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.

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.

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.

Effects of multiple putative anticarcinogens on the carcinogenicity of trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-1,2,4-oxadiazole.

In an attempt to dissociate the chemotherapeutic from the carcinogenic properties of the antischistosomal and antitrypanosomal nitrovinylfuran trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]1,2,4-oxadiazole [(SQ18506) CAS: 28754-68-9; (E)-5-amino-3-(2-(5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole], potential inhibitors of carcinogenesis were administered to female outbred CD-1 mice before and during exposure to SQ18506. The compounds tested were ascorbic acid, etretinate, butylated hydroxyanisole (BHA), cysteamine hydrochloride, cysteine hydrochloride, dimercaprol, disulfiram, 1,4-dithiothreitol, reduced glutathione, and spermidine phosphate. The primary types of tumors observed were squamous cell carcinomas of the stomach and thymic and nonthymic lymphomas. BHA reduced the incidence of malignant tumors to control levels, whereas cysteine hydrochloride, spermidine phosphate, and disulfiram reduced the incidence of chemically induced tumors by 42, 34, and 32%, respectively. Although cysteamine hydrochloride and disulfiram had no or only a modest effect on the overall incidence of tumors, the data suggested possible tissue-specific anticarcinogenic properties for these agents. Of the 8 antioxidants tested, only 1 had marked anticarcinogenic properties against SQ18506. These data indicate that antioxidant properties alone cannot account for the anticarcinogenic activity of the compounds tested. Coadministration of the anticarcinogen BHA with SQ18506 also blocked the chemotherapeutic effects of this agent on female CD-1 mice infected with Schistosoma mansoni.

Carcinogenicity of the antischistosomal nitrofuran trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-1,2,4-oxadiazole.

The antischistosomal and antitrypanosomal drug trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-1,2,4-oxadiazole [(SQ18506) CAS: 28754-68-9; (E)-amino-3-(2-(5-nitro-2-furyl)-vinyl)-1,2,4-oxadiazole] was carcinogenic for both male and female CD-1 mice when it was administered either in the diet or by gastric intubation. Dose-dependent increases in tumors of the forestomach and lymphatic tissues were observed in all groups receiving SQ18506 including mice infected with Schistosoma mansoni. The predominant tumor observed was squamous cell carcinoma of the forestomach. The presence or absence of schistosome infection did not appear to alter the incidence or distribution of tumors at comparable doses of SQ18506. The incidence of bladder tumors was positively correlated with the dose in gastric intubation studies and inversely correlated with the dose in dietary studies. The carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (CAS: 24554-26-5) was fed to male and female CD-1 mice in the diet as a positive control. The predominant tumor observed in these groups was transitional cell carcinoma of the bladder. These data indicate that SQ18506 is unsuitable for use in the treatment of parasitic diseases.

Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones.

1,2-Dithiol-3-thiones, reported constituents of cruciferous vegetables, are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, and chemoprotective activities. The effects of dietary administration of a substituted 1,2-dithiol-3-thione, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione], a potent antischistosomal agent, on aflatoxin B1 (AFB1) metabolism, DNA adduct formation, and hepatic tumorigenesis were examined in male F344 rats. Rats were fed graded doses of oltipraz (0.01-0.1%) for 4 wk. During the second and third wk of oltipraz feeding rats were gavaged with 250 micrograms of AFB1/kg five times a wk. Rats were finally restored to control diet 1 wk after cessation of AFB1 dosing. At 4 months focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for gamma-glutamyl transpeptidase activity. Treatment with oltipraz at all doses reduced by greater than 90% the volume of liver occupied by gamma-glutamyl transpeptidase-positive foci. Levels of AFB1 bound to hepatic DNA were reduced between 40 and 80% in animals fed increasing doses of dietary oltipraz (0.01-0.1%) for 1 wk prior to a single exposure to AFB1. Feeding of the higher levels of oltipraz led to marked increases in the specific activity of glutathione S-transferases, presumably serving to facilitate the detoxication of the ultimate electrophilic form of AFB1, the 8,9-oxide. At low dietary concentrations of oltipraz (0.01%), the only inductive effects seen were on the activities of selected cytochrome P-450 monooxygenases. Therefore, the protection afforded by oltipraz may be due to both the enhancement of electrophile detoxication pathways as well as modified oxidative metabolism of AFB1. In in vitro metabolism studies with hepatic post-mitochondrial supernatant, low-dose oltipraz pretreatment facilitated the oxidative production of aflatoxins P1 and Q1, but not M1, from AFB1. High-dose (0.1%) oltipraz pretreatment enhanced the primary metabolism of AFB1 to aflatoxins P1, M1, and Q1 as well as the formation of chloroform-insoluble metabolites. Feeding studies with a series of 1,2-dithiol-3-thione and 1,2-dithiol-3-one derivatives of oltipraz demonstrated that the inductive activity for cytochrome P-450-dependent monooxygenases and electrophile detoxication enzymes, such as glutathione S-transferases, could be readily separated by minor modifications of the 1,2-dithiol-3-thione structure. The unsubstituted 1,2-dithiol-3-thione nucleus strongly induced electrophile detoxication enzymes, but not the monooxygenases, and was the most effective inhibitor of the binding of AFB1 to hepatic DNA in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Lipoprotein-acid mucopolysaccharide complexes of human atherosclerotic lesions.

Lipoprotein-acid mucopolysaccharide complexes occurring in different types of human atherosclerotic lesions were isolated and partially characterized. Complexes from fatty streaks and fibrous plaques were extracted from pooled tissues with 0.15 M NaCl, purified by gel filtration, and fractionated by ultracentrifugation. Both low and very low density lipoproteins were present; low density lipoprotein was predominant. The complexes were analyzed for uronic acid, cholesterol, phospholipid, and Ca-2+ contents; there was no significant difference in the relative molar ratios between complexes from fatty streaks and fibrous plaques. Acid mucopolysaccharides were isolated from the complexes and identified by electrophoresis and enzymatic studies. Chondroitin sulfate C and hyaluronic acid were found in complexes from fatty streaks and fibrous plaques. Heparin was detected only in fibrous plaques.

Skeletal muscle GLUT4 protein concentration and aging in humans.

The insulin resistance of aging has been attributed to a postreceptor defect in skeletal muscle. The present study examined whether a reduction in the concentration of the insulin-stimulated glucose transporter (GLUT4) in skeletal muscle was associated with advancing age in men (n = 55) and women (n = 29). Insulin sensitivity (minimal model) was negatively associated (P < 0.001) with age (range, 18-80 years) in men (r = -0.44) and women (r = -0.58). GLUT4 protein concentration in the vastus lateralis was also negatively associated (P < 0.05) with age (men, r = -0.28; women, r = -0.51). There was no relation (P > 0.15) between GLUT4 content in the gastrocnemius and age. GLUT4 concentration in the vastus lateralis was positively associated (P < 0.01) with insulin sensitivity in both sexes (r = 0.42); this relationship persisted in the men after adjusting for overall adiposity, regional adiposity, and cardiorespiratory fitness. These findings suggest that a decrement in GLUT4 protein concentration in skeletal muscle may at least partially contribute to the insulin resistance of aging in humans.

Predictive value of molecular dosimetry: individual versus group effects of oltipraz on aflatoxin-albumin adducts and risk of liver cancer.

