Evaluating Children’s Advocacy Centers’ Response to Child Sexual Abuse

Children’s Advocacy Centers (CACs) play an increasingly significant role in the response to child sexual abuse and other child maltreatment in the United States. First developed in the 1980s, CACs were designed to reduce the stress on child abuse victims and families created by traditional child abuse investigation and prosecution procedures and to improve the effectiveness of the response. According to several experts (Fontana, 1984; Pence and Wilson, 1992; Whitcomb, 1992), child victims were subjected to multiple, redundant interviews about their abuse by different agencies, and were questioned by professionals who had no knowledge of children’s developmental limitations or experience working with children. Child interviews would take place in settings like police stations that would further stress already frightened children. Moreover, the response was hampered because the multiple agencies involved did not coordinate their investigations, and children’s need for services could be neglected

Can Enhanced Diffusion Improve Helioseismic Agreement for Solar Models with Revised Abundances?

Recent solar photospheric abundance analyses (Asplund et al. 2004, 2005; Lodders 2003) have revised downward the C, N, O, Ne, and Ar abundances by 0.15 to 0.2 dex compared to previous determinations of Grevesse & Sauval (1998). With these revisions, the photospheric Z/X decreases to 0.0165 (0.0177 Lodders), and Z to ~0.0122 (0.0133 Lodders). A number of papers report that solar models evolved with standard opacities and diffusion treatment using these new abundances give poor agreement with helioseismic inferences. Here we explore evolved solar models with varying diffusion treatments to reduce the photospheric abundances while keeping the interior abundances about the same as earlier standard models. While enhanced diffusion improves agreement with some helioseismic constraints compared to a solar model evolved with the new abundances using nominal input physics, the required increases in thermal diffusion rates are unphysically large, and none of the variations tried restores the good agreement attained using the earlier abundances. A combination of modest opacity increases, diffusion enhancements, and abundance increases near the level of the uncertainties, while somewhat contrived, remains the most physically plausible means to restore agreement with helioseismology. The case for enhanced diffusion would be improved if the inferred convection-zone helium abundance could be reduced; we recommend reconsidering this derivation in light of new equations of state with modified abundances and other improvements. We also recommend considering, as a last resort, diluting the convection zone, which contains only 2.5% of the sun's mass, by accretion of material depleted in these more volatile elements C, N, O, Ne, & Ar after the sun arrived on the main sequence.Comment: Version 2: 24 pages, 3 figures; Accepted to ApJ with omission of g-mode predictions and discussion that are included in this preprin

Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments and molecular dynamics simulations to identify the D2R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2 and 7 determine the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism through which to fine-tune the intrinsic efficacy of D2R agonists

Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: An 8-year retrospective cohort study

BackgroundCardiac surgical procedures can be associated with significant morbidity and mortality. Recently, it has been recognized that statins might induce multiple biologic effects independent of lipid lowering that could potentially ameliorate adverse surgical outcomes. Accordingly, this study tested the central hypothesis that pretreatment with statins before cardiac surgery would reduce adverse postoperative surgical outcomes.MethodsDemographic and outcomes data were collected retrospectively for 3829 patients admitted for planned cardiac surgery between February 1994 and December 2002. Statin pretreatment occurred in 1044 patients who were comparable with non–statin-pretreated (n = 2785) patients with regard to sex, race, and age. Primary outcomes examined included postoperative mortality (30-day) and a composite morbidity variable.ResultsThe odds of experiencing 30-day mortality and morbidity were significantly less in the statin-pretreated group, with unadjusted odds ratios of 0.43 (95% confidence interval [CI], 0.28-0.66) and 0.72 (95% CI, 0.61-0.86), respectively. Risk-adjusted odds ratios for mortality and morbidity were 0.55 (95% CI, 0.32-0.93) and 0.76 (95% CI, 0.62-0.94), respectively, by using a logistic regression model and 0.51 (95% CI, 0.27-0.94) and 0.71 (95% CI, 0.55-0.92), respectively, in the propensity-matched model, demonstrating significant reductions in 30-day morbidity and mortality. In a subsample of patients undergoing valve-only surgery (n = 716), fewer valve-only patients treated with statins experienced mortality, although these results were not statistically significant (1.96% vs 7.5%).ConclusionsThese findings indicate that statin pretreatment before cardiac surgery confers a protective effect with respect to postoperative outcomes

Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

Effect of losartan on performance and physiological responses to exercise at high altitude (5035 m)

