Sensitivity and mechanisms of taxol-resistant prostate adenocarcinoma cells to Vernonia amygdalina extract

Prostate cancer (PC) patients once Paclitaxel (TAX) treatment responsive later develop hormone refractory PC, thus becoming TAX-insensitive. This underscores the urgent need to develop novel anti-PC therapies. Vernonia amygdalina (VA) could be one such candidate agent. We have shown that androgen-independent PC-3 cells are sensitive to VA treatment in vitro. VA extract (0.01, 0.1 and 1 mg/ml) inhibited DNA synthesis by 12%, 45% (p < 0.05), and 73% (p < 0.01) respectively. In contrast, TAX (0.01, 0.1, and 1 μM) failed to significantly affect cell growth, suggesting TAX resistance. We tested molecular mechanisms which may lend to the observed PC-3 cell VA sensitivity/TAX resistance. Though both VA and TAX stimulated MAPK activity, VA's induction was more intense, but transient, compared to TAX's sustained action. NF-κB activation was inhibited on average by 50% by either 1 mg/ml VA or 1 μM TAX. VA extract caused 35% and 45% increases in c-Myc activity at 10 and 60 min intervals respectively, with the highest stimulation attained 1 h after treatment. In contrast, similar levels were attained by TAX rapidly (within 5 min) and were sustained compared to the slow/multi-phasic action of VA. VA extract treatments had no effect on AKT gene expression, while TAX treatments yielded a four-fold (P < 0.01) increase; and P-glycoprotein (P-gp) activity was inhibited by VA and stimulated by TAX, compared to control (basal ATPase activity). This study shows that TAX-resistant PC-3 cells are sensitive to VA, perhaps explained by differential regulatory patterns of MAPK, c-Myc, AKT, and Pgp activities/expressions.     

Attitudes towards homosexuals in seven Caribbean countries: implications for an effective HIV response

Between 2000 and 2015, the number of people newly infected with HIV in the Caribbean decreased by 76% and HIV-related deaths by 42%. The number of people living with HIV (PLHIV) on anti-retroviral therapy (ART) increased from near zero to 50% (44% to 57%) in 2015. In many Caribbean countries communities of men-who-have-sex-with-other-men (MSM) have higher incidence and prevalence of HIV. They are often stigmatized and subjected to both social and institutional discrimination. This study compared attitudes of the general public obtained through public opinion polls 2013–2014 towards homosexuals and willingness to socialize with them in seven Caribbean countries. Informants were asked if they “hate, tolerate or accept” homosexuals and if they would socialize with them. In St. Vincent 53% indicated they “hate” homosexuals, compared with 12% in Suriname; the converse was observed for those who “accept” homosexuals; 63% of St. Vincent informants would not socialize with homosexuals, compared with 25% in Suriname. Findings for the other 5 countries fell within these ranges. Women were more likely to accept and socialize with homosexuals, as were informants with a tertiary education and “passive” religious believers. These groups are less likely to adhere to a culture of “compulsory heterosexuality” or “hyper-masculinity” dominant among Caribbean men. The homophobic views expressed by these cultures result in stigma and discrimination by members of the “general” public towards MSM. This negatively affects the involvement of MSM in successful national HIV responses. Public messaging, communications campaigns and educational measures need to be employed to change the culture of “compulsory heterosexuality” or “hyper-masculinity” that result in stigma and discrimination of homosexuals to improve early access to services by MSM. Repeat use of well performed opinion polls is one method that can be employed to monitor progress over time in “key” and “general” populations.     

Transferences and Countertransferences in the Analysis of Disorders of the Self

The experience of interiority is central to the psychoanalytic endeavor. Interiority represents the base from which we can recognize sameness and difference so that engagement with others does not obscure or negate a feeling of personal aliveness. We confront a tricky clinical situation when working with individuals who cannot access and articulate interior experience. I discuss the development of interior experience and the clinical dilemmas we face when our patient cannot contact or sustain inner process. In one clinical situation, my patient located desire in the Other and was unable to “find” his own wishes in the dyadic context. In the second, inner states were consistently attributed to the Other who was held in a sadistic position vis-à-vis the self. In both treatment situations, ordinary analytic work tended to recapitulate the patient's reliance on the Other for interior definition.     

A benefit/risk approach towards selecting appropriate pharmaceutical dosage forms - An application for paediatric dosage form selection

The design and selection of new pharmaceutical dosage forms involves the careful consideration and balancing of a quality target product profile against technical challenges and development feasibility. Paediatric dosage forms present particular complexity due to the diverse patient population, patient compliance challenges and safety considerations of this vulnerable population. This paper presents a structured framework for assessing the comparative benefits and risks of different pharmaceutical design options against pre-determined criteria relating to (1) efficacy, (2) safety and (3) patient access. This benefit/risk framework has then been applied to three hypothetical, but realistic, scenarios for paediatric dosage forms in order to explore its utility in guiding dosage form design and formulation selection. The approach allows a rigorous, systematic and qualitative assessment of the merits and disadvantages of each dosage form option and helps identify mitigating strategies to modify risk. The application of a weighting and scoring system to the criteria depending on the specific case could further refine the analysis and aid decision-making. In this paper, one case study is scored for illustrative purposes. However, it is acknowledged that in real development scenarios, the generation of actual data considering the very specific situation for the patient/product/developer would come into play to drive decisions on the most appropriate dosage form strategy.