Studies in animals and humans have established serum aflatoxin-albumin adducts as biomarkers of exposure to aflatoxin B1 (AFB1), a food-borne hepatocarcinogen. To assess the utility of measurements of aflatoxin-albumin adducts to predict risk of hepatocellular carcinoma (HCC), 123 male F344 rats were dosed with 20 microg of AFB1 daily for 5 weeks after randomization into three groups: no intervention; delayed-transient (500 ppm of oltipraz, weeks 2 and 3 relative to AFB1); or persistent (500 ppm oltipraz, weeks -1 to 5). Serial blood samples were collected from each animal at weekly intervals throughout aflatoxin B1 exposure and assayed for levels of aflatoxin-albumin by radioimmune assay. Area under the curve (AUC) values for aflatoxin-albumin adducts decreased 20 and 39% in the delayed-transient and persistent oltipraz intervention groups, respectively, as compared to no intervention. Similarly, the total incidence of HCC dropped from 83 to 60% (P = 0.03) and 48% (P < 0.01) in these groups. Tumor multiplicity was also reduced in the two oltipraz intervention groups, whereas time to HCC was increased. Mononuclear cell leukemia, a common neoplasm in F344 rats, was seen in 39% of the control animals, whereas the two oltipraz interventions reduced incidence to 18% (P = 0.05) and 13% (P = 0.01), respectively. Overall, a significant association was seen between biomarker AUC and risk of HCC (P = 0.01). However, when the predictive value of aflatoxin-albumin adducts was assessed within treatment groups, there was no association between AUC and risk of HCC (P = 0.56). Thus, aflatoxin-albumin adducts can be useful for monitoring population-based changes induced by interventions, such as in chemoprevention trials, but have limited utility in identifying individuals destined to develop HCC. As a consequence, the use of this biomarker in quantitative risk assessment should be pursued cautiously.

Conceptually new sulfone analogues of the hormone 1alpha, 25-dihydroxyvitamin D(3): synthesis and preliminary biological evaluation.

A conceptually new series of vitamin D(3)-like nonfluorinated and fluorinated 16-ene side chain tert-butyl sulfones 3-7 has been synthesized. Even though these novel C,D-ring side chain analogues of the hormone 1alpha,25-dihydroxyvitamin D(3) (1,1,25D(3)) lack a terminal OH group, thought previously to be essential for high biological activity, they are highly antiproliferative and, in several cases, transcriptionally active in vitro but desirably noncalcemic in vivo. The side chain sulfone group may be binding to the nVDR as a hydrogen-bond acceptor, in contrast to the hydrogen-bond donor function of the 25-OH group of natural 1,25D(3).

Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha, 25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation.

Four new hybrid analogues of 1alpha,25-dihydroxyvitamin D3 (1) have been synthesized in a convergent manner by joining A-ring and C, D-ring fragments. Each hybrid analogue, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analogue with 1beta, 3alpha-substituent stereochemistry (i.e., analogues 3b and 4b) showed a pharmacologically desirable combination of in vitro high antiproliferative activity in two different cell lines and high transcriptional activity with also low calcemic activity in vivo.

1 alpha,25-dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: design, synthesis, and preliminary biological testing.

Aromatic compounds 2a-c, analogs of 1 alpha, 25-dihydroxyvitamin (calcitriol, 1), and heteroaromatic compounds 4a-c and 5a-c, analogs of 19-nor-1 alpha, 25-dihydroxyvitamin D3 (3), were designed to simulate the topology of their biologically potent parent compounds while avoiding previtamin D equilibrium. Convergent and facile total syntheses of the analogs (+)-2b, (+)-2c, (-)-4b, and (-)-5b were achieved via carbonyl addition of regiospecifically formed organolithium nucleophiles to the enantiomerically pure C,D-ring ketone (+)-17, characteristic of natural calcitriol (1). Likewise, hybrid analogs 20a-c were prepared to determine whether incorporation of a known potentiating side chain would lead to increased biological activity. Preliminary in vitro biological testing showed that aromatic analogs (+)-2b, (+)-2c, and 20a-c as well as heteroaromatic analogs (-)-4b and (-)-5b have very low affinities for the calf thymus vitamin D receptor but considerable antiproliferative activities in murine keratinocytes at micromolar concentration. No biological advantage was observed in this keratinocyte assay for the doubly modified hybrid analogs 20a-c over the singly modified parent (+)-2b. Analog (+)-2b, but surprisingly not the corresponding analog 20b differing from (+)-2b only in the side chain, showed considerable activity in nongenomic opening of calcium channels in rat osteosarcoma cells.

Antimalarial, antiproliferative, and antitumor activities of artemisinin-derived, chemically robust, trioxane dimers.

