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.

Introduction to the Costs of Alzheimer's Disease and Related Dementias.

This special issue is the result of the Michigan Center for Contextual Factors in Alzheimer's Disease (MCCFAD) third Summer Data Immersion (SDI) program held on May 23-26, 2022. Thirty-seven researchers from 17 universities participated in the program, which emphasized racial/ethnic and other contextual factors in the study of Alzheimer's disease and related dementias (ADRD) costs using a team science approach. During the program, data from the Health and Retirement Study were used to investigate multiple topics related to both financial and non-financial costs of ADRD including: (1) life course socioeconomic factors, (2) costs of preclinical ADRD, (3) COVID-19, (4) family members' employment outcomes, (5) geographic contexts, (6) monetary value of unpaid ADRD care, and (7) spousal relations for couples living with ADRD.

COVID-19 Stress and Cognitive Disparities in Black, MENA, and White Older Adults.

BACKGROUND AND OBJECTIVES: Population aging has led to an increased interest in cognitive health and, in particular, the role that stress plays in cognitive disparities. This paper extends previous work by characterizing coronavirus disease 2019 (COVID-19) stress type prevalence and its association with cognitive health in metro-Detroit among Black, Middle Eastern/Arab (MENA), and White older adults. RESEARCH DESIGN AND METHODS: Data come from a regionally representative sample of adults aged 65+ in metro-Detroit (N = 600; MENA n = 199; Black n = 205; White n = 196). We used generalized linear models to compare groups on sociodemographic, objective stress, and social stress indicators. Multiple group structural equation models evaluated whether COVID-19 stress predicted cognitive health and whether that association varied across racial/ethnic groups. RESULTS: MENA and Black older adults reported higher levels of objective stress than Whites. There were no racial/ethnic group differences in social stress. More objective stress was associated with better cognitive health, and more social stress was associated with worse cognitive health. The positive effect of objective stress was especially apparent for White older adults. DISCUSSION AND IMPLICATIONS: Though it appears that minority stress was not exacerbated in the context of pandemic stress, links between greater objective stress and better cognitive health apparent among White older adults were not evident among MENA or Black older adults. Broadening health disparities research by including underrepresented populations allows us to elevate scientific knowledge by clarifying what is universal and what is unique about the stress process.

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.

An asiatic acid derived trisulfamate acts as a nanomolar inhibitor of human carbonic anhydrase VA.

This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1-5, followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21-25. Inhibition assays against hCAs I, II, VA, and IX demonstrated noteworthy outcomes. A derivative of betulinic acid, compound 23, exhibited a Ki value of 88.1 nM for hCA VA, and a derivative of asiatic acid, compound 25, displayed an even lower Ki value of 36.2 nM for the same isoform. Notably, the latter compound displayed enhanced inhibitory activity against hCA VA when compared to the benchmark compound acetazolamide (AAZ), which had a Ki value of 63.0 nM. Thus, this compound surpasses the inhibitory potency and isoform selectivity of the standard compound acetazolamide (AAZ). In conclusion, the research offers insights into the inhibitory potential of selected triterpenoic acids across diverse hCA isoforms, emphasizing the pivotal role of structural attributes in determining isoform-specific inhibitory activity. The identification of compound 25 as a robust and selective hCA VA inhibitor prompts further exploration of its therapeutic applications.

The impact of cannabidiol placebo on responses to an acute stressor: A replication and proof of concept study.

BACKGROUND: Our group has previously reported that cannabidiol (CBD) expectancy alone blunts markers of stress, particularly during anticipation, but it is not clear the extent to which such findings were specific to the methods utilized. AIMS: To examine CBD-related placebo effects on stress reactivity and anticipation and to validate a protocol to be used in a neuroimaging study. METHODS: Forty-eight healthy adults (24 female) were randomly assigned to be informed that they ingested a CBD-containing oil or a CBD-free oil despite receiving the same oil (CBD-free). Following oil administration, participants engaged in a laboratory stressor and were then incorrectly informed that they would engage in a second more difficult task following a waiting period. Subjective state (sedation, energy, stress, anxiety) and heart rate were assessed at baseline, post-oil administration, immediately following the first stressor, and while anticipating the second stressor. RESULTS: Subjective stress and anxiety were significantly elevated immediately following the stressor (p-values < 0.001). CBD expectancy was associated with increased subjective sedation (p < 0.01) and tended to be associated with blunted subjective stress (p = 0.053). Post hoc within-condition pairwise compassions suggested a return to pre-stressor levels during the anticipation period in the CBD condition for subjective stress and anxiety (p = 0.784, 0.845), but not the CBD-free condition (p = 0.025, 0.045). CONCLUSION: Results replicate and extend previous findings that CBD expectancy alone can impact stress- and anxiety-relevant responses in the laboratory context.

