Robust, tunable, and high purity triggered single photon source at room temperature using a nitrogen-vacancy defect in diamond in an open microcavity.

We report progress in the development of tunable room temperature triggered single photon sources based on single nitrogen-vacancy (NV) centres in nanodiamond coupled to open access optical micro-cavities. The feeding of fluorescence from an NV centre into the cavity mode increases the spectral density of the emission and results in an output stream of triggered single photons with spectral line width of order 1 nm, tunable in the range 640 - 700 nm. We record single photon purities exceeding 96% and estimated device efficiencies up to 3%. We compare performance using plano-concave microcavities with radii of curvature from 25 µm to 4 µm and show that up to 17% of the total emission is fed into the TEM00 mode. Pulsed Hanbury-Brown Twiss (HBT) interferometry shows that an improvement in single photon purity is facilitated due to the increased spectral density.

Nanoparticle Trapping and Characterization Using Open Microcavities.

Characterization and trapping of nanoparticles in solution is of great importance for lab-on-a-chip applications in biomedical, environmental, and materials sciences. Devices are now starting to emerge allowing such manipulations and investigations in real-time. Better insights into the interaction between the nanoparticle and the optical trap is therefore necessary in order to move forward in this field. In this work, we present a new kind of nanotweezers based on open microcavities. We show that by monitoring the cavity mode wavelength shift as the particle diffuses through the cavity, it is possible to establish both the nanoparticle polarizability and its coefficient of friction. Additionally, our experiment provides a deep insight in the interaction between the nanoparticle and the cavity mode. The technique has built-in calibration of the trap strength and spring constant, making it attractive for practical applications. This work illustrates the potential of such optical microcavities for future developments in nanoparticle sensors and lab-on-a-chip devices.

Vertebroplasty reduces progressive ׳creep' deformity of fractured vertebrae.

Elderly vertebrae frequently develop an "anterior wedge" deformity as a result of fracture and creep mechanisms. Injecting cement into a damaged vertebral body (vertebroplasty) is known to help restore its shape and stiffness. We now hypothesise that vertebroplasty is also effective in reducing subsequent creep deformations. Twenty-eight spine specimens, comprising three complete vertebrae and the intervening discs, were obtained from cadavers aged 67-92 years. Each specimen was subjected to increasingly-severe compressive loading until one of its vertebrae was fractured, and the damaged vertebral body was then treated by vertebroplasty. Before and after fracture, and again after vertebroplasty, each specimen was subjected to a static compressive force of 1kN for 1h while elastic and creep deformations were measured in the anterior, middle and posterior regions of each adjacent vertebral body cortex, using a 2D MacReflex optical tracking system. After fracture, creep in the anterior and central regions of the vertebral body cortex increased from an average 4513 and 885 microstrains, respectively, to 54,107 and 34,378 microstrains (both increases: P<0.001). Elastic strains increased by a comparable amount. Vertebroplasty reduced creep in the anterior and central cortex by 61% (P=0.006) and 66% (P=0.017) respectively. Elastic strains were reduced by less than half this amount. Results suggest that the beneficial effects of vertebroplasty on the vertebral body continue long after the post-operative radiographs. Injected cement not only helps to restore vertebral shape and elastic properties, but also reduces subsequent creep deformation of the damaged vertebra.

Open-access optical microcavities for lab-on-a-chip refractive index sensing.

Open-access optical microcavities provide a novel approach to label-free lab-on-a-chip optofluidic sensing. They offer direct access to a highly confined electromagnetic field, and yield a femtoliter detection volume. This article describes the characteristics of these devices for refractive index sensing. We show that most of the ambient noise can be removed from the refractive index data by simultaneous tracking of resonances across an array of cavities. A sensitivity of 3.5 × 10(-4) RIU is demonstrated which corresponds to detecting the refractive index change caused by the presence of 500,000 glucose molecules in aqueous solution.

Do intervertebral discs degenerate before they herniate, or after?