Nine C-10 non-acetal derivatives of the natural trioxane artemisinin (1) were prepared as dimers using some novel chemistry. As designed, each dimer was stable chemically. C-10 Olefinic dimers 7 and C-10 saturated dimers 8-13 all showed good to excellent antimalarial and antiproliferative activities in vitro. Dimers 8, 10, and 12 were especially potent and selective at inhibiting growth of some human cancer cell lines in the NCI in vitro 60-cell line assay.

Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1alpha,25-dihydroxyvitamin D(3): synthesis and biological evaluation.

New C,D-ring side-chain-modified sulfone 4a, with natural 1alpha, 3beta-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1beta, 3alpha-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.

Conversion of pancreas allograft rejection to acceptance by liver transplantation.

BACKGROUND: Liver allografts of PVG(RT1c)-->DA(RT1a) are spontaneously accepted, whereas pancreas, heart, and kidney allografts are rejected. Our previous studies have shown that simultaneous liver and pancreas transplantation prevents pancreas allograft rejection. The aim of this study was to examine the effect of liver transplantation on subsequent pancreas allografts and on ongoing pancreas rejection. METHODS: Heterotopic, duct-ligated segmental pancreas grafts were transplanted into streptozotocin-induced diabetic recipients (60 mg/kg body weight i.p.) with or without orthotopic liver grafting at different times. Experimental design was as follows. Group 1 received PVG-->PVG pancreas syngrafts (n=6); group 2, PVG-->DA pancreas allografts (n=7); groups 3-5, PVG-->DA pancreas allografts followed by liver transplantation on day 2 (n=6), on day 4 (n=5), and on day 6 (n=5), respectively, group 6, PVG-->DA pancreas allografts after liver transplantation at 4 weeks (n=6). RESULTS: The results showed that pancreas allografts in group 2 were rejected from postoperative day 7 to 13. Liver transplantation prevented subsequent pancreas allograft rejection in group 6. Ongoing pancreas rejection was reversed by liver transplantation with subsequent graft acceptance in groups 3-5. Significant graft-infiltrating lymphocyte apoptosis was demonstrated at 2 weeks in pancreas transplants associated with liver grafting. Graft-versus-host disease was not detected in the pancreas recipients. CONCLUSIONS: We conclude that pancreas allografts in the PVG-->DA combination are rejected rapidly with median survival time of 9 days. Liver transplantation can protect subsequent pancreas grafts from rejection and reverse ongoing pancreas graft rejection with subsequent pancreatic acceptance. Graft-infiltrating lymphocyte apoptosis may be associated with the process of graft acceptance.

The effect of experience of illness on health state valuations.

There is increasing interest in health status measurement and the relative weights that patients and the general public attach to different states of health and illness. One important question that has been raised is whether preferences differ according to the characteristics of the respondents, such as their experience of illness. The results presented in this article suggest that current health status has an important effect on the valuations attached to different health states, with those in poorer health generally giving higher valuations. Past experience of illness, on the other hand, appears to have a negligible effect on valuations. These findings pose real problems for policy makers. To the problem of whose values should count can be added the problem of when these values should count, since the results imply that different valuations may be given by the same respondent depending on how recent their experience of illness was.

Effect of prior exercise on maximal short-term power output in humans.

The effect of prior exercise (PE) on subsequent maximal short-term power output (STPO) was examined during cycling exercise on an isokinetic ergometer. In the first series of experiments the duration of PE at a power output equivalent to 98% maximum O2 uptake (VO2max) was varied between 0.5 and 6 min before measurement of maximal STPO. As PE duration increased subsequent STPO fell to approximately 70% of control values after 3-6 min. In series ii the effect of varying the intensity of PE of fixed 6-min duration was studied in five subjects. After PE less than 60% VO2max there was an increase of 12% in STPO, but after greater than 60% VO2max there was a progressive fall in STPO as PE intensity increased, indicating a reduction of approximately 35% at 100% VO2max compared with control values. In series iii we examined the effect on STPO of allowing a recovery period after a fixed intensity (mean = 87% VO2max) of 6 min PE before measurement of STPO. This indicated a rapid recovery of dynamic function with a half time of approximately 32 s, which is similar to the kinetics of PC resynthesis and taken with the other findings suggests the dominant role that PC exerts on the STPO under these conditions.