Overcoming challenges in managing a high-risk pregnancy with placenta previa and newly diagnosed Bombay phenotype.

BACKGROUND: Bombay phenotype is rare and characterized by a lack of H antigen on the surface of red blood cells (RBCs) with naturally occurring anti-H antibodies. The presence of anti-H necessitates the exclusive use of Bombay phenotype RBCs for transfusion. We present a case of a pregnant woman with Bombay phenotype who required urgent cesarean section delivery due to high-risk placenta previa. CASE DESCRIPTION: A 36-year-old G1P0 woman of Indian origin presented at 36 weeks and 4 days gestation for management of a high-risk pregnancy with complete placenta previa. Bombay phenotype was unexpectedly identified on routine testing. Given the rarity of the blood, advanced gestation, and risk of post-partum hemorrhage associated with complete placenta previa and spontaneous labor, prompt strategic planning commenced for a successful delivery. Two frozen allogeneic Bombay phenotype RBCs were available as part of a concise transfusion plan. Intraoperative cell salvage was successfully employed and allogeneic transfusion was not required. CONCLUSION: Management of patients with rare blood types can be extremely challenging and guidance for those presenting later in pregnancy is scarce. Our patient's gestational age precluded the use of well-known effective strategies, including hemoglobin optimization, autologous and directed donation, and procurement of large quantities of rare blood. Rather, our approach utilized multidisciplinary expertise and strategic planning to yield a successful outcome.

Toward a new predoctoral model: Education and training in clinical psychopharmacology.

A ubiquitous research finding in regional and national studies is that at least 40% of persons with mental disorders cannot access mental health services, and pharmacotherapy in particular. The American Psychological Association's (APA) designated programs for the provision of education and training in clinical psychopharmacology can be of great help in alleviating this national need. We address key developments relevant to the foundation of a predoctoral model of clinical psychopharmacology education and training. To this end, an overview of the Master of Science in Clinical Psychopharmacology (MSCP) program at The Chicago School of Professional Psychology (TCSPP) is presented. TCSPP is now enrolling its eleventh consecutive cohort of MSCP students, many of whom are doctoral students who are concurrently attending various APA accredited Health Service Psychology (HSP) programs. We provide two predoctoral routes for completing MSCP training: (a) a route allowing for the creation of concentrations in clinical psychopharmacology in Health Service Psychology (HSP) doctoral programs, providing up to half of MSCP coursework; and (b) a joint doctoral PsyD or PhD/MSCP program meeting APA accreditation and designation standards integrated into a 5-year curriculum to impart HSP graduates with the competencies to provide both psychotherapy and pharmacotherapy. We conclude with a discussion about the future direction of predoctoral clinical psychopharmacology education and training. Given its emphasis on neuroscience and interdisciplinary health care, such curricular models may help to address the nation's immediate mental health care needs, while serving to enhance the sustainability of HSP education and professional practice in the 21st Century. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Enhancement of transgene expression by the ß-catenin inhibitor iCRT14.

The innate immune response is an essential defense mechanism that allows cells to detect pathogen-associated molecular patterns (PAMPs) like endotoxin or cytosolic DNA and then induce the expression of defensive genes that restrict the replication of viruses and other pathogens. However, the therapeutic DNA used in some gene therapy treatments can also trigger the innate immune response, which activates host cell genes that may inhibit transgene expression. The goal of this study was to enhance transgene expression by inhibiting key components of the innate immune response with small molecule inhibitors (iCRT14, curcumin, Amlexanox, H-151, SC-514, & VX-702). Most of the inhibitors significantly increased transgene (luciferase) expression at least 2-fold, but the ß-catenin/TCF4 inhibitor iCRT14 showed the highest enhancement (16 to 35-fold) in multiple cell lines (PC-3, MCF7, & MB49) without significantly decreasing cellular proliferation. Alternatively, cloning a ß-catenin/TCF4 binding motif (TCAAAG) into the EF1α promoter also enhanced transgene expression up to 8-fold. To further investigate the role of ß-catenin/TCF4 in transgene expression, mRNA-sequencing experiments were conducted to identify host cell genes that were upregulated following transfection with PEI but down-regulated after the addition of iCRT14. As expected, transfection with plasmid DNA activated the innate immune response and upregulated hundreds (687) of defensive genes, but only 7 of those genes were down-regulated in the presence of iCRT14 (e.g., PTGS2 & PLA1A). Altogether, these results show that transgene expression can be enhanced by inhibiting the innate immune response with SMIs like iCRT14, which inhibits ß-catenin/TCF4 to prevent the expression of specific host cell genes.

Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats.

Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of >40 days. Although the in vivo duration of CCRQ CocE's action was <24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE's actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose-response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine's reinforcing and interoceptive effects of >30-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate- and food-reinforced responding, these effects were short-lived, lasting <24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans.

Effects of pramipexole on the reinforcing effectiveness of stimuli that were previously paired with cocaine reinforcement in rats.

RATIONALE: Dopamine D(2)-like agonists maintain responding when substituted for cocaine in laboratory animals. However, these effects appear to be mediated by an interaction with stimuli that were previously paired with cocaine reinforcement (CS). OBJECTIVES: To evaluate the extent to which the pramipexole-maintained and pramipexole-induced responding are influenced by cocaine-paired stimuli. METHODS: Rats were trained to nosepoke for cocaine under fixed ratio 1 (FR1) or progressive ratio (PR) schedules of reinforcement. In FR1-trained rats, pramipexole was substituted for cocaine with injections either paired with CSs, or delivered in their absence. The capacity of experimenter-administered pramipexole to induce FR1 and PR responding for CS presentation was evaluated. The effects of altering stimulus conditions, as well as pretreatments with D(2)- (L: -741,626) and D(3)-preferring (PG01037) antagonists on pramipexole-induced PR responding were also evaluated. RESULTS: When substituted for cocaine, pramipexole maintained responding at high rates when injections were paired with CSs, but low rates when CSs were omitted. Similarly, experimenter-administered pramipexole induced dose-dependent increases in FR1 or PR responding, with high rates of responding observed when the CS was presented, and low rates of responding when CS presentation was omitted. D(2) and D(3) antagonists differentially affected pramipexole-induced PR responding, with L: -741,626 and PG01037 producing rightward, and downward shifts in the dose-response curve for CS-maintained responding, respectively. CONCLUSIONS: These data indicate that pramipexole is capable of enhancing the reinforcing effectiveness of conditioned stimuli, and raise the possibility that similar mechanisms are responsible for the increased occurrence of impulse control disorders in patients being treated with pramipexole.

Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats.

BACKGROUND: A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine's cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine's cardiovascular, convulsant, and lethal effects in male and female rats. METHODS: Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats. RESULTS: Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4h, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity. CONCLUSIONS: Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity.