Dissociable Contributions of Basolateral Amygdala and Ventrolateral Orbitofrontal Cortex to Flexible Learning Under Uncertainty.

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including the highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, the unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory designer receptors exclusively activated by designer drugs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-/post-reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of the ventrolateral orbitofrontal cortex (vlOFC), but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.

Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease.

OBJECTIVES: Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinson's disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra-brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD. MATERIALS AND METHODS: This open-label pilot study included 6 patients who were assessed in the motoric, cognitive, and neuropsychiatric domains prior to and after RUL UBP ECT. Primary endpoints were changes in total score on the HAM-D-17 and GDS-30 rating scales. RESULTS: Patients were found to improve in motoric and psychiatric domains following RUL UBP ECT without cognitive side effects, both immediately following ECT and at 1-month follow-up. CONCLUSIONS: This study demonstrates that RUL UBP ECT is safe, feasible, and potentially efficacious in treating multiple domains of PD, including motor and mood, without clear cognitive side effects.

Comparison of 2 Doses for ACTH Stimulation Testing in Dogs Suspected of or Treated for Hyperadrenocorticism.

BACKGROUND: Lowering the cosyntropin dose needed for ACTH stimulation would make the test more economical. OBJECTIVES: To compare the cortisol response to 1 and 5 µg/kg cosyntropin IV in dogs being screened for hyperadrenocorticism (HAC) and in dogs receiving trilostane or mitotane for pituitary-dependent HAC. ANIMALS: Healthy dogs (n = 10); client-owned dogs suspected of having HAC (n = 39) or being treated for pituitary-dependent HAC with mitotane (n = 12) or trilostane (n = 15). PROCEDURES: In this prospective study, healthy dogs had consecutive ACTH stimulation tests to ensure 2 tests could be performed in sequence. For the first test, cosyntropin (1 µg/kg IV) was administered; the second test was initiated 4 hours after the start of the first (5 µg/kg cosyntropin IV). Dogs suspected of having HAC or being treated with mitotane were tested as the healthy dogs. Dogs receiving trilostane treatment were tested on consecutive days at the same time post pill using the low dose on day 1. RESULTS: In dogs being treated with mitotane or trilostane, the 2 doses were pharmacodynamically equivalent (90% confidence interval, 85.1-108.2%; P = 0.014). However, in dogs suspected of having HAC, the doses were not pharmacodynamically equivalent (90% confidence interval, 73.2-92.8%; P = 0.37); furthermore, in 23% of the dogs, clinical interpretation of test results was different between the doses. CONCLUSIONS AND CLINICAL RELEVANCE: For dogs suspected of having HAC, 5 µg/kg cosyntropin IV is still recommended for ACTH stimulation testing. For dogs receiving mitotane or trilostane treatment, a dose of 1 µg/kg cosyntropin IV can be used.

In vitro antibacterial activity of NB-003 against Propionibacterium acnes.

NB-003 and NB-003 gel formulations are oil-in-water nanoemulsions designed for use in bacterial infections. In vitro susceptibility of Propionibacterium acnes to NB-003 formulations and comparator drugs was evaluated. Both NB-003 formulations were bactericidal against all P. acnes isolates, including those that were erythromycin, clindamycin, and/or tetracycline resistant. In the absence of sebum, the MIC(90)s/minimum bactericidal concentrations (MBC(90)s) for NB-003, NB-003 gel, salicylic acid (SA), and benzoyl peroxide (BPO) were 0.5/2.0, 1.0/2.0, 1,000/2,000, and 50/200 µg/ml, respectively. In the presence of 50% sebum, the MIC(90)s/MBC(90)s of NB003 and BPOs increased to 128/1,024 and 400/1,600 µg/ml, respectively. The MIC(90)s/MBC(90)s of SA were not significantly impacted by the presence of sebum. A reduction in the MBC(90)s for NB-003 and BPO was observed when 2% SA or 0.5% BPO was integrated into the formulation, resulting in MIC(90)s/MBC(90)s of 128/256 µg/ml for NB003 and 214/428 µg/ml for BPO. The addition of EDTA enhanced the in vitro efficacy of 0.5% NB-003 in the presence or absence of 25% sebum. The addition of 5 mM EDTA to each well of the microtiter plate resulted in a >16- and >256-fold decrease in MIC(90) and MBC(90), yielding a more potent MIC(90)/MBC(90) of ≤1/<1 µg/ml. The kinetics of bactericidal activity of NB-003 against P. acnes were compared to those of a commercially available product of BPO. Electron micrographs of P. acnes treated with NB-003 showed complete disruption of bacteria. Assessment of spontaneous resistance of P. acnes revealed no stably resistant mutant strains.