The belief that an intervertebral disc must degenerate before it can herniate has clinical and medicolegal significance, but lacks scientific validity. We hypothesised that tissue changes in herniated discs differ from those in discs that degenerate without herniation. Tissues were obtained at surgery from 21 herniated discs and 11 non-herniated discs of similar degeneration as assessed by the Pfirrmann grade. Thin sections were graded histologically, and certain features were quantified using immunofluorescence combined with confocal microscopy and image analysis. Herniated and degenerated tissues were compared separately for each tissue type: nucleus, inner annulus and outer annulus. Herniated tissues showed significantly greater proteoglycan loss (outer annulus), neovascularisation (annulus), innervation (annulus), cellularity/inflammation (annulus) and expression of matrix-degrading enzymes (inner annulus) than degenerated discs. No significant differences were seen in the nucleus tissue from herniated and degenerated discs. Degenerative changes start in the nucleus, so it seems unlikely that advanced degeneration caused herniation in 21 of these 32 discs. On the contrary, specific changes in the annulus can be interpreted as the consequences of herniation, when disruption allows local swelling, proteoglycan loss, and the ingrowth of blood vessels, nerves and inflammatory cells. In conclusion, it should not be assumed that degenerative changes always precede disc herniation. Cite this article: Bone Joint J 2013;95-B:1127-33.

Prioritizing investments in public health: a multi-criteria decision analysis.

BACKGROUND: The evidence on public health interventions has traditionally focussed on a limited number of costs and benefits, adopted inconsistent methods and is not always relevant to the UK context. This paper develops a multi-criteria decision analysis (MCDA) approach to overcome these challenges. METHODS: A document review and stakeholder consultation was used to identify interventions and the criteria against which they should be assessed. The interventions were measured against these criteria using literature reviews and decision models. Criteria weights were generated using a discrete choice experiment. RESULTS: Fourteen interventions were included in the final ranking. Taxation was ranked as the highest priority. Mass-media campaigns and brief interventions ranked in the top half of interventions. School-based educational interventions, statins and interventions to address mental health problems ranked in the bottom half of interventions. CONCLUSIONS: This paper demonstrates that it is possible to incorporate criteria other than cost-effectiveness in the prioritization of public health investment using an MCDA approach. There are numerous approaches available that adopt the MCDA framework. Further research is required to determine the most appropriate approach in different settings.

Transglutaminase 2 protects against ischemic stroke.

Transglutaminase 2 (TG2) is a multifunctional protein that modulates cell survival and death pathways. It is upregulated in numerous ischemic models, and protects primary neurons from oxygen and glucose deprivation. TG2 binds to the hypoxia inducible factor (HIF) 1beta and decreases the upregulation of hypoxic-induced proapoptotic genes. To investigate the role of TG2 in ischemic stroke in vivo, we used the murine, permanent middle cerebral artery (MCA) ligation model. TG2 mRNA levels are increased after MCA ligations, and transgenic mice that express human TG2 in neurons had significantly smaller infarct volumes than wild type littermates. Further, TG2 translocates into the nucleus within 2h post ligation. Nuclear-localized TG2 is also apparent in human stroke cases. TG2 suppressed the upregulation of the HIF-induced, proapoptotic gene, Noxa. The findings of this study indicate that TG2 plays a role in attenuating ischemic-induced cell death possibly by modulating hypoxic-induced transcriptional processes.

Vertebral fractures in the elderly may not always be "osteoporotic".

INTRODUCTION: Vertebral fractures in the elderly are often assumed to be "osteoporotic" and require anti-osteoporosis therapy. However, some of these fractures may represent traumatic injuries to vertebrae that have comparatively normal bone mineral density (BMD). We hypothesize that radiographic appearances can be used to differentiate between "osteoporotic" fractures of vertebrae with low BMD and strength, and "traumatic" fractures of vertebrae with normal BMD and strength. METHODS: 73 cadaveric specimens (each comprising two vertebrae with the intervening intervertebral disc and ligaments) were obtained from donors aged 42 to 91 (mean 74) years. Areal BMD was measured in the lateral projection for each vertebral body, using DXA. Each specimen was secured in metal cups containing dental plaster, and compressed to failure at 3mm/s on a computer-controlled materials testing machine. Mechanical failure was detected by a reduction in the gradient of the load-deformation curve. Compressive deformation for each specimen was limited to 4mm in order to prevent gross destruction of the vertebra. Radiographs, obtained before and after mechanical loading, were assessed by an experienced radiologist (GJ) who was blinded to BMD and mechanical data. The algorithm-based qualitative method (ABQ) was used to assign each specimen to two possible outcomes: no discernible fracture of either vertebra, or fracture. The latter were further classified into specimens with osteoporotic fracture and those with traumatic fracture, by applying additional criteria for differential diagnosis. The relationship of failure load to BMD was tested using correlation. BMD and failure load for the three diagnostic outcomes were compared using one-way analysis of variance (ANOVA). RESULTS: Failure load was proportional to BMD (R=0.63, p<0.001). "Osteoporotic," "traumatic" and "no discernible" fractures were reported in 16, 26 and 31 specimens respectively. "Traumatic" fracture specimens had higher BMD and failed at higher loads than "osteoporotic" fracture specimens (p<0.05). CONCLUSIONS: Some vertebral fractures in the elderly may be traumatic rather than osteoporotic in origin. Our radiological criteria help to differentiate between them.

