 6 ml/min ( approximately 5% normal cardiac output). Lungs received either gas ventilation or 5 or 10 ml/kg PLV. Segmental pressures and vascular resistances were determined, as was transcapillary fluid flux. The relationship between individual hemodynamic parameters and PLV dose was examined using linear regression, with n=5 in each study group. PLV at both the 5 and 10 ml/kg dose produced no detectable changes in pulmonary blood flow or in transcapillary fluid flux (all R(2) values<0.20). CONCLUSION: In an isolated perfused lung model of low flow conditions, normal segmental hemodynamic behavior was preserved during liquid ventilation. These data support further investigation of this technique as an adjunct to cardiopulmonary resuscitation.