Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome

Review of 20 patients with glucocorticoid deficiency (three cases also with salt loss) associated with absent tear secretion (19 cases) and achalasia of the cardia (15 cases) revealed neurological abnormalities in 17 including hyper-reflexia, muscle weakness, dysarthria, and ataxia together with impaired intelligence and abnormal autonomic function, particularly postural hypotension. These findings indicate that significant neurological problems are common in this multisystem disorder.     

Quantitative analysis of neuropeptide Y receptor association with ��-arrestin2 measured by bimolecular fluorescence complementation

Background and purpose:

β-Arrestins are critical scaffold proteins that shape spatiotemporal signalling from seven transmembrane domain receptors (7TMRs). Here, we study the association between neuropeptide Y (NPY) receptors and β-arrestin2, using bimolecular fluorescence complementation (BiFC) to directly report underlying protein–protein interactions.

Experimental approach:

Y1 receptors were tagged with a C-terminal fragment, Yc, of yellow fluorescent protein (YFP), and β-arrestin2 fused with the complementary N-terminal fragment, Yn. After Y receptor–β-arrestin association, YFP fragment refolding to regenerate fluorescence (BiFC) was examined by confocal microscopy in transfected HEK293 cells. Y receptor/β-arrestin2 BiFC responses were also quantified by automated imaging and granularity analysis.

Key results:

NPY stimulation promoted association between Y1–Yc and β-arrestin2–Yn, and the specific development of BiFC in intracellular compartments, eliminated when using non-interacting receptor and arrestin mutants. Responses developed irreversibly and were slower than for downstream Y1 receptor–YFP internalization, a consequence of delayed maturation and stability of complemented YFP. However, β-arrestin2 BiFC measurements delivered appropriate ligand pharmacology for both Y1 and Y2 receptors, and demonstrated higher affinity of Y1 compared to Y2 receptors for β-arrestin2. Receptor mutagenesis combined with β-arrestin2 BiFC revealed that alternative arrangements of Ser/Thr residues in the Y1 receptor C tail could support β-arrestin2 association, and that Y2 receptor–β-arrestin2 interaction was enhanced by the intracellular loop mutation H155P.

Conclusions and implications:

The BiFC approach quantifies Y receptor ligand pharmacology focused on the β-arrestin2 pathway, and provides insight into mechanisms of β-arrestin2 recruitment by activated and phosphorylated 7TMRs, at the level of protein–protein interaction.     

Acetate metabolism and aging: An emerging connection

Sirtuins are NAD⁺-dependent protein deacetylases that regulate gene silencing, energy metabolism and aging from bacteria to mammals. SIRT3, a mammalian mitochondrial sirtuin, deacetylates acetyl-CoA synthetase (AceCS2) in the mitochondria. AceCS2 is conserved from bacteria to humans, catalyzes the conversion of acetate to acetyl-CoA and enables peripheral tissues to utilize acetate during fasting conditions. Here, we review the regulation of acetate metabolism by sirtuins, the remarkable conservation of this metabolic regulatory pathway and its emerging role in the regulation of aging and longevity.     

Use of novel prokinetic agents to facilitate return of gastrointestinal motility in adult critically ill patients

PURPOSE OF REVIEW: Intolerance of enteral feeding due to impaired gastrointestinal motility is common in critically ill patients. Strategies to prevent or treat gastrointestinal hypomotility include the use of prokinetic agents. Many currently employed prokinetic agents are associated with serious adverse drug reactions. The novel prokinetic agents - alvimopan, tegaserod, and dexloxiglumide - are reviewed. RECENT FINDINGS: Alvimopan exerts mixed, but generally favorable, effects on restoration of gastrointestinal motility in patients with postoperative ileus. The observation of increased opioid requirements (without increased pain scores) and associated clinical ramifications requires further study. Tegaserod stimulates the peristaltic reflex and improves motility in multiple sites along the gastrointestinal tract. Its efficacy in improving gastrointestinal hypomotility in the critically ill population has not yet been determined. Furthermore, its use has been associated with the development of ischemic colitis and increased requirement for abdominal/pelvic surgery. Dexloxiglumide may be beneficial for improving gastric emptying in critically ill patients, especially those receiving lipid-enriched enteral feeds. SUMMARY: Novel prokinetic agents show promise for management of gastrointestinal hypomotility in the critically ill population. However, further study is required before these agents can be recommended for use.