Vertebral fractures usually affect the cranial endplate because it is thinner and supported by less-dense trabecular bone.

INTRODUCTION: Cranial endplates of human vertebrae are injured more often than caudal, in both young and elderly spines. We hypothesise that cranial endplates are inherently vulnerable to compressive loading because of structural asymmetries in the vertebrae. METHODS: Sixty-two "motion segments" (two vertebrae and the intervening disc and ligaments) were obtained post-mortem from thirty-five human spines (17F/18M, age 48-92 yrs, all spinal levels from T8-9 to L4-5). Specimens were compressed to failure while positioned in 2-6 degrees of flexion, and the resulting damage characterised from radiographs and at dissection. 2 mm-thick slices of 94 vertebral bodies (at least one from each motion segment) were cut in the mid-sagittal plane, and in a para-sagittal plane through the pedicles. Microradiographs of the slices were subjected to image analysis to determine the thickness of each endplate at 10 locations. Optical density of the endplates and adjacent trabecular bone was also measured. Measurements obtained in cranial and caudal regions, and in mid-sagittal and pedicle slices, were compared using repeated measures ANOVA with age, level and gender included as between-subject factors. Linear regression was used to determine significant predictors of compressive strength (failure stress). RESULTS: Fracture affected the cranial endplate in 55/62 specimens. Cranial endplates were thinner than caudal (p=0.003) by 14% and 11% on average, in mid-sagittal and pedicle slices respectively. Caudal but not cranial endplates were thicker at lower spinal levels (p=0.01). Optical density of trabecular bone adjacent to the endplates was 6% lower cranially than caudally (p=0.004), and the average optical density of trabecular bone in mid-sagittal slices was 10% lower in women than in men (p=0.025). Vertebral yield stress (mean 2.22 MPa, SD 0.77 MPa) was best predicted by the density of trabecular bone underlying the cranial endplate of the mid-sagittal slice of the fractured vertebra (r(2)=0.67, p=0.0006). CONCLUSIONS: When vertebrae are compressed naturally by adjacent intervertebral discs, cranial endplates usually fail before caudal endplates because they are thinner and supported by less dense trabecular bone.

Syndrome-based discrimination of single nucleotide polymorphism.

The ability to discriminate nucleic acid sequences is necessary for a wide variety of applications: high throughput screening, distinguishing genetically modified organisms (GMOs), molecular computing, differentiating biological markers, fingerprinting a specific sensor response for complex systems, etc. Hybridization-based target recognition and discrimination is central to the operation of nucleic acid sensor systems. Therefore developing a quantitative correlation between mishybridization events and sensor out put is critical to the accurate interpretation of results. In this work, using experimental data produced by introducing single mutations (single nucleotide polymorphisms, SNPs) in the probe sequence of computational catalytic molecular beacons (deoxyribozyme gates) [1], we investigate coding theory algorithms for uniquely categorizing SNPs based on the calculation of syndromes.

Neural arch load-bearing in old and degenerated spines.

We validate a technique for measuring neural arch load-bearing in cadaveric spines, and use it to test the hypothesis that such load-bearing rises to high levels in old and degenerated spines. Fifty-nine cadaveric lumbar motion segments, aged 19-92 yr, were subjected to compressive creep loading to reduce intervertebral disc water content and height to in vivo levels. The distribution of compressive "stress" within the disc was then measured by pulling a miniature pressure transducer, side-mounted in a 1.3mm-diameter needle, along its mid-sagittal diameter. During these measurements, the motion segment was subjected to a compressive load of 2 kN, and positioned in 2 degrees of extension to simulate erect standing. Measurements of compressive "stress" were integrated over disc area, and this force subtracted from the applied 2 kN to give the force resisted by the neural arch. An empirical calibration factor was applied to normalise results from each disc to values obtained under conditions when all of the compressive force could be assumed to pass through the disc. Disc degeneration was graded macroscopically on a scale of 1-4. Validation tests showed that calculated values of disc loading were proportional to actual applied load (r(2)>0.96) and predicted it with errors of 2-8%. Neural arch load-bearing in non-degenerated specimens was generally less than 20%, but averaged 49% for specimens aged over 70 yr. Multiple regression showed that neural arch load bearing (%)=14.4 x disc degeneration score+0.46 x age-35. These results indicate a substantial shift in vertebral load-bearing with increasing age and degeneration.