Objective: Altitude-related and exercise-related elevations in blood pressure (BP) increase the likelihood of developing pulmonary hypertension and high-altitude illness during high-altitude sojourn. This study examined the antihypertensive effect and potential exercise benefit of the angiotensin II receptor antagonist losartan when taken at altitude. Methods: Twenty participants, paired for age and ACE genotype status, completed a double-blinded, randomised study, where participants took either losartan (100 mg/day) or placebo for 21 days prior to arrival at 5035 m (Whymper Hut, Mt Chimborazo, Ecuador). Participants completed a maximal exercise test on a supine cycle ergometer at sea level (4 weeks prior) and within 48 hours of arrival to 5035 m (10-day ascent). Power output, beat-to-beat BP, oxygen saturation (SpO2) and heart rate (HR) were recorded during exercise, with resting BP collected from daily medicals during ascent. Before and immediately following exercise at 5035 m, extravascular lung water prevalence was assessed with ultrasound (quantified via B-line count). Results: At altitude, peak power was reduced relative to sea level (p<0.01) in both groups (losartan vs placebo: down 100±29 vs 91±28 W, p=0.55), while SpO2 (70±6 vs 70±5%, p=0.96) and HR (146±21 vs 149±24 bpm, p=0.78) were similar between groups at peak power, as was the increase in systolic BP from rest to peak power (up 80±37 vs 69±33 mm Hg, p=0.56). Exercise increased B-line count (p<0.05), but not differently between groups (up 5±5 vs 8±10, p=0.44). Conclusion: Losartan had no observable effect on resting or exercising BP, exercise-induced symptomology of pulmonary hypertension or performance at 5035 m

Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents.

The development of novel therapeutics is urgently required for diseases where existing treatments are failing due to the emergence of resistance. This is particularly pertinent for parasitic infections of the tropics and sub-tropics, referred to collectively as neglected tropical diseases, where the commercial incentives to develop new drugs are weak. One such disease is schistosomiasis, a highly prevalent acute and chronic condition caused by a parasitic helminth infection, with three species of the genus Schistosoma infecting humans. Currently, a single 40-year old drug, praziquantel, is available to treat all infective species, but its use in mass drug administration is leading to signs of drug-resistance emerging. To meet the challenge of developing new therapeutics against this disease, we developed an innovative computational drug repurposing pipeline supported by phenotypic screening. The approach highlighted several protein kinases as interesting new biological targets for schistosomiasis as they play an essential role in many parasite's biological processes. Focusing on this target class, we also report the first elucidation of the kinome of Schistosoma japonicum, as well as updated kinomes of S. mansoni and S. haematobium. In comparison with the human kinome, we explored these kinomes to identify potential targets of existing inhibitors which are unique to Schistosoma species, allowing us to identify novel targets and suggest approved drugs that might inhibit them. These include previously suggested schistosomicidal agents such as bosutinib, dasatinib, and imatinib as well as new inhibitors such as vandetanib, saracatinib, tideglusib, alvocidib, dinaciclib, and 22 newly identified targets such as CHK1, CDC2, WEE, PAKA, MEK1. Additionally, the primary and secondary targets in Schistosoma of those approved drugs are also suggested, allowing for the development of novel therapeutics against this important yet neglected disease

Mulat-estetiek: ’n Analise van Adam Small se dramas

Opsomming In hierdie artikel word die dramakonvensies van Adam Small ondersoek met besondere aandag aan perspektiewe op die mulat as ’n sosiale gegewe. Hierdie element bied ’n gepaste invalshoek omdat dit enersyds ‘n verskynsel is wat Small in sy dramas en ander skryfwerk aansny en daar andersyds ’n uitgebreide literatuur bestaan waarin oor die dramatiese, lewensbeskoulike en literêr-teoretiese inkleding daarvan besin word. Die werk van onder andere Langston Hughes en Derek Walcott word ondersoek om ’n leesstrategie te ontwikkel waarmee die Small-teks geanaliseer kan word.Web of Scienc

Semi-Analytical Approaches to Local Electroweak Baryogenesis

We examine two semi-analytical methods for estimating the baryon asymmetry of the universe (BAU) generated in scenarios of ``local'' electroweak baryogenesis (in which the requisite baryon number violation and CP violation occur together in space and time). We work with the standard electroweak theory augmented by the addition of a CP violating dimension six operator. We work in the context of a first order phase transition, but the processes we describe can also occur during the evolution of a network of topological defects. Both the approaches we explore deal with circumstances where the bubble walls which convert the high temperature phase to the low temperature phase are thin and rapidly moving. We first consider the dynamics of localized configurations with winding number one which remain in the broken phase immediately after the bubble wall has passed. Their subsequent decay can anomalously produce fermions. In a prelude to our analysis of this effect, we demonstrate how to define the C and CP symmetries in the bosonic sector of the electroweak theory when configurations with nonzero winding are taken into account. Second, we consider the effect of the passage of the wall itself on configurations which happen to be near the crest of the ridge between vacua as the wall arrives. We find that neither of the simple approaches followed here can be pushed far enough to obtain a convincing estimate of the BAU which is produced. A large scale numerical treatment seems necessary.Comment: 31 pages, revtex, one figure, epsf. This is the version to appear in Phys Rev D; only changes are small clarification

Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharma- cology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R