Acid-labile mPEG-vinyl ether-1,2-dioleylglycerol lipids with tunable pH sensitivity: synthesis and structural effects on hydrolysis rates, DOPE liposome release performance, and pharmacokinetics.

A family of 3-methoxypoly(ethylene glycol)-vinyl ether-1,2-dioleylglycerol (mPEG-VE-DOG) lipopolymer conjugates, designed on the basis of DFT calculations to possess a wide range of proton affinities, was synthesized and tested for their hydrolysis kinetics in neutral and acidic buffers. Extruded ∼100 nm liposomes containing these constructs in ≥90 mol % 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) produced dispersions that retained their calcein cargo for more than 2 days at pH 7.5, but released the encapsulated contents over a wide range of time scales as a function of the electronic properties of the vinyl ether linkage, the solution pH, and the mPEG-VE-DOG composition in the membrane. The in vivo performance of two different 90:10 DOPE:mPEG-VE-DOG compositions was also evaluated for blood circulation time and biodistribution in mice, using (125)I-tyraminylinulin as a label. The pharmacokinetic profiles gave a t(1/2) of 7 and 3 h for 90:10 DOPE:ST302 and 90:10 DOPE:ST502, respectively, with the liposomes being cleared predominantly by liver and spleen uptake. The behavior of these DOPE:mPEG-VE-DOG formulations is consistent with their relative rates of vinyl ether hydrolysis, i.e., the more acid-sensitive mPEG-VE-DOG derivatives produced faster leakage rates from DOPE:mPEG-VE-DOG liposomes, but decreased the blood circulation times in mice. These findings suggest that the vinyl ether-based PEG-lipid derivatives are promising agents for stabilizing acid-sensitive DOPE liposomes to produce formulations with a priori control over their pH responsiveness in vitro. Our data also suggest, however, that the same factors that contribute to enhanced acid sensitivity of the DOPE:mPEG-VE-DOG dispersions are also likely responsible for their reduced pharmacokinetic profiles.

Effects of temporary psychiatric holds on length of stay and readmission risk among persons admitted for psychotic disorders.

The practice of involuntary psychiatric commitment is central to the acute treatment of persons with severe mental illness and others in psychiatric crisis. Deciding whether a patient should be admitted involuntarily requires weighing respect for autonomy against beneficence, considering the clinical needs of the patient, and navigating ambiguous legal standards. The relative dearth of information about the impact of involuntary commitment on objective patient outcomes complicates matters ethically, legally, and clinically. To address this gap in the literature, we sought to determine the association between temporary psychiatric holds and length of stay and readmission rates among a retrospective sample of adult patients admitted to a large psychiatric hospital with diagnoses of schizophrenia, schizoaffective disorder, mania, and other psychotic disorders. In total, we identified 460 patients and 559 unique encounters meeting our inclusion criteria; 90 of the encounters were voluntary (involving a temporary psychiatric hold) and 469 were involuntary. Univariable and multivariable analyses suggested that temporary psychiatric holds were not significantly associated with either length of stay or readmission rate. These findings are relevant to clinicians who must decide whether to admit a patient involuntarily, as they suggest that making a patient involuntary is not associated with differences in length of stay or readmission risk.

Pseudologia Fantastica: An Elaborate Tale of Combat-related PTSD.

Pseudologia fantastica (PF), also known as mythomania or pathologic lying, is a well-known yet controversial phenomenon in psychiatry. There is no firm conceptualization of PF, nor are there any widely accepted diagnostic criteria for PF. The condition may be related to low self-esteem, and it shows some overlap with narcissistic personality disorder and other Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) cluster B personality disorders. Given the mysteriousness and rarity of PF, there is a dearth of information to guide diagnosis and even more limited information about effective treatments. Here, we discuss a case in which an adult male patient exhibited protracted symptoms that were consistent with PF, which consisted of elaborate falsifications pertaining to a history of military service that had duped even close family members. We describe the patient's presentation and the careful process of confrontation and acquisition of collateral information used to reach the diagnosis, along with the patient's efforts to avoid accepting the truth by constructing a series of even more elaborate stories. Finally, we underscore the importance of maintaining a therapeutic alliance in caring for patients with PF through frequent displays of uniform positive regard, and we describe the approach to treatment used during the patient's hospital stay.

Selective detection of protein crystals by second harmonic microscopy.

The unique symmetry properties of second harmonic generation (SHG) microscopy enabled sensitive and selective imaging of protein microcrystals with negligible contributions from solvated proteins or amorphous protein aggregates. In studies of microcrystallites of green fluorescent protein (GFP) prepared in 500 pL droplets, the SHG intensities rivaled those of fluorescence, but with superb selectivity for crystalline regions. GFP in amorphous aggregates and in solution produced substantial background fluorescence, but no detectable SHG. The ratio of the forward-to-backward detected SHG provides a measure of the particle size, suggesting detection limits down to crystallites 100 nm in diameter under low magnification (10x). In addition to being sensitive and highly selective, second-order nonlinear optical imaging of chiral crystals (SONICC) is directly compatibility with virtually all common protein crystallization platforms.

Challenges and opportunities for new protein crystallization strategies in structure-based drug design.

Structure-based drug design (SBDD) has emerged as a valuable pharmaceutical lead discovery tool, showing potential for accelerating the discovery process,while reducing developmental costs and boosting potencies of the drug that is ultimately selected. SBDD is an iterative, rational, lead compound sculpting process that involves both the synthesis of new derivatives and the evaluation of their binding to the target structure either through computational docking or elucidation of the target structure as a complex with the lead compound. This method heavily relies on the production of high resolution(< 2 Å) 3D structures of the drug target, obtained through X-ray crystallographic analysis, in the presence or absence of the drug candidate.The lack of generalized methods for high quality crystal production is still a major bottleneck in the process of macromolecular crystallization. This review provides a brief introduction to SBDD and describes several macromolecular crystallization strategies, with an emphasis on advances and challenges facing researchers in the field today. Recent trends in the development of more universal macromolecular crystallization techniques, particularly nucleation-based techniques that are applicable to both soluble and integral membrane proteins, are also discussed.