Reducing adverse events associated with the glucagon stimulation test for the assessment of growth hormone deficiency in adults with a high prevalence of pituitary hormone deficiencies.

DESIGN: A retrospective review of the adverse events (AEs) in 78 patients during the glucagon stimulation test (GST) for the assessment of growth hormone deficiency (GHD) before and after protocol amendments which aimed to reduce AEs in a group of patients with a high prevalence of pituitary hormone deficiencies. PATIENTS: Based on our observations of frequent AEs during the standard GST protocol in an initial 25 patients (cohort 1), a modified protocol was introduced to include the routine administration of 20 mg of hydrocortisone pre-GST in a subsequent 53 patients (cohort 2). Post hoc analysis of the effect of glucocorticoid dosing pre-GST on AEs was examined in those receiving <20 mg hydrocortisone (group A, n = 19) vs ≥20 mg hydrocortisone (group B, n = 59). MEASUREMENTS: AEs including hypotension, hypoglycaemia and nausea/vomiting. RESULTS: Of the 78 patients undergoing the GST, 79% had ≥2 hormone deficiencies. Rates of AEs were 41% vs 30% for hypotension, 60% vs 28% for hypoglycaemia (p < .05) and 20% vs 13% for nausea/vomiting in cohort 1 compared with cohort 2, respectively. Post hoc analysis revealed lower rates of AEs in those receiving ≥20 mg hydrocortisone (group B) compared to those receiving <20 mg due to a reduction in hypoglycaemic events (82% vs 26%, p < .001) and hypotension (50% vs 27%, p = .05). Similar numbers of patients in group A and group B met criteria for GHD. CONCLUSIONS: In patients with a high prevalence of pituitary deficiencies, a modified GST protocol of additional stress dose glucocorticoid attenuated the frequency of AEs without appearing to compromise the performance of the GST.

Comprehensive Dual- and Triple-Feature Intersectional Single-Vector Delivery of Diverse Functional Payloads to Cells of Behaving Mammals.

The resolution and dimensionality with which biologists can characterize cell types have expanded dramatically in recent years, and intersectional consideration of such features (e.g., multiple gene expression and anatomical parameters) is increasingly understood to be essential. At the same time, genetically targeted technology for writing in and reading out activity patterns for cells in living organisms has enabled causal investigation in physiology and behavior; however, cell-type-specific delivery of these tools (including microbial opsins for optogenetics and genetically encoded Ca2+ indicators) has thus far fallen short of versatile targeting to cells jointly defined by many individually selected features. Here, we develop a comprehensive intersectional targeting toolbox including 39 novel vectors for joint-feature-targeted delivery of 13 molecular payloads (including opsins, indicators, and fluorophores), systematic approaches for development and optimization of new intersectional tools, hardware for in vivo monitoring of expression dynamics, and the first versatile single-virus tools (Triplesect) that enable targeting of triply defined cell types.

Higher risk of phaeochromocytoma/paraganglioma (Phaeo-Pgl) in SDHD than SDHB carriers: an Australian cohort study.

Carriers of succinate dehydrogenase (SDHx) mutations are at risk of developing phaeochromocytomas, catecholamine secreting extra-adrenal paragangliomas and non-secretory head and neck paragangliomas and require lifelong surveillance. There is no current consensus on the optimal surveillance strategy. This study describes the outcomes of a cohort of 50 SDHx mutation carriers followed at a tertiary Australian hospital using a surveillance protocol involving annual clinical review with plasma/urine metanephrines and biennial magnetic resonance imaging from skull base to pelvis.

Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice.

Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity-based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons. Surprisingly, both of these distinct, real-time, and reversible optogenetic modulations acutely rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2 Using fiber photometry, we discovered that native mPFC PV neuronal activity differed between CNTNAP2 knockout and wild-type mice. During social interactions with other mice, PV neuron activity increased in wild-type mice compared to interactions with a novel object, whereas this difference was not observed in CNTNAP2 knockout mice. Together, these results suggest that real-time modulation of E:I balance in the mouse prefrontal cortex can rescue social behavior deficits reminiscent of autism phenotypes.

ß-Carotene supplementation decreases placental transcription of LDL receptor-related protein 1 in wild-type mice and stimulates placental ß-carotene uptake in marginally vitamin A-deficient mice.

The human diet contains ß-carotene as the most abundant precursor of vitamin A, an essential nutrient for embryogenesis. Our laboratory previously showed the importance of ß-carotene metabolism via ß-carotene-15,15'-oxygenase (CMOI) to support mouse embryonic development. However, the mechanisms regulating embryonic acquisition and utilization of ß-carotene from the maternal circulation via placenta remain unknown. We used wild-type (WT) and Lrat(-/-)Rbp(-/-) (L(-/-)R(-/-)) mice, the latter being a model of marginal vitamin A deficiency. Pregnant dams, fed a nonpurified diet sufficient in vitamin A throughout life, were i.p. supplemented with ß-carotene or vehicle at 13.5 d postcoitum (dpc). Effects of this acute maternal supplementation on retinoid and ß-carotene metabolism in maternal (serum, liver) and developing tissues (placenta, yolk sac, embryo) were investigated at 14.5 dpc. We showed that, upon supplementation, placental ß-carotene concentrations were greater in L(-/-)R(-/-) than in WT mice. However, the retinoid (retinol and retinyl ester) concentrations remained unchanged in placenta (and in all other tissues analyzed) of both genotypes upon ß-carotene administration. We also showed that upon a single i.p. ß-carotene supplementation, placental LDL receptor-related protein (Lrp1) mRNA expression was lower in WT mice, and embryonic CmoI mRNA expression was greater in L(-/-)R(-/-) mice. Together, these data suggest a potential role of LRP1 in mediating the uptake of ß-carotene across the placenta and that even a marginally impaired maternal vitamin A status may influence uptake and utilization of ß-carotene by the placenta and the embryo.

Alpha-adrenergic activation upregulates expression of relaxin receptor RXFP1 in cardiomyocytes.

Cardiac RXFP1 was upregulated upon activation of the alpha(1)-adrenergic receptor (AR) through signal pathways involving protein kinase A and C and ERK. In contrast, beta(1)-AR activation downregulated expression of cardiac RXFP1 and it further counteracted the alpha(1)-AR-mediated RXFP1 upregulation.