Robust and efficient synthetic method for forming DNA microarrays.

The field of DNA microarray technology has necessitated the cooperative efforts of interdisciplinary scientific teams to achieve its primary goal of rapidly measuring global gene expression patterns. A collaborative effort was established to produce a chemically reactive surface on glass slide substrates to which unmodified DNA will covalently bind for improvement of cDNA microarray technology. Using the p-aminophenyl trimethoxysilane (ATMS)/diazotization chemistry that was developed, microarrays were fabricated and analyzed. This immobilization method produced uniform spots containing equivalent or greater amounts of DNA than commercially available immobilization techniques. In addition, hybridization analyses of microarrays made with ATMS/diazotization chemistry showed very sensitive detection of the target sequence, two to three orders of magnitude more sensitive than the commercial chemistries. Repeated stripping and re-hybridization of these slides showed that DNA loss was minimal, allowing multiple rounds of hybridization. Thus, the ATMS/diazotization chemistry facilitated covalent binding of unmodified DNA, and the reusable microarrays that were produced showed enhanced levels of hybridization and very low background fluorescence.

Lumbar loading during lifting: a comparative study of three measurement techniques.

Low back loading during occupational lifting is thought to be an important causative factor in the development of low back pain. In order to regulate spinal loading in the workplace, it is necessary to measure it accurately. Various methods have been developed to do this, but each has its own limitations, and none can be considered a "gold standard". The purpose of the current study was to compare the results of three contrasting techniques in order to gain insight into possible sources of error to which each is susceptible. The three techniques were a linked segment model (LSM), an electromyographic (EMG)-based model, and a neural network (NN) that used both EMG and inertial sensing techniques. All three techniques were applied simultaneously to calculate spinal loading when eight volunteers performed a total of eight lifts in a laboratory setting. Averaged results showed that, in comparison with the LSM, the EMG technique calculated a 25.5+/-33.4% higher peak torque and the NN technique a 17.3+/-10.5% lower peak torque. Differences between the techniques varied with lifting speed and method of lifting, and could be attributed to differences in anthropometric assumptions, antagonistic muscle activity, damping of transient force peaks by body tissues, and, specific to the NN, underestimation of trunk flexion. The results of the current study urge to reconsider the validity of other models by independent comparisons.

A non-calcemic sulfone version of the vitamin D(3) analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin.

Novel side-chain diene sulfones 5, analogues of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Company's drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9-->10) and Horner-Wadsworth-Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1alpha,3beta-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 microg/kg of rat body weight.

Equity in health: the importance of different health streams.

This paper develops a conceptual framework in which preferences about the distribution of future health gains depend on differences in four 'health streams'. These are as follows: (1) the amount of health to be gained; (2) the no-treatment profiles; (3) the amount of health experienced thus far: and (4) the amount of health gained previously as a result of public health interventions. This classification puts the well-established concerns for severity (stream 2) and age weights (stream 3) into a more complete analytical framework. Stream 4 has not been discussed to date and the paper suggests some moral arguments about the distributive relevance of this stream of health.

Role of phase 2 enzyme induction in chemoprotection by dithiolethiones.

One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, terpenoids and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B(1) (AFB(1))-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of AFB(1) can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the "antioxidant response element" (ARE), leading to transcriptional activation of a score of genes involved in carcinogen detoxication and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to dithiolethiones; moreover, basal expression of these genes is typically repressed. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, PR China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB(1), AFM(1), when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population.

Utilitarianism and the measurement and aggregation of quality--adjusted life years.

It is widely accepted that one of the main objectives of government expenditure on health care is to generate health. Since health is a function of both length of life and quality of life, the quality-adjusted life-year (QALY) has been developed in an attempt to combine the value of these attributes into a single index number. The QALY approach--and particularly the decision rule that health care resources should be allocated so as to maximise the number of QALYs generated--has often been equated with the utilitarian philosophy of maximising 'the greatest happiness of the greatest number'. This paper considers the extent to which the measurement and aggregation of QALYs really is utilitarian by developing a new taxonomy in order to classify utilitarianism and the different aspects of the QALY approach. It is shown that the measurement of QALYs is consistent with a number of different moral positions and that QALYs do not have to be aggregated according to the maximisation rule. Therefore it is inappropriate to necessarily equate QALYs with utilitarianism. It is shown that much turns on what in principle the QALY represents and how in practice it can be operationalised. The paper highlights the category confusion that is often present here and suggests possible avenues for future theoretical and empirical research.

