Light-Sensitive Ruthenium Complex-Loaded Cross-linked Polymeric Nanoassemblies for the Treatment of Cancer.

This work focuses on improving the efficacy of photoactivatable Ru complexes for photodynamic therapy by employing cross-linked nanoassemblies (CNAs) as a delivery approach. The effects of complex photoactivation, hydrophobicity, and solution ionic strength and pH on complex loading and release from CNAs were analyzed. The cell cytotoxicity of CNA formulations was similar to free Ru complexes despite reduced or eliminated DNA interactions. The release rate and the amount of each Ru complex released (%) varied inversely with complex hydrophobicity, while the effect of solution ionic strength was dependent on complex hydrophobicity. Premature release of two photoactivatable prodrugs prior to irradiation was believed to account for higher activity in cells studies compared to DNA interaction studies; however, for photostable 1O2 generator-loaded CNAs this cannot explain the high cytotoxicity and lack of DNA interactions because release was incomplete after 48 hrs. The cause remains unclear, but among other possibilities, accelerated release in a cell culture environment may be responsible.

Structure-activity and immunochemical data provide evidence of developmental- and tissue-specific myosuppressin signaling.

Myosuppressin peptides dramatically diminish contractions of the gut and heart. Thus, delineating mechanisms involved in myosuppressin signaling may provide insight into peptidergic control of muscle contractility. Drosophila myosuppressin (DMS, TDVDHVFLRFamide) structure-activity relationship (SAR) was investigated to identify an antagonist and explore signaling. Alanyl-substituted, N-terminal truncated, and modified amino acid analogs identified residues and peptide length required for activity. Immunochemistry independently provided insight into myosuppressin mechanisms. DMS decreased gut motility and cardiac contractility dose dependently; the different effective concentrations at half maximal-response were indicative of tissue-specific mechanisms. Replacement of aspartic acid 2 (D2) generated an analog with different developmental- and tissue-specific effects; [A2] DMS mimicked DMS in adult gut (100% inhibition), yet decreased larval gut contractions by only 32% with increased potency in pupal heart (126% inhibition). The DMS active core differed across development and in tissues; adult (DHVFLRFamide) and larval gut (TDVDHVFLRFamide), and adult (VFLRFamide) and pupal heart (VFLRFamide). Substitution of D2 and D4 with a modified amino acid, p-benzoyl-phenylalanine, produced developmental- and tissue-specific antagonists. In the presence of protease inhibitors, DMS and VFLRFamide were more effective in adult gut, but lower or unchanged in pupal heart compared to peptide or analog alone, respectively. DMS-specific antisera stained neurons that innervated the gut or heart. This study describes novel antagonists and data to identify developmental- and tissue-specific mechanisms underlying the pleotropic effects of myosuppressin in muscle physiology.

Ceramic nanoparticle assemblies with tailored shapes and tailored chemistries via biosculpting and shape-preserving inorganic conversion.

A novel biosynthetic paradigm is introduced for fabricating three-dimensional (3-D) ceramic nanoparticle assemblies with tailored shapes and tailored chemistries: biosculpting and shape-preserving inorganic conversion (BaSIC). Biosculpting refers to the use of biomolecules that direct the precipitation of ceramic nanoparticles to form a continuous 3-D structure with a tailored shape. We used a peptide derived from a diatom (a type of unicellular algae) to biosculpt silica nanoparticle based assemblies that, in turn, were converted into a new (nonsilica) composition via a shape-preserving gas/silica displacement reaction. Interwoven, microfilamentary silica structures were prepared by exposing a peptide, derived from the silaffin-1A protein of the diatom Cylindrotheca fusiformis, to a tetramethylorthosilicate solution under a linear shear flow condition. Subsequent exposure of the silica microfilaments to magnesium gas at 900 degrees C resulted in conversion into nanocrystalline magnesium oxide microfilaments with a retention of fine (submicrometer) features. Fluid(gas or liquid)/silica displacement reactions leading to a variety of other oxides have also been identified. This hybrid (biogenic/synthetic) approach opens the door to biosculpted ceramic microcomponents with multifarious tailored shapes and compositions for a wide range of environmental, aerospace, biomedical, chemical, telecommunications, automotive, manufacturing, and defense applications.

Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects.