Friendship trajectories and health across the lifespan.

Friends are a vital source of social relations throughout the lifespan and across developmental stages. Our knowledge of how friendships develop over time, especially from childhood through adulthood, is limited. Furthermore, it is now recognized that this specific type of relationship influences health across the life course in unique ways. Using the Convoy Model of Social Relations as a guiding framework, this study charts the multiple and unique trajectories of friendship across adulthood and tests whether these trajectories influence health differentially by age. The sample for the study consisted of 553 adults from the longitudinal Social Relations Study. Respondents ranged in age from 13 to 77 at Wave 1 (1992), and included only those who reported a best friend in each wave, that is, Wave 2 (2005) and Wave 3 (2015). Approximately 65% of the respondents were women, and 24.5% were people of color. Latent growth curve analysis identified three trajectories of the presence of friends in one's network over time, two trajectories of positive friend quality, and three for negative quality. The most consistent findings are associated with positive friend relations over time. Gender was associated with friendship quality where women reported more positive friend relations over time, and increasing positive friend relations predicted better health 23 years later. These findings demonstrate that consistent and increasing positive friendships yield health benefits over time, whereas the presence of friends and negative quality does not have an effect. Overall, findings advance understanding of the long-term effects of social relations across the lifespan and life course. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

Network Types and Functional Health in Old Age: It is Not Just the Size of the Network That Matters.

OBJECTIVES: Findings on the effect of network size and support on functional health are mixed. We examine whether network types, that simultaneously incorporate multiple network characteristics, are associated with functional health in late life. METHODS: Data are from the National Social Life, Health, and Aging Project (N = 3005). We estimated the longitudinal effect of membership in five multidimensional network types on disability in six activities of daily living using negative binomial regression, and on mobility (assessed using a timed walk test) using a generalized linear mixed model. RESULTS: Compared to those in the large without strain network, older adults in the small, restricted, high contact network had fewer disabilities but worse mobility, while those in the large network with strain also had worse mobility. DISCUSSION: Care plans focusing on function and mobility should consider multiple aspects of older adults' social networks including network size, diversity, and relationship strain.

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).

Employment Dynamics Among Adult Children at the Onset of Parental Dementia: Variation by Sociodemographic Characteristics.

OBJECTIVES: To examine the influence of sociodemographic factors on employment changes among adult children following onset of parental Alzheimer's disease and related dementia (ADRD). METHODS: We used Health and Retirement Study (2010-2018; N = 20,110) data to examine adult child (ages 50-70) changes in employment and work hours at onset of parental ADRD and potential variation by gender, age, race, ethnicity, and education. RESULTS: Parental ADRD onset was not associated with changes in adult child employment overall, although associations differed substantially across subpopulations defined by education level. Sons with the lowest education were least likely to cease employment, while daughters with the lowest education were most likely to reduce work hours. Sons at older ages were increasingly likely to reduce work hours or end employment following parental ADRD onset. DISCUSSION: The potential impact of parental ADRD on adult child employment is complex and should be considered in the context of sociodemographic factors.

The Impact of Cannabidiol Expectancy on Cortisol Responsivity in the Context of Acute Stress: Associations with Biological Sex.

Background: Cannabidiol (CBD), a nonpsychoactive cannabinoid found in the cannabis plant, has gained interest for its purported stress- and anxiety-reducing effects. However, the mechanisms underlying these effects remain unclear. Our group previously found that CBD expectancy alone resulted in lower state anxiety (vs. CBD-free expectancy) among those who strongly believed it was helpful for such purposes, in addition to influencing physiological measures (i.e., heart rate variability). Aims: Using data collected as part of this previously published larger study, we aimed to explore the extent to which CBD expectancy alone impacts cortisol in the context of a laboratory stressor. Methods: A sample of 43 healthy adults (23 female) participated in one orientation and two experimental laboratory sessions. They received the same oil (CBD-free) during both experimental sessions but were told they received CBD oil in counterbalanced order in one of their sessions. Participants then engaged in a laboratory stressor (the Maastricht Acute Stress Test; MAST) and salivary cortisol samples were collected throughout [T1: baseline; T2: 90-min postabsorption (PA); T3: poststress (0-PS); T4: 10-min poststress (10-PS); T5: 30-min poststress (30-PS)]. Linear marginal models were used for analyses. Results: Findings indicated that a physiological stress response was elicited in the context of the MAST, which is consistent with what has been reported previously. Interestingly, while cortisol levels were significantly lower in the CBD expectancy condition (vs. CBD-free) immediately following the MAST (0-PS) and 10-min later (10-PS), this effect seems to be largely driven by males, evidenced by a three-way interaction. Cortisol levels did not reliably vary across expectancy conditions at any other time point. Conclusion: Overall, these results suggest that CBD expectancy appears to blunt cortisol in anticipation of a stressor, particularly in males. Findings suggest that it is important to consider the impact of drug-related expectations when assessing CBD-related effects on stress-related processes.