Recent advances in lumbar spinal mechanics and their significance for modelling.

Mathematical models are often used to quantify the overall forces and moments acting on the lumbar spine. However, if the purpose of the research is to explain how spinal tissues can be injured, it is necessary to distribute the overall forces and moments between (and within) different spinal structures, because it is the concentration of force which causes injury, and elicits pain. This paper reviews recent experimental evidence concerning the distribution of forces and moments acting on the lumbar spine. Lordotic postures increase loading of the posterior annulus and apophyseal joints, whereas moderately flexed postures tend to equalise compressive stress across the disc, and unload the apophyseal joints. Sustained compression reduces the volume and pressure of the nucleus pulposus, while increasing compressive stresses in the annulus and neural arch. Sustained compression also reduces disc height, giving some slack to collagen fibres in the intervertebral disc and ligaments, and causing them to resist bending less. Disc degeneration has a similar effect on disc height, and stress distributions. On the other hand, discs and ligaments can be subjected to greater bending moments following a period of sustained or repetitive bending, because sustained bending impairs the normal protective reflex from the back muscles, and repetitive bending fatigues the back muscles, reducing their ability to protect the spine. Incorporating this information into mathematical models will make them better able to identify which activities are most likely to injure the lumbar spine in life.

An EMG technique for measuring spinal loading during asymmetric lifting.

OBJECTIVES: To compare two methods of calibrating the erector spinae electromyographic signal against moment generation in order to predict extensor moments during asymmetric lifting tasks, and to compare the predicted moments with those obtained using a linked-segment model. METHODS: Eight men lifted loads of 6.7 and 15.7 kg at two speeds, in varying amounts of trunk rotation. For each lift, the following were recorded at 60 Hz; the rectified and averaged surface electromyographic signal, bilaterally at T10 and L3, lumbar curvature using the 3-Space Isotrak, movement of body segments using a 4-camera Vicon system, and ground reaction forces using a Kistler force-plate. Electromyographic (EMG) and Isotrak data were used to calculate lumbosacral extensor moments using the electromyographic model, whereas movement analysis data and ground reaction forces were used to estimate net moments using the linked-segment model. For the electromyographic technique, predictions of extensor moment were based on two different sets of EMG-extensor moment calibrations: one performed in pure sagittal flexion and the other in flexion combined with 45 degrees of trunk rotation. RESULTS: Extensor moments predicted by the electromyographic technique increased significantly with load and speed of lifting but were not influenced by the method of calibration. These moments were 7-40%greater than the net moments obtained with the linked-segment model, the difference increasing with load and speed. CONCLUSIONS: The calibration method does not influence extensor moments predicted by the electromyographic technique in asymmetric lifting, suggesting that simple, sagittal-plane calibrations are adequate for this purpose. Differences in predicted moments between the electromyographic technique and linked-segment model may be partly due to different anthropometric assumptions and different amounts of smoothing and filtering in the two models, and partly due to antagonistic muscle forces, the effects of which cannot be measured by linked-segment models. RelevanceAsymmetric lifting is a significant risk factor for occupationally-related low back pain. Improved techniques for measuring spinal loading during such complex lifting tasks may help to identify work practices which place the spine at risk of injury.

Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice.

Induction of phase 2 enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, appears to be an effective means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part, through the antioxidant response element (ARE) found in the regulatory regions of their genes. The transcription factor Nrf2, which binds to the ARE, appears to be essential for the induction of prototypical phase 2 enzymes such as glutathione S-transferases (GSTs) and NAD(P)H:quinone oxidoreductase (NQO1). Constitutive hepatic and gastric activities of GST and NQO1 were reduced by 50-80% in nrf2-deficient mice compared with wild-type mice. Moreover, the 2- to 5-fold induction of these enzymes in wild-type mice by the chemoprotective agent oltipraz, which is currently in clinical trials, was almost completely abrogated in the nrf2-deficient mice. In parallel with the enzymatic changes, nrf2-deficient mice had a significantly higher burden of gastric neoplasia after treatment with benzo[a]pyrene than did wild-type mice. Oltipraz significantly reduced multiplicity of gastric neoplasia in wild-type mice by 55%, but had no effect on tumor burden in nrf2-deficient mice. Thus, Nrf2 plays a central role in the regulation of constitutive and inducible expression of phase 2 enzymes in vivo and dramatically influences susceptibility to carcinogenesis. Moreover, the total loss of anticarcinogenic efficacy of oltipraz in the nrf2-disrupted mice highlights the prime importance of elevated phase 2 gene expression in chemoprotection by this and similar enzyme inducers.