• Central nervous system histoplasmosis: Multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment

      Wheat, Joseph; Myint, Thein; Guo, Ying; Kemmer, Phebe; Hage, Chadi; Terry, Colin; Azar, Marwan M.; Riddell, James; Ender, Peter; Chen, Sharon; et al. (LIPPINCOTT WILLIAMS & WILKINS, 2018-03)
      Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report literature reviews. Therefore, a larger study of central nervous system (CNS) histoplasmosis is needed in order to guide the approach to diagnosis, and treatment.A convenience sample of 77 patients with histoplasmosis infection of the CNS was evaluated. Data was collected that focused on recognition of infection, diagnostic techniques, and outcomes of treatment.Twenty nine percent of patients were not immunosuppressed. Histoplasma antigen, or anti-Histoplasma antibodies were detected in the cerebrospinal fluid (CSF) in 75% of patients. One year survival was 75% among patients treated initially with amphotericin B, and was highest with liposomal, or deoxycholate formulations. Mortality was higher in immunocompromised patients, and patients 54 years of age, or older. Six percent of patients relapsed, all of whom had the acquired immunodeficiency syndrome (AIDS), and were poorly adherent with treatment. While CNS histoplasmosis occurred most often in immunocompromised individuals, a significant proportion of patients were previously, healthy. The diagnosis can be established by antigen, and antibody testing of the CSF, and serum, and antigen testing of the urine in most patients. Treatment with liposomal amphotericin B (AMB-L) for at least 1 month; followed by itraconazole for at least 1 year, results in survival among the majority of individuals. Patients should be followed for relapse for at least 1 year, after stopping therapy.
    • Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity

      Abbeduto, Leonard; Berry-Kravis, Elizabeth; Sterling, Audra; Sherman, Stephanie; Edgin, Jamie O; McDuffie, Andrea; Hoffmann, Anne; Hamilton, Debra; Nelson, Michael; Aschkenasy, Jeannie; et al. (BMC, 2020-03-24)
      Background The evaluation of treatment efficacy for individuals with fragile X syndrome (FXS) or intellectual disability (ID) more generally has been hampered by the lack of adequate outcome measures. We evaluated expressive language sampling (ELS) as a procedure for generating outcome measures for treatment research in FXS. We addressed: (a) feasibility, (b) practice effects over two administrations, (c) test-retest reliability over the repeated administrations, and (d) construct validity. We addressed these issues for the full sample as well as for subgroups defined by age, IQ, and ASD status. Methods Participants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ < 70). ELS procedures for collecting samples in conversation and narration were followed and analyzed separately. Five measures were derived from transcripts segmented into C-units (i.e., an independent clause and its modifiers): number of C-units per minute (talkativeness), number of different word roots (vocabulary), C-unit length in morphemes (syntax), percentage of C-units containing dysfluency (utterance planning), and percentage of C-units that were fully or partly unintelligible (articulatory quality). ELS procedures were administered twice at 4-week intervals for each participant. Standardized tests and informant reports were administered and provided measures for evaluating construct validity of ELS measures. Results We found low rates of noncompliance, suggesting the task can be completed meaningfully by most individuals with FXS, although noncompliance was higher for younger, lower IQ, and more autistic participants. Minimal practice effects and strong test-retest reliability over the 4-week interval were observed for the full sample and across the range of ages, IQs, and autism symptom severity. Evidence of convergent construct validity was observed for the measures of vocabulary, syntax, and unintelligibility for the full sample and across the range of IQ and autism symptom severity, but not for participants under age 12. Conversation and narration yielded largely similar results in all analyses. Conclusions The findings suggest that the ELS procedures are feasible and yield measures with adequate psychometric properties for a majority of 6 to 23 years with FXS who have ID. The procedures work equally well regardless of level of ID or degree of ASD severity. The procedures, however, are more challenging and have somewhat less adequate psychometric properties for individuals with FXS under age 12.
    • Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response

      Chowdhury, Shamim A K; Warren, Chad M; Simon, Jillian N; Ryba, David M; Batra, Ashley; Varga, Peter; Kranias, Evangelia G; Tardiff, Jil C; Solaro, R John; Wolska, Beata M; et al. (FRONTIERS MEDIA SA, 2020-03-10)
      Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in different genes mainly encoding myofilament proteins and therefore called a "disease of the sarcomere." Despite the discovery of sarcomere protein mutations linked to HCM almost 30 years ago, the cellular mechanisms responsible for the development of this disease are not completely understood and likely vary among different mutations. Moreover, despite many efforts to develop effective treatments for HCM, these have largely been unsuccessful, and more studies are needed to better understand the cellular mechanisms of the disease. In experiments reported here, we investigated a mouse model expressing the mutant cTnT-R92Q, which is linked to HCM and induces an increase in myofilament Ca2+ sensitivity and diastolic dysfunction. We found that early correction of the diastolic dysfunction by phospholamban knockout (PLNKO) was able to prevent the development of the HCM phenotype in troponin T (TnT)-R92Q transgenic (TG) mice. Four groups of mice in FVB/N background were generated and used for the experiments: (1) non-transgenic (NTG)/PLN mice, which express wild-type TnT and normal level of PLN; (2) NTG/PLNKO mice, which express wild-type TnT and no PLN; (3) TG/PLN mice, which express TnT-R92Q and normal level of PLN; (4) TG/PLNKO mice, which express TnT-R92Q and no PLN. Cardiac function was determined using both standard echocardiographic parameters and speckle tracking strain measurements. We found that both atrial morphology and diastolic function were altered in TG/PLN mice but normal in TG/PLNKO mice. Histological analysis showed a disarray of myocytes and increased collagen deposition only in TG/PLN hearts. We also observed increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation only in TG/PLN hearts but not in TG/PLNKO hearts. The rescue of the HCM phenotype was not associated with differences in myofilament Ca2+ sensitivity between TG/PLN and TG/PLNKO mice. Moreover, compared to standard systolic echo parameters, such as ejection fraction (EF), speckle strain measurements provided a more sensitive approach to detect early systolic dysfunction in TG/PLN mice. In summary, our results indicate that targeting diastolic dysfunction through altering Ca2+ fluxes with no change in myofilament response to Ca2+ was able to prevent the development of the HCM phenotype and should be considered as a potential additional treatment for HCM patients.
    • Randomized controlled trial of supportive care interventions to manage psychological distress and symptoms in Latinas with breast cancer and their informal caregivers