Measurement and structural invariance of a neuropsychological battery among Middle Eastern/North African, Black, and White older adults.

OBJECTIVE: There is a lack of guidance on common neuropsychological measures among Arabic speakers and individuals who identify as Middle Eastern/North African (MENA) in the United States. This study evaluated measurement and structural invariance of a neuropsychological battery across race/ethnicity (MENA, Black, White) and language (Arabic, English). METHOD: Six hundred six older adults (128 MENA-English, 74 MENA-Arabic, 207 Black, 197 White) from the Detroit Area Wellness Network were assessed via telephone. Multiple-group confirmatory factor analyses examined four indicators corresponding to distinct cognitive domains: episodic memory (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] Word List), language (Animal Fluency), attention (Montreal Cognitive Assessment [MoCA] forward digit span), and working memory (MoCA backward digit span). RESULTS: Measurement invariance analyses revealed full scalar invariance across language groups and partial scalar invariance across racial/ethnic groups suggesting a White testing advantage on Animal Fluency; yet this noninvariance did not meet a priori criteria for salient impact. Accounting for measurement noninvariance, structural invariance analyses revealed that MENA participants tested in English demonstrated lower cognitive health than Whites and Blacks, and MENA participants tested in Arabic demonstrated lower cognitive health than all other groups. CONCLUSIONS: Measurement invariance results support the use of a rigorously translated neuropsychological battery to assess global cognitive health across MENA/Black/White and Arabic/English groups. Structural invariance results reveal underrecognized cognitive disparities. Disaggregating MENA older adults from other non-Latinx Whites will advance research on cognitive health equity. Future research should attend to heterogeneity within the MENA population, as the choice to be tested in Arabic versus English may reflect immigrant, educational, and socioeconomic experiences relevant to cognitive aging. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.

Longitudinal Associations Between Loneliness and Self-Rated Health Among Black and White Older Adults.

OBJECTIVES: This study examined the longitudinal association between loneliness and self-rated health (SRH), and whether there were race differences between non-Hispanic Black and White adults in these associations. METHOD: A total of 1,407 participants were drawn Social Relations Study, a regional study of social relations across the life span with 3 waves of data collection in 1992, 2005, and 2015 (Wave 1, W1: Mage = 50.28, 28% Black, 59% women). Cross-lagged structural equation models examined the association between loneliness and SRH over 3 waves. We adjusted for baseline age, gender, social network size, and depressive symptoms. RESULTS: There were no race differences in loneliness at any wave. Loneliness W1 was associated with Loneliness W2; Loneliness W2 was associated with Loneliness W3. We had similar findings for associations among SRH. However, only one of the cross-lagged paths was significant. Worse SRH W2 was associated with more Loneliness W3. The only path that varied across race was in the association between SRH W2 and Loneliness W3, and this path was significant only in Whites. DISCUSSION: Findings indicate that worse SRH at later midlife may increase risk for loneliness in later life, particularly for Whites. As a valid indicator of health, SRH can be used in the body of research on health correlates of loneliness as adults age. Use of the current sample of Black and White adults provides nuanced understanding in the ways in which racially diverse adults experience loneliness and should be useful in refining and developing culturally competent interventions for older adults.

Perceptions about THC and CBD effects among adults with and without prior cannabis experience.

BACKGROUND: Cannabis is associated with a range of therapeutic and non-therapeutic, positive and negative effects. While some benefits and harms may be specific to individual cannabinoid constituents (THC, CBD), individual expectancies may also play a role. OBJECTIVES: Evaluate the extent to which individuals hold expectancies about the effects of CBD, THC, and THC & CBD combined, and whether this differs with prior cannabis experience. METHODS: Canadian adults (N = 345; n = 58 no prior cannabis use, n = 287 prior cannabis use) completed a Qualtrics survey. Participants provided information regarding their expectancies about the effects of cannabinoids (THC, CBD, THC & CBD combined) via a 15-item questionnaire, which included various therapeutic (e.g., helps with pain) and non-therapeutic positive (e.g., enhances positive feelings) and negative (e.g., risk for addiction) effects. They recorded their perceptions about the effects of each cannabinoid on a scale (0="definitely not true", 10="definitely true"). Data was analyzed using linear mixed models. RESULTS: For most therapeutic effects, CBD-containing products (CBD, THC & CBD) were rated higher than THC. For most positive and negative non-therapeutic effects, THC-containing products (THC, THC & CBD) were rated higher than CBD. Those with prior cannabis use (vs no prior use) rated all cannabinoids higher regarding their association with many therapeutic and positive effects, while endorsing weaker expectancies about their role in some negative effects. CONCLUSIONS: Adults endorsed stronger expectancies that CBD-containing products are responsible for producing a rage of therapeutic effects. Those with prior cannabis use experience tended to emphasize the benefits and minimize potential harmful effects of cannabinoids.

