Rationale
Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in ...rodents.
Objectives
To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated.
Results
In vitro, mouse NPS
1–20
(mNPS
1–20
) and the C-terminal glutamine-truncated mouse NPS
1–19
bound mNPSR with high affinity (
K
i
= 0.203 ± 0.060, 0.635 ± 0.141 nM, respectively) and potently activated intracellular calcium release (EC
50
= 3.73 ± 1.08, 4.10 ± 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose MED: mNPS
1–20
= 0.2 μg, mNPS
1–19
= 0.02 μg), similar to the reference anxiolytic, alprazolam (MED 0.5 μg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS
1–20
= 0.1 μg, mNPS
1–19
= 1.0 μg), like the reference anxiolytic, chlordiazepoxide (MED 56 μg). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS
1–20
= 2.0 μg, mNPS
1–19
= 0.0002 μg) and mNPS
1–20
increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity.
Conclusions
These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.
Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among ...persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances.
Pterygium is a common ocular surface disease characterized by fibrovascular invasion of the cornea and is sight-threatening due to astigmatism, tear film disturbance, or occlusion of the visual axis. ...However, the mechanisms for formation and post-surgical recurrence of pterygium are not understood, and a valid animal model does not exist. Here, we investigated the possible mechanisms of pterygium pathogenesis and recurrence.
First we performed a genome wide expression analysis (human Affymetrix Genechip, >22000 genes) with principal component analysis and clustering techniques, and validated expression of key molecules with PCR. The controls for this study were the un-involved conjunctival tissue of the same eye obtained during the surgical resection of the lesions. Interesting molecules were further investigated with immunohistochemistry, Western blots, and comparison with tear proteins from pterygium patients.
Principal component analysis in pterygium indicated a signature of matrix-related structural proteins, including fibronectin-1 (both splice-forms), collagen-1A2, keratin-12 and small proline rich protein-1. Immunofluorescence showed strong expression of keratin-6A in all layers, especially the superficial layers, of pterygium epithelium, but absent in the control, with up-regulation and nuclear accumulation of the cell adhesion molecule CD24 in the pterygium epithelium. Western blot shows increased protein expression of beta-microseminoprotein, a protein up-regulated in human cutaneous squamous cell carcinoma. Gene products of 22 up-regulated genes in pterygium have also been found by us in human tears using nano-electrospray-liquid chromatography/mass spectrometry after pterygium surgery. Recurrent disease was associated with up-regulation of sialophorin, a negative regulator of cell adhesion, and never in mitosis a-5, known to be involved in cell motility.
Aberrant wound healing is therefore a key process in this disease, and strategies in wound remodeling may be appropriate in halting pterygium or its recurrence. For patients demonstrating a profile of 'recurrence', it may be necessary to manage as a poorer prognostic case and perhaps, more adjunctive treatment after resection of the primary lesion.
To determine factors associated with the occurrence of human immunodeficiency virus (HIV) infection and tuberculosis (TB) disease (HIV-TB) and the associated survival rate, we analyzed patients with ...HIV-TB at Grady Memorial Hospital, Atlanta, Georgia, from 1991 through 2000. Overall, 644 patients with HIV-TB were seen. The number of HIV-TB cases per year was highest in 1992 (102 cases) and declined to 39 cases in 2000. Over time, patients were more likely to be enrolled in the HIV outpatient clinic (P < .01), but, in 1997, only 21 (51%) of 41 patients were enrolled in HIV-infection care programs and only 9 (22%) of 41 received HAART. The 1-year survival rate for patients with HIV-TB was 58% in 1991, 81% in 1994, and 83% in 1997 (P < .001). The increase in survival for patients with HIV-TB between 1991 and 1994 was likely due to improved TB and HIV therapy. More effective strategies for enrolling and maintaining HIV-TB patients in HIV-infection care programs could further increase survival.
To describe the use of an autologous serum-free derived cultivated conjunctival epithelial equivalent in the treatment of extensive recurrent viral papillomata.
Interventional case report.
A ...10-year-old child with extensive recurrent viral papillomata involving the superior and inferior tarsal, forniceal, and bulbar conjunctiva underwent surgical excision of all diseased areas and double freeze-thaw cryotherapy. Autologous serum-free cultivated conjunctival equivalents were used to reconstruct the ocular surface and conjunctival fornices.
Almost complete epithelialization was achieved within 5 days postoperatively. A good cosmetic and functional result was obtained, and no recurrences or cicatricial complications developed during 12-month follow-up.
Transplantation of autologous cultivated conjunctiva was effectively used in the reconstruction of the ocular surface after extensive excision of recurrent viral papillomata. This modality of treatment may be useful in the treatment of ocular surface disorders in which extensive conjunctival and fornix reconstruction is required.
High performance YBCO films have been fabricated using a metallorganic deposition (MOD) approach consisting of a hybrid of Ba–trifluoroacetate (Ba–TFA) with non-fluorine containing Cu and Y solution ...precursors on rolling-assisted-biaxially-textured substrates (RABiTS). A high
J
c of 2.4
MA/cm
2 at 77
K for 0.6
μm YBCO films on RABiTS corresponding to an
I
c over 140
A/cm-w was obtained.
T
c measurements showed sharp transitions with zero resistance above 90
K. Extrapolation of the normal state resistivity results in an intercept below zero at 0
K, indicating the absence of second phases at grain boundaries. This first report on obtaining high
J
c with significantly reduced fluorine in the precursor is important for scale-up to manufacturing since the volume of corrosive hydrofluoric gas (HF), which is a by-product of the conversion, is greatly reduced.
BAK is a pro-apoptotic BCL-2 family protein that localizes to mitochondria. Here we evaluate the function of BAK in several mouse models of neuronal injury including neuronotropic Sindbis virus ...infection, Parkinson's disease, ischemia/stroke, and seizure. BAK promotes or inhibits neuronal death depending on the specific death stimulus, neuron subtype, and stage of postnatal development. BAK protects neurons from excitotoxicity and virus infection in the hippocampus. As mice mature, BAK is converted from anti- to pro-death function in virus-infected spinal cord neurons. In addition to regulating cell death, BAK also protects mice from kainate-induced seizures, suggesting a possible role in regulating synaptic activity. BAK can alter neurotransmitter release in a direction consistent with its protective effects on neurons and mice. These findings suggest that BAK inhibits cell death by modifying neuronal excitability.
In situ mechanical tensile tests coupled with electron backscatter diffraction (EBSD) analysis were conducted using specimens of two 304L steels with ~8 and 10.4% Ni content, respectively. Twinning ...was observed in steel with 10.4% Ni content, whereas steel with 8% Ni content demonstrated martensitic transformation. Testing showed that the kinetics of martensitic transformation in steel with 8% Ni content was influenced by the electron beam current used during EBSD scans. Continuous scanning using 32 nA nominal beam current led to suppression of the phase instability in the near-surface layer, but acceptable comparable-to-the-bulk results were obtained using 8 nA beam current. The exact mechanism of the beam current role is unclear, but it appears to be neutral regarding Kernel Average Misorientation behavior and deformation-induced twinning.
•In situ SEM-EBSD tensile tests were conducted using 304L steels with 8 and 10.4% Ni.•KAM and GROD evolution, twinning, and phase instability were investigated.•Phase transformation in 8% Ni-steel was sensitive to the electron beam current.
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