      Badger, Terry A; Segrin, Chris; Sikorskii, Alla; Pasvogel, Alice; Weihs, Karen; Lopez, Ana Maria; Chalasani, Pavani; Univ Arizona, Coll Nursing; Univ Arizona, Dept Commun; Univ Arizona, Dept Psychiat; et al. (ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD, 2019-06-12)
      Objective: The purpose of this study was to test two 2-month psychosocial interventions (Telephone Interpersonal Counseling [TIPC] and Supportive Health Education [SHE]) to improve quality of life (QOL) outcomes for Latinas with breast cancer and their informal caregivers. Methods: Two hundred and forty-one Latinas with breast cancer and their caregivers were assessed at baseline, immediately after the 2-month intervention, at 4 and 6 months after baseline. QOL outcomes were psychological distress, symptoms and social support. Results: Linear mixed effects models showed that for cancer survivors at 2 months, TIPC produced lower adjusted mean depression scores compared to SHE. At 4 months, SHE had reduced total number of symptoms, global symptom distress, and social isolation compared to TIPC. Only total number of symptoms was lower in SHE than in TIPC at 6 months. Among caregivers at 2 months, total number of symptoms, global symptom distress, and anxiety were lower, and self-efficacy for symptom management was higher in SHE compared to TIPC. Caregiver depression was lower in TIPC compared to SHE at 4 months. Conclusions: These telephone delivered interventions improved different outcomes. TIPC demonstrated superior benefits for depression management and SHE was more successful in anxiety and cancer-related symptom management.
    • Relationship between a Weighted Multi-Gene Algorithm and Blood Pressure Control in Hypertension

      Phelps, Pamela K; Kelley, Eli F; Walla, Danielle M; Ross, Jennifer K; Simmons, Jerad J; Bulock, Emma K; Ayres, Audrie; Akre, Monica K; Sprissler, Ryan; Olson, Thomas P; et al. (MDPI, 2019-02-28)
      Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis (n = 384; age = 61.0 ± 0.9, 11% non-white). A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1⁻4 as most to least likely to respond based on the algorithmic assessment of individual patient's genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.
    • Treatment for Early, Uncomplicated Coccidioidomycosis: What Is Success?

      Galgiani, John N; Blair, Janis E; Ampel, Neil M; Thompson, George R; Univ Arizona, Coll Med, Valley Fever Ctr Excellence; Univ Arizona, Coll Med, Dept Med (OXFORD UNIV PRESS INC, 2019-09-23)
      The care of primary pulmonary coccidioidomycosis remains challenging. Such infections produce a variety of signs, symptoms, and serologic responses that cause morbidity in patients and concern in treating clinicians for the possibility of extrapulmonary dissemination. Illness may be due to ongoing fungal growth that produces acute inflammatory responses, resulting in tissue damage and necrosis, and for this, administering an antifungal drug may be of benefit. In contrast, convalescence may be prolonged by other immunologic reactions to infection, even after fungal replication has been arrested, and in those situations, antifungal therapy is unlikely to yield clinical improvement. In this presentation, we discuss what findings are clinical indicators of fungal growth and what other sequelae are not. Understanding these differences provides a rational management strategy for deciding when to continue, discontinue, or reinstitute antifungal treatments.
    • Virtual Reality Reward Training for Anhedonia: A Pilot Study

      Chen, K.; Barnes-Horowitz, N.; Treanor, M.; Sun, M.; Young, K.S.; Craske, M.G.; Department of Psychology, University of Arizona (Frontiers Media S.A., 2021)
      Anhedonia is a risk factor for suicide and poor treatment response in depressed individuals. Most evidence-based psychological therapies target symptoms of heightened negative affect (e.g., negative inferential style) instead of deficits in positive affect (e.g., attenuated reward response) and typically show little benefit for anhedonia. Viewing positive scenes through virtual reality (VR) has been shown to increase positive affect and holds great promise for addressing anhedonic symptoms. In this pilot study, six participants with clinically significant depression completed 13 sessions of exposure to positive scenes in a controlled VR environment. Significant decreases were found in self-reported anhedonia, depression, anxiety, and impairments in functioning from baseline to 1-month follow-up. Negative affect decreased over all 13 sessions, and positive affect increased over sessions 8–13. Results suggest that positive experiences in VR may be a novel avenue for the treatment of anhedonia in depressed individuals. © Copyright © 2021 Chen, Barnes-Horowitz, Treanor, Sun, Young and Craske.