Characteristics and Predictors of Sleep Among Spousal Care Dyads Living With Chronic Conditions.

OBJECTIVES: Poor sleep is common among older adults with chronic health conditions and their spousal caregivers. However, dyadic sleep patterns among spouses are underexplored within the literature. This study examines dyadic sleep characteristics and associated contextual factors among spousal care dyads. METHODS: Participants included 462 older adult spousal care dyads from the 2015 National Health and Aging Trends Study and National Study of Caregiving (mean ages of care recipients/caregivers = 79 and 76 years, respectively; 22% of dyads were living with dementia). Self-reported sleep included frequency of (a) trouble falling back asleep among dyads, (b) care-related sleep disturbances among caregivers, and (c) trouble initiating sleep among care recipients. Predictors included between-dyad characteristics such as whether respondents had dementia, care burden and support, relationship quality, neighborhood cohesion, and within-dyad characteristics such as demographics, depression, and positive affect. We conducted multilevel dyadic analysis and actor-partner interdependence modeling. RESULTS: Sleep was correlated more among dyads living with dementia than those with other chronic conditions. Care dyads had poorer sleep if caregivers reported higher care burden; however, better relationship quality marginally ameliorated the association. Depressive symptoms had a partner effect on poorer sleep among care dyads, whereas positive emotions and older age only had an actor effect on better sleep for care recipients and spousal caregivers. Neighborhood cohesion, care support, and other demographic characteristics were not associated with dyadic sleep outcomes. DISCUSSION: Addressing both care recipient- and caregiver-related factors may improve sleep health for both members of the care dyad living with chronic conditions.

Development of social convoys: Trajectories of convoy structure and composition from childhood through adulthood.

Personal networks undergo changes in structure and composition throughout the life span, adapting to developmental transitions and changing circumstances in a dynamic way. This study examines stability and change in social convoys from childhood to adulthood and variation in trajectories of convoy characteristics by gender and race. Multilevel models for convoy structure and composition characteristics were estimated using three waves of longitudinal data spanning 23 years. The regionally representative sample included 193 children aged 8 to 12 in Wave 1 (1992) who were surveyed again in their 20s (Wave 2) and 30s (Wave 3). The Wave 1 sample comprised 52% girls, 32% Black children, and 59% White children with average maternal educational attainment of 13 years. Overall, changes in composition, proximity, and contact frequency were observed at each wave. Between Waves 1 and 2, the changes reflect age-normative trends toward network diversification typical of the transition to adulthood, whereas between Waves 2 and 3, the changes were consistent with those expected as young adults settle into stable roles. We also identified convoy characteristics that differed between men and women and between Black and White individuals, emphasizing the importance of considering personal characteristics to fully understand form and function of social relations. Social convoy trajectories early in the life span provide direction for more in-depth examinations of the implications of social ties during these critical life periods. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Multidimensional Social Network Types and Their Correlates in Older Americans.

BACKGROUND AND OBJECTIVES: Social support networks of older adults have been linked to their health and well-being; however, findings regarding the effects of specific network characteristics have been mixed. Additionally, due to demographic shifts increasing numbers of older adults live outside of traditional family structures. Previous studies have not systematically examined the resulting complexity and heterogeneity of older adults' social networks. Our objectives were to examine this complexity and heterogeneity by developing a multidimensional typology of social networks that simultaneously considers multiple structural and functional network characteristics, and to examine differences in network type membership by sociodemographic characteristics, health characteristics, and birth cohort. RESEARCH DESIGN AND METHODS: Participants included 5,192 adults aged 57-85 years in the National Social Life, Health, and Aging Project at rounds 1 (2005-2006) and 3 (2015-2016). Data were collected on social relationships including network size, diversity, frequency of contact, and perceived support and strain in relationships. We used latent class analysis to derive the network typology and multinomial logistic regression to examine differences in network type membership by sociodemographic characteristics, health characteristics, and birth cohort. RESULTS: Older adults were classified into 5 distinct social network types: (i) large, with strain; (ii) large, without strain; (iii) small, diverse, low contact; (iv) small, restricted, high contact; and (v) medium size and support. Membership in these network types varied by age, gender, marital status, race/ethnicity, education, mental health, and birth cohort. DISCUSSION AND IMPLICATIONS: Network typologies can elucidate the varied interpersonal environments of older adults and identify individuals who lack social connectedness on multiple network dimensions and are therefore at a higher risk of social isolation.