Folate supplementation appears to reduce the risk for neural tube defects (NTDs). Methylenetetrahydrofolate reductase (MTHFR) is a candidate gene in the folate metabolism pathway that has been extensively studied in different human populations. We examined the risk associated with having the thermolabile variant (TT) of MTHFR in a study of 175 American Caucasians with NTDs and their families. We found a significant association in patients compared with 195 unrelated controls [odds ratio (OR) = 2.13, 95% confidence interval (95% CI) = 1.11-4.09)], but not in mothers (OR = 1.29, 95% CI = 0.622-2.67) or in fathers (OR = 1.45, 95% CI = 0.681-3.09). We found no evidence for unequal transmission from parents to an affected child (p > 0.10). We failed to find a previously reported association for a combined haplotype for MTHFR and cystathionine beta-synthase, except in subjects with NTDs compared with 559 pooled controls (OR = 2.87, 95% CI = 1.03-8.03). We found no evidence for an association for a novel CA-repeat polymorphism identified in a gene closely linked to MTHFR (p > 0.10). Our studies continue to suggest that additional candidate genes other than MTHFR may be responsible for an increased risk to NTD in some American Caucasian families.

Retrospective analysis of axial skeleton osteosarcoma in 22 large-breed dogs.

Medical-records of 22 large-breed dogs (>15 kg) with osteosarcoma (OSA) of the axial skeleton were reviewed to determine prevalence of metastasis and survival associated with this neoplasm. All dogs were treated with more than 1 mode of therapy including palliative radiation (n = 12), definitive radiation (n = 8), surgery (n = 7), chemotherapy (n = 12), or some combination of these therapies. Metastasis was documented in 10 of 22 dogs (46%), and the median survival for all dogs was 137 days. Primary cause of death was local tumor recurrence (54%). Breed (retriever versus purebred versus mixed-breed survival was 100, 182, and 264 days, respectively) and radiation therapy protocol (survival in dogs treated with palliative radiation therapy versus those treated with definitive radiation therapy was 79 and 265 days, respectively) were significantly related to survival (P < .05). Prevalence of metastasis and median survival for large-breed dogs with axial skeleton OSA seems to be similar to that reported for large-breed dogs with appendicular skeleton OSA. Definitive radiation therapy may have a role in the treatment of axial skeleton osteosarcoma.

Induced mood and persistence at gaming.

AIMS: Using the affect infusion model (AIM), this study aimed to assess the impact of prior mood on gaming persistence in regular and non-regular gamblers (assumed to be motivated and heuristic decision-makers, respectively). DESIGN, MEASURES AND SETTING: A 2 x 3 experimental design in a laboratory setting employed factors of gambler type (regular, non-regular) and prior mood (happy, neutral, depressed). Measures were number of trials played on a gambling game, and mood ratings (post-mood induction, during and after play). PARTICIPANTS AND INTERVENTIONS: Sixty regular and 60 non-regular gamblers (all male students) were assigned randomly to watch a video inducing one of the three mood conditions. They were then given AUD$10.00 to gamble in a computerized card-cutting game. FINDINGS: AIM predictions were supported: prior mood did not affect gaming persistence for regular gamblers, but non-regulars showed reduced persistence across happy, neutral and depressed moods. After-play mood ratings were related to winnings for regulars, and losing regulars were significantly more unhappy after-play compared to during-play, and compared to both their winning counterparts and non-regulars. Mood and winnings were unrelated for non-regulars, with little during- to after-play mood change. CONCLUSIONS: The findings speak to depression as a causal factor in addictive gambling. Depressed mood did not enhance persistence in regular gamblers, but rather failed to have the inhibitory effect observed in non-regular gamblers. Evidence of mood changes during gambling was obtained, although multiple measures (self-report, physiological indicators, anticipated states) of both affective valence and arousal are advocated for future studies.

Contemporary issues and future directions for research into pathological gambling.