NB-002, a novel nanoemulsion with broad antifungal activity against dermatophytes, other filamentous fungi, and Candida albicans.

NB-002 is an oil-in-water emulsion designed for use for the treatment of skin, hair, and nail infections. The activity of NB-002 was compared to the activities of the available antifungal drugs against the major dermatophytes responsible for cutaneous infections, Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum spp., as well as 12 other genera of filamentous fungi. NB-002 consistently displayed fungicidal activity against all dermatophytes. The comparator compounds were either fungistatic or fungicidal, and for some strain-drug combinations, tolerance was observed. Assessment of the development of spontaneous resistance to NB-002 in different dermatophyte species yielded few stably resistant mutants. For filamentous nondermatophyte fungi, the MIC range varied from 0.06 to 0.5 microg/ml for Alternaria spp. to 2 to 8 microg/ml for Paecilomyes spp. NB-002 had activity against both azole-susceptible and -resistant Candida albicans yeast isolates, with MIC(90)s of 2 microg/ml, respectively, and minimum fungicidal concentrations at which 90% of isolates are inhibited of 4 and 8 microg/ml, respectively. The kinetics of the fungicidal activity of NB-002 against T. rubrum isolates were compared to those of the other antifungal drugs. NB-002 killed both mycelia and microconidia even when the fungal forms were dormant or not actively growing. Electron micrographs of mycelia and spores treated with NB-002 showed the significant disruption of the fungal structure. The in vitro broad coverage of NB-002 against filamentous fungi, dermatophytes, and C. albicans, as well as its rapid fungicidal activity, warrants further investigations to ascertain if NB-002 would be useful for the treatment of cutaneous mycoses.

Enhanced transformation of polycyclic aromatic hydrocarbons using a combined Fenton's reagent, microbial treatment and surfactants.

The potential for using Fenton's reagent (H(2)O(2)+ Fe(2+)) as an advanced oxidation pretreatment process to enhance microbial transformation of two model polycyclic aromatic hydrocarbons, anthracene and benzo[a]pyrene, in an aqueous system was evaluated. Fenton's reagent at a concentration of 0.5% H(2)O(2) and 10 mM Fe(2+) (molar ratio, 15:1) was most effective in transforming anthracene at pH 4. Application of non-ionic surfactants during Fenton's pre-treatment was found to be more effective in the transformation of both anthracene and benzo[a]pyrene. The extent of removal of substrates by a combined Fenton's-biotreatment was 2-4 times higher than with Fenton's treatment or biotreatment alone. In a chemical-biological treatment train, 48 h of Fenton's pre-treatment in the presence of a non-ionic surfactant, followed by 7 days of biological treatment resulted in 80-85% removal of PAHs (100 ppm).

Role of arterial design on pulse wave reflection in a fractal pulmonary network.

A novel interpretation of pulmonary arterial input impedance was evaluated for the lung as a fractal vascular network. We hypothesized that local sources of reflection introduce trends of global reflection into the input impedance spectra. These trends are related to the network topology, geometry, and design according to Rb = Rdx, where Rb is the branching ratio, Rd is the diameter ratio, and x is the fractal dimension quantifying design. Simulations using values of Rd and x, which were derived morphometrically, confirmed two patterns of global reflection: a continuous trend attributed to a single effective site of reflection caused by frequency-dependent sources of impedance contrast and a discrete trend arising from a longitudinal distribution of frequency-independent sources of reflection. The continuous trend depended only on the network parameter Rd, whereas the discrete trend depended on Rd and x. Our results indicate that the impedance-matching properties of a deterministic pulmonary fractal network encode arterial geometry and topology via function and that typical values of Rd and x for the pulmonary circulation facilitate shear stress amplification in its peripheral vessels. Thus, inasmuch as shear forces may be involved in the endothelial mechanisms for pathological, or physiological, vascular remodeling, broadband input impedance analysis may reveal interactions between network organization and vascular function.