Synthesis of Rhodamine-Conjugated Lupane Type Triterpenes of Enhanced Cytotoxicity.

Various conjugates with rhodamines were prepared by starting with betulinic acid (BA) and platanic acid (PA). The molecules homopiperazine and piperazine, which were identified in earlier research, served as linkers between the rhodamine and the triterpene. The pentacyclic triterpene's ring A was modified with two acetyloxy groups in order to possibly boost its cytotoxic activity. The SRB assays' cytotoxicity data showed that conjugates 13-22, derived from betulinic acid, had a significantly higher cytotoxicity. Of these hybrids, derivatives 19 (containing rhodamine B) and 22 (containing rhodamine 101) showed the best values with EC50 = 0.016 and 0.019 µM for A2780 ovarian carcinoma cells. Additionally, based on the ratio of EC50 values, these two compounds demonstrated the strongest selectivity between malignant A2780 cells and non-malignant NIH 3T3 fibroblasts. A375 melanoma cells were used in cell cycle investigations, which showed that the cells were halted in the G1/G0 phase. Annexin V/FITC/PI staining demonstrated that the tumor cells were affected by both necrosis and apoptosis.

Synthesis and Enzymatic Evaluation of a Small Library of Substituted Phenylsulfonamido-Alkyl Sulfamates towards Carbonic Anhydrase II.

A small library of 79 substituted phenylsulfonamidoalkyl sulfamates, 1b-79b, was synthesized starting from arylsulfonyl chlorides and amino alcohols with different numbers of methylene groups between the hydroxyl and amino moieties yielding intermediates 1a-79a, followed by the reaction of the latter with sulfamoyl chloride. All compounds were screened for their inhibitory activity on bovine carbonic anhydrase II. Compounds 1a-79a showed no inhibition of the enzyme, in contrast to sulfamates 1b-79b. Thus, the inhibitory potential of compounds 1b-79b towards this enzyme depends on the substituent and the substitution pattern of the phenyl group as well as the length of the spacer. Bulkier substituents in the para position proved to be better for inhibiting CAII than compounds with the same substituent in the meta or ortho position. For many substitution patterns, compounds with shorter spacer lengths were superior to those with long chain spacers. Compounds with shorter spacer lengths performed better than those with longer chain spacers for a variety of substitution patterns. The most active compound held inhibition constant as low as Ki = 0.67 µM (for 49b) and a tert-butyl substituent in para position and acted as a competitive inhibitor of the enzyme.

Adapted MoCA for Use among Arabic-Speaking Immigrants in the United States.

OBJECTIVE: Neuropsychological assessment among U.S. Arabic-speaking older adults is virtually non-existent due to lack of translated measures and normative data, as well as researchers' limited access to Middle Eastern/Arab Americans. The Montreal Cognitive Assessment (MoCA) is the only validated, widely-used dementia screen with Arabic language norms/cutoffs, yet, Arabic MoCA translations vary across countries and studies. We examined utility of a modified translation among Arabic-speaking immigrants in metro-Detroit. METHODS: The Arabic MoCA was modified to reflect consistency with the original English version while remaining meaningful in the Arabic language. The MoCA was then administered to 32 Arabic-speaking adults age 65 + living in metro-Detroit. Eight (25%) had an Alzheimer's disease or related dementia (ADRD) diagnosis. Each item was standardized and Cronbach's alpha assessed reliability. Ordinary least squares models examined whether an ADRD diagnosis predicts the total MoCA score and each item, adjusting for demographics. RESULTS: The mean age of the sample was 73 years old. The alpha was acceptably high at 0.87. Bivariate analyses show those with ADRD diagnosis scored lower overall on the MoCA. However, probability of diagnosis and age were confounded in the sample such that in multivariate analyses ADRD diagnosis did not explain additional variation beyond what is explained by age. Orientation, cube-copy test and serial 7s best distinguished those with ADRD. CONCLUSION: The modified Arabic language MoCA shows promise distinguishing those with an ADRD diagnosis. This translation provides a resource for neuropsychologists looking for translated tests when working with Arabic-speaking patients in the U.S.

Developing an Amide-Spacered Triterpenoid Rhodamine Hybrid of Nano-Molar Cytotoxicity Combined with Excellent Tumor Cell/Non-Tumor Cell Selectivity.

Asiatic acid, a pentacyclic triterpene, was converted into a series of piperazinyl, homopiperazinyl, and 1,5-diazocinyl spacered rhodamine conjugates, differing in the type of spacer and the substitution pattern on the rhodamine moiety of the hybrids. The compounds were tested for cytotoxic activity in SRB assays and compound 12, holding an EC50 of 0.8 nM, was the most cytotoxic compound of this series, but compound 18 (containing a ring expanded 1,5-diazocinyl moiety and n-propyl substituents on the rhodamine) was the most selective compound exhibiting a selectivity factor of almost 190 while retaining high cytotoxicity (EC50 = 1.9 nM, for A2780 ovarian carcinoma).

Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates.

Acetylated triterpenoids betulin, oleanolic acid, ursolic acid, and glycyrrhetinic acid were converted into their succinyl-spacered acetazolamide conjugates. These conjugates were screened for their inhibitory activity onto carbonic anhydrase II and their cytotoxicity employing several human tumor cell lines and non-malignant fibroblasts. As a result, the best inhibitors were derived from betulin and glycyrrhetinic acid while those derived from ursolic or oleanolic acid were significantly weaker inhibitors but also of diminished cytotoxicity. A betulin-derived conjugate held a Ki = 0.129 µM and an EC50 = 8.5 µM for human A375 melanoma cells.

Ureidobenzenesulfonamides as Selective Carbonic Anhydrase I, IX, and XII Inhibitors.

Sulfonamides remain an important class of drugs, especially because of their inhibitory effects on carbonic anhydrases. Herein, we have synthesized several sulfonamides and tested them for their inhibitory activity against carbonic anhydrases hCA I, hCA II, hCA IX, and hCA XII, respectively. Thereby, biphenyl- and benzylphenyl-substituted sulfonamides showed high selectivity against hCA IX and hCA XII; these enzymes are common targets in the treatment of hypoxic cancers, and noteworthy inhibitory activity was observed for several compounds toward hCA I that might be of interest for future applications to treat cerebral edema. Compound 3 (4-[3-(2-benzylphenyl)ureido]benzenesulfonamide) held an exceptionally low Ki value of 1.0 nM for hCA XII.

Beyond the Nuclear Family: Children's Social Networks and Depressive Symptomology.

This study identified social network profiles among children, determined whether profiles vary across sociodemographic characteristics, and investigated links between childhood profiles and depressive symptomology using three waves of data spanning 23 years (Wave 1, 1992 Metro-Detroit representative sample: n = 193, ages 8-12). Latent profile analysis revealed three profiles: Close Family (22%), Varied Family (57%), Friend and Family (21%). White children were more likely than Black children to be in the Friend and Family profile. Children in the Close Family profile reported the lowest levels of depressive symptomology in childhood, but exhibited the steepest increase over time. Findings suggest that close, family centric networks are protective in childhood, but less so as children develop into adulthood, highlighting the importance of considering developmental perspectives.

Against the nihilism of 'legal age change': response to Räsänen.

Räsänen has attempted to make a moral case for permitting some people to change their legal age: if someone considers that their chronological age does not correspond to their emotional age or biological age, and they face age-based discrimination as a result, they may change the legal record of their age. This response considers some of the problems with Räsänen's paper, including its reliance on equivocation. It concludes that what is billed as a moral argument turns out to be a conflicted case for deception which relies on a nihilistic outlook on reality.

Conscientious objection: unmasking the impartial spectator.

Hoping to bring some objectivity to the debate, Ben-Moshe has argued that conscientious objection in medicine should be accommodated based on its concordance with the 'impartial spectator', a metaphor for conscience drawn from the writings of Adam Smith. This response finds fault with this account on two fronts: first, that its claim to objectivity is unsubstantiated; second, that it implicitly relies on moral absolutes, despite claiming that conscience is a social construct, thereby calling its coherence and claims into question. Briefly, a traditional account of conscience is then described, before ending with a related thesis for future discussion.

Hormone replacement therapy: informed consent without assessment?

Florence Ashley has argued that requiring patients with gender dysphoria to undergo an assessment and referral from a mental health professional before undergoing hormone replacement therapy (HRT) is unethical and may represent an unconscious hostility towards transgender people. We respond, first, by showing that Ashley has conflated the self-reporting of symptoms with self-diagnosis, and that this is not consistent with the standard model of informed consent to medical treatment. Second, we note that the model of informed consent involved in cosmetic surgery resembles the model Ashley defends, and that psychological assessment and referral is recognised as an important aspect of such a model. Third, we suggest that the increased prevalence of psychiatric morbidity in the transgender population arguably supports the requirement of assessment and referral from a mental health professional prior to undergoing HRT.

Can conscientious objection lead to eugenic practices against LGBT individuals?

In a recent article in this journal, Abram Brummett argues that new and future assisted reproductive technologies will provide challenging ethical questions relating to lesbian, gay, bisexual and transgender (LGBT) persons. Brummett notes that it is likely that some clinicians may wish to conscientiously object to offering assisted reproductive technologies to LGBT couples on moral or religious grounds, and argues that such appeals to conscience should be constrained. We argue that Brummett's case is unsuccessful because he: does not adequately interact with his opponents' views; equivocates on the meaning of 'natural'; fails to show that the practice he opposes is eugenic in any non-trivial sense; and fails to justify and explicate the relevance of the naturalism he proposes. We do not argue that conscience protections should exist for those objecting to providing LGBT people with artificial reproductive technologies, but only show that Brummett's arguments are insufficient to prove that they should not.

Mistakes and missed opportunities regarding cosmetic surgery and conscientious objection.

In her paper 'Cosmetic surgery and conscientious objection', Minerva rightly identifies cosmetic surgery as an interesting test case for the question of conscientious objection in medicine. Her treatment of this important subject, however, seems problematic. It is argued that Minerva's suggestion that a doctor has a prima facie duty to satisfy patient preferences even against his better clinical judgment, which we call Patient Preference Absolutism, must be regarded with scepticism. This is because (1) it overlooks an important distinction regarding autonomy's meaning and place in clinical practice, and (2) it makes obsolete the important concepts of expert clinical judgment and beneficence. Finally, we discuss two ideas which emerge from consideration of cosmetic surgery in relation to conscientious objection. These are the possible analogy between clinical judgment and conscientious objection, and the possible role the goals of medicine can play in defining the scope of conscientious objection.

Clinical Experience With Once-Daily Dapsone Gel, 7.5% Monotherapy in Patients With Acne Vulgaris.

BACKGROUND: Dapsone gel, 7.5% is a topical medication approved for acne in patients aged 12 years and older. Clinical trials have demonstrated the safety and efficacy of once-daily dapsone gel, 7.5% in patients with moderate acne. OBJECTIVE: The objective of this report is to describe the clinical course of 8 patients who participated in a 12-week program using once-daily dapsone gel, 7.5% as monotherapy for acne in a real-world clinical setting. MONOTHERAPY PROGRAM: Male and female adults and adolescents with facial acne, representing a broad range of ages, skin phototypes, and ethnicities, and with no prior use of dapsone gel, 7.5% applied the product once daily for 12 weeks as monotherapy for acne. Photographs were taken at baseline and at 12 weeks. The treating dermatologists recorded observations of baseline disease, treatment tolerability, and outcomes. An independent rater assessed Global Acne Assessment Score (GAAS) at baseline and at 12 weeks based on photographs. Patients provided testimonials of their experience with treatment. PROGRAM OUTCOMES: Acne improvement was evident in the photographs of the 8 patients. Changes in GAAS at week 12 of treatment, as assessed by an independent rater, ranged from 1- to 3-grade improvement from baseline. CONCLUSION: Photographs, dermatologist reports, and patient commentary in an office-based practice demonstrated that 12 weeks of treatment with only topical dapsone gel, 7.5%, applied once daily, was effective and well tolerated as a stand-alone treatment in 8 patients with facial acne vulgaris, with results that are consistent with the phase 3 pivotal trials. J Drugs Dermatol. 2018;17(6):602-608.

The history of autonomy in medicine from antiquity to principlism.

Respect for Autonomy (RFA) has been a mainstay of medical ethics since its enshrinement as one of the four principles of biomedical ethics by Beauchamp and Childress' in the late 1970s. This paper traces the development of this modern concept from Antiquity to the present day, paying attention to its Enlightenment origins in Kant and Rousseau. The rapid C20th developments of bioethics and RFA are then considered in the context of the post-war period and American socio-political thought. The validity and utility of the RFA are discussed in light of this philosophical-historical account. It is concluded that it is not necessary to embrace an ethic of autonomy in order to guard patients from coercion or paternalism, and that, on the contrary, the dominance of autonomy threatens to undermine those very things which have helped doctors come to view and respect their patients as persons.

A medical curriculum in transition: audit and student perspective of undergraduate teaching of ethics and professionalism.

INTRODUCTION: The General Medical Council (GMC) stipulates that doctors must be competent professionals, not merely scholars and practitioners. Medical school curricula should enable students to develop professional values and competencies. Additionally, medical schools are moving towards integrated undergraduate curricula, Cardiff's C21 being one such example. METHODS: We carried out an audit to determine the extent to which C21 delivers GMC professionalism competencies, and a student questionnaire to explore student perspective on ethics and professionalism. RESULTS AND DISCUSSION: C21 delivers explicit or implicit teaching for all major GMC competencies, though some missed opportunities remain. The questionnaire responses showed that most students value ethics and professionalism teaching, and that it is most well received when delivered in a variety of ways and contexts throughout the curriculum. We also note that some respondents confuse ethics and professionalism with the policing of student behaviour. CONCLUSIONS: C21 and curricula like it offer many opportunities for nurturing ethically and professionally competent physicians. Students appear to value this, though there remains confusion between medical school discipline and ethics and professionalism which needs further explication.

Euthanasia in Belgium: legal, historical and political review.

This article describes and evaluates the Belgian euthanasia experience by considering its practice and policy, both before and after the formal decriminalisation of euthanasia in 2002. The pre-legal practice of euthanasia, the evolution of euthanasia legislation, criticism of this legislation, the influence of politics, and later changes to the 2002 Act on Euthanasia are discussed, as well as the subject of euthanasia of minors and the matter of organ procurement. It is argued that the Belgian euthanasia experience is characterised by political expedition, and that the 2002 Act and its later amendments suffer from practical and conceptual flaws. Illegal euthanasia practices remain a live concern in Belgium, something which nations who are seeking to decriminalise euthanasia should consider.

The Efficacy and Safety of Topical Dapsone Gel, 5% for the Treatment of Acne Vulgaris in Adult Females With Skin of Color.

BACKGROUND: Topical dapsone gel, 5% is approved for treatment of acne vulgaris but has not been studied specifically in women with skin of color (SOC; Fitzpatrick skin types IV, V, or VI). OBJECTIVE: Evaluate safety and efficacy of dapsone gel, 5% applied topically twice daily for 12 weeks in women with SOC. METHODS: Females with SOC aged 18 years and older with facial acne participated in a multicenter, open-label, single-group, 12-week pilot study of twice-daily monotherapy with dapsone gel, 5%. The investigator-rated 5-point Global Acne Assessment Score (GAAS) was used to assess efficacy. The impact of acne on subjects was assessed using the validated Acne Symptom and Impact Scale (ASIS). RESULTS: The study enrolled and treated 68 women with SOC and facial acne. GAAS decreased significantly from baseline to week 12 (mean, -1.2 [95% CI, -1.4, -1.0]; P<.001), a 39.0% improvement. Overall, 42.9% of subjects were responders based on a GAAS of 0 or 1 at week 12. Subjects also experienced significant reductions in mean total lesions (52% decrease), inflammatory lesions (65%), and comedo counts (41%; all P<.001). Dapsone gel, 5% monotherapy was associated with significant improvement in subject-assessed acne signs (P<.001) and impact on quality of life (QOL; P<.001), based on ASIS. Dapsone gel, 5% used twice daily was well tolerated, with no treatment-related adverse events. The local dermal tolerability scores tended to remain stable or decrease from baseline to week 12. CONCLUSIONS: Monotherapy with dapsone gel, 5% administered twice daily was safe and effective for treatment of facial acne in women with SOC. Significant improvement in overall acne severity and both inflammatory lesions and comedones was observed. Further, study subjects reported considerable improvement in both acne signs and impact on QOL.

Familism, Social Network Characteristics, and Well-being among Older Adults in Mexico.

Familism, is a cultural value considered to be central to Mexican culture. Older generations are thought to more strongly adhere to familistic values; however, little is known about the implications of familism in late-life. The goal of the current study was to examine links between familism, social network characteristics, and well-being among Mexican older adults. A sample of 556 older adults (50-99 years old) was drawn from the Study of Social Relations and Well-being in Mexico. Various aspects of social network characteristics and familism varied by age, gender, and education status. Familism was correlated with contact frequency and geographic proximity, but not proportion of family in network. Regression analyses indicated higher familism was associated with better psychological and physical well-being, yet familism interacted with proportion of family to predict both self-rated health and chronic conditions indicating that a discrepancy between familistic values and actual family support may be detrimental for older Mexicans' physical health. The discussion highlights the complex interrelationships and potential protective effects of familism. Future research should continue to examine the implications of familism and family relationships in the Mexican context; in particular, how generational shifts in familism influence intergenerational relations and well-being.

Family relations and health over the life course. A Lebanese perspective.

The link between family relations and well-being in old age has received ample attention in the international literature, but remains least examined in the Arab region where cultural ideals assume positive intergenerational relations within families as the norm. In this paper, we employ survey data collected in Greater Beirut in 2009 to explore associations between family relations and health. over the life course. We tested (1) the extent to which age and social relation characteristics predict health; and (2) whether the association between age and health is stronger for those who report: smaller social networks and poorer relationship quality. We employed self-rated health and self-reported chronic illness as the health outcome measures and:social network size, positive quality and negative quality with family members as the social relations measures. Our findings suggest that social relations are differentially important depending on the health status indicator examined. The single dimension that influenced both self-rated health and the probability of reporting a chronic illness was positive relationship quality with spouse. Further, social relations, particularly having a negative relationship quality with spouse and adult child, exert stronger effects on both self-rated health and chronic illness for older compared to younger adults. The findings of the present study are important for clinical practitioners who often consider the role and importance of available social resources as they address the health needs of older adults.