The recent healthy increase in research into all aspects of gambling is noted. The dominant theme accounting for most of this research is the mental disorder model of pathological gambling and measures that have been derived from this conceptualization. It is suggested that an alternative approach focusing on the construct of choice or subjective control over gambling may be a research direction that will ensure that progress is maintained. In this paper a context for the discussion is provided by first identifying briefly fundamental conceptual and methodological issues associated with the mental disorder model. In particular it is argued that the heterogeneity of the diagnosis of pathological gambling makes the research task of assessing truly independent variables extremely difficult. Subsequently an illustrative schema is presented that demonstrates both the potential advantages and some of the complexities associated with the dependent variable of self-control over gambling behaviour. The main advantages are argued to be (a) the focus of research is narrowed to one potential cause of harmful impacts rather than the great diversity of impacts themselves, (b) prospective studies of regular gamblers in real gambling venues may be a key source of insight into the development of pathological gambling and (c) it promotes the development of theoretical links with the mainstream of the discipline of psychology. Despite the conceptual difficulties that may be associated with the variable of self-control, it is suggested that these may be overcome because contemporary research into the addictive behaviours has demonstrated considerable success in the definition and measurement of control and related themes such as craving, restraint and temptation.

Females' coping styles and control over poker machine gambling.

An investigation of the relationship between impaired control over gambling, coping strategies, and demographic variables was conducted by surveying female poker machine players (N = 163) in their gaming venues. Metropolitan (n = 14) and regional (n = 6) gaming venues in Victoria, Australia participated. Control over gambling was measured using the Impaired Control Over Gambling Scale (Baron & Dickerson, 1994). Coping strategies were measured using (Folkman et al., 1986) adaptation of the Revised Ways of Coping Checklist (Vitaliano et al., 1985). MANOVA supported the hypothesis that the lower the control over gambling the greater the reliance on emotion-focused coping (blamed self, wishful thinking, avoidance) with F = 9.92, 13.35, 14.04 respectively, all significant at p <.001. MANOVA failed to supported the hypothesis that problem-focused strategies (problem focus, seek social support) would be significantly related to control over gambling with F =.82 and.21 respectively. Control over gambling was not related to age, employment, relationship status, education, or distress from significant life events, further supporting the relationship between control and coping strategies. Ways in which coping styles might be related to pathological gambling are discussed.

An experimental study of the effect of prior alcohol consumption on a simulated gambling activity.

UNLABELLED: Previous survey research with both clinical populations and random samples of the general population has established that individuals may experience harmful impacts arising from both their gambling and their consumption of alcohol. Experimental study of the interaction of alcohol consumption on gambling is notable for its absence from the literature. AIM: To experimentally study the interaction of alcohol consumption and gambling behaviour. DESIGN: Participants were randomly allocated into two groups--placebo administered and alcohol administered, thus making an independent samples experimental design. SETTING: Laboratory. PARTICIPANTS: Forty young, male, regular EGM players, who also regularly consumed alcohol. MEASUREMENTS: The NEO Personality Inventory; The Scale of Gambling Choices (Revised) (SGC); persistence at gambling while losing, as measured by the number of gambling trials played and amount wagered. FINDINGS: Subjects either received a prior intake of three alcoholic drinks each containing approximately 10 g of pure alcohol (beer or wine) or an equal volume of an equivalent non-alcoholic beverage. The alcohol group persisted for twice as many gaming trials as the placebo group with significantly more players who had consumed alcohol losing all their original cash stake (50% compared with 15% of the placebo group). CONCLUSIONS: The consumption of alcohol appeared to eliminate the strong associations found in placebo group between individual difference measures and persistence. The analogue game was accepted by participants as a valid form of gambling. The result showed that relatively small quantities of alcohol have a significant effect on the psychological processes that underpin self-control over gambling. This finding challenges the conceptual research paradigm of studying co-morbidity or dual-addicted clinical populations as the most appropriate method of understanding how two addictive behaviours interact.

Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization.

Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM(1)-hM(5)) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM(1) and hM(3) CHO cells and inhibited forskolin-activated cAMP accumulation in hM(2) and hM(4) CHO cells. Additionally, it decreased K(+)-stimulated release of [(3)H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to approximately 30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.

The effects of distraction on desensitization and reprocessing.

The present analogue study of seventy-two students with mild spider anxiety assessed the role of distraction in the desensitization and reprocessing of aversive information. Accessing different components of Baddeley's model of short-term memory, three treatment groups involving distraction tasks and one control group maintaining focussed exposure were compared in a pre-test post-test experimental design. The results indicated that all groups experienced a similar reduction in both self-report and heart-rate measures of anxiety. However, at the follow up phase, the groups containing a distraction task showed an increase in anxiety levels significantly greater than that for the control condition. No differences were reported between any of the distraction groups.

Is low AT III a significant risk factor for coronary artery disease? Anecdotal observations.

I report on my 6-year experience identifying the correlation of low antithrombin III (AT III) levels with coronary artery disease in a rural Missouri family practice setting. I measured plasma AT III levels in 78 patients who were at risk for coronary artery disease. I also tracked lipid profiles, HBA1C, blood pressure, body mass index, hostility, and nicotine use. I measured AT III levels using Baxter Diagnostic AG Dade antithrombin III chromogenic coagulation assays of antithrombin III (normal range, 88% to 126%) at the Boone County Hospital Laboratory, Columbia, Missouri. I analyzed the patient records and looked for the worst recording of each of the above risk factors, selecting the highest blood pressure, total cholesterol, LDL cholesterol, triglycerides, HBA1C, weight, and age. I selected the lowest AT III level, which often occurred when the patient was stressed. When the worst risk factors were picked over a long period of time, low AT III correlated with an arbitrary coronary artery disease scale 24% of the time. This negative correlation (r = -.49) was higher than any other risk factor in these selected patients.

The causal role for genital ulcer disease as a risk factor for transmission of human immunodeficiency virus. An application of the Bradford Hill criteria.

BACKGROUND AND OBJECTIVES: Genital ulcer disease (GUD) has been reported to increase the risk for the acquisition of human immunodeficiency virus (HIV). Although many investigators have reported an increased risk for HIV infection in persons with concurrent or previous GUD, not all studies have been designed to determine whether GUD causes an increased risk for HIV infection or acts only as a risk marker for infection. The evidence from the literature is discussed, and the criteria for causal inference proposed by Sir Austin Bradford Hill are applied. GOAL: To evaluate the strength of the association between GUD and infection by HIV. STUDY DESIGN: Case-control, cross-sectional, and cohort studies that examined the association between HIV seroconversion and GUD were chosen from the literature. Twenty-seven epidemiologic studies were selected for analysis, many of which reported separate analyses of the association between HIV infection and herpes simplex virus infection, syphilis, or nonspecified GUD. The studies were analyzed to investigate the magnitude of association between GUD and HIV, and the evidence evaluated using Hill's criteria. RESULTS: Approximately two thirds of the analyses reported a statistically significant association between GUD and HIV infection. Fourteen studies reported 29 separate analyses using a case-control design, 18 of which reported a statistically significant association between GUD (GUD, herpes, and syphilis) and HIV infection, four analyses were of varying significance depending on the analytical technique used, and seven were nonsignificant. Thirteen studies reported 23 separate longitudinal analyses that used a nested case-control or cohort design: 11 reported a significant association, 11 had nonsignificant findings, and results of one study varied. No study reported a statistically significant negative association. When applying the literature to Hill's criteria, all nine criteria for causal inference were met, providing additional evidence that genital ulcers are associated with an increased risk for the development of HIV infection. CONCLUSIONS: The published evidence suggests that GUD increases the risk for HIV acquisition. Few studies, however, have examined carefully the temporal association between preexisting GUD and subsequent HIV acquisition. The analyses that simultaneously controlled for additional risks for HIV infection, such as lifetime sex partners or history of injection drug use, report a generally lower risk for HIV associated with GUD. It is likely that studies that adequately control for risk factors will find a lower risk associated with GUD than was reported in the literature earlier in the HIV epidemic. Future research needs and the problems associated with conducting these types of studies are discussed.

Estimating the extent and degree of Gambling related problems in the Australian population: A national survey.

A stratified random doorknock method was used to interview 2744 respondents in four state capitals in Australia. The interview was in 3 parts with the latter two only administered to regular, once per week or more often gamblers (N=290). The measures completed by this group included the South Oaks Gambling Screen and a range of psychological measures. A conservative interpretation of the results was that "problem gamblers," defined in terms of a range of personal and interpersonal gambling-related costs, comprised 1.16% (±0.34%) of the Australian population. It was estimated that problem players' losses may account for about one quarter of all expenditures on gambling.

Prevalence studies and the development of services for problem gamblers and their families.

Where funded by government, prevalence studies have typically led to the development of services for problem gamblers and their families. Such assessments of the need for services have been seen as the appropriate political response to growing expressions of concern about problem gambling that often follow moves to legislate for an increasing range of gambling products. This theme is apparent for Australia, Canada, New Zealand and the United States. In this paper, initiatives in these different jurisdictions are briefly summarized and tabulated.