Functional consequences of GABAA receptor alpha 4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells

Background: The α4 subunit‐containing γ‐aminobutyric acid (A) receptors (GABA_ARs) are highly expressed primarily at extrasynaptic sites in the dentate gyrus (DG) and thalamus and are suspected to contribute to tonic inhibition that is sensitive to potentiation by gaboxadol and ethanol (EtOH). Global α4 subunit knockout (KO) mice exhibit greatly reduced tonic currents and insensitivity to ataxic, sedative and analgesic effects of gaboxadol compared to wild type (WT) controls. The α4 KO mice were also significantly more sensitive to pentylenetetrazol‐induced seizures. However, no differences were observed between α4 KO and WT mice in other baseline behaviors or in the effects of EtOH on these behaviors. To examine possible functional and pharmacological GABA_AR alterations, and search for causes for the lack of differences in EtOH behaviors we studied the effects of acute EtOH application on GABA_AR‐currents of DG cells from α4 KO and WT control mice complemented by Western blot measurements. Methods: We studied the consequences of α4 subunit deletion using Western immunoblotting and whole cell patch recordings from DG cells in brain slices from α4 KO and WT mice. Results: The magnitude of tonic current and its potentiation by EtOH (10 to 100 mM), alphaxalone (3 μM), and Ro15‐4513 (0.3 μM) was greatly attenuated in α4 KO mice. The kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in α4 KO mice were significantly slower compared to WT mice. Potentiation of mIPSCs by alphaxalone was greatly reduced in α4 KO mice. Ro15‐4513 had no effect on mIPSCs from WT or KO mice. However, mIPSCs of α4 KO mice were significantly more sensitive to EtOH than those from WT mice. The γ2 subunit protein levels were selectively increased in hippocampus and thalamus, but not cortex of α4 KO mice. Conclusions: These data suggest that the global loss of α4 subunits leads to region‐ and cell location‐specific compensatory increases in γ2 subunits, which in turn alter the pharmacological sensitivity of synaptic and extrasynaptic GABA_AR‐currents. Our data also suggests that while enhancement of tonic inhibitory currents by gaboxadol, alphaxalone, and EtOH are reduced, and behavioral sensitivity to gaboxadol and alphaxalone may be reduced, compensatory changes in synaptic GABA_AR subunits may prevent similar reductions in behavioral sensitivity to EtOH.     

The case of "Judge Nodd" and other sleeping judges--media, society, and judicial sleepiness

STUDY OBJECTIVES: Review cases of judicial sleepiness and subsequent outcomes, including media and community attitudes. DESIGN: Index case report and Internet search in English language at 2 recent time points. PARTICIPANTS: Index case and 14 other cases of judicial sleepiness reported on the Internet. MEASUREMENTS: Qualitative review of media and Internet reports. RESULTS: The index and other cases highlighted the role of the media seeking a punitive approach to occupational sleepiness, similar to that observed within the transport sector. In the index case, the judge's driver's license was withdrawn, despite official acknowledgement of effective treatment of sleep apnea. In 10 cases, judicial sleepiness resulted in a retrial and, in up to 5 cases, resulted in dismissal or retirement of the judge. In most cases, the cause of sleepiness was not determinable. CONCLUSION: Judicial sleepiness is not uncommon and is viewed negatively by the media, community, and judicial system. Active monitoring of the judiciary for sleepiness and sleep disorders is suggested.     

Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic fluids for hyperthermia application

In this study, lauric acid-coated, superparamagnetic, nanoparticle-based magnetic fluids of different ferrites (Fe(3)O(4), MnFe(2)O(4), and CoFe(2)O(4)) were prepared and compared in terms of heating ability and biocompatibility to evaluate the feasibility of use in hyperthermia treatment of cancer. All the magnetic fluids prepared had particles of average sizes 9-11 nm. Heating ability of these magnetic fluids was evaluated by calorimetric measurement of specific absorption rate (SAR) at 300 kHz frequency and 15 kA/m field. Fe(3)O(4) and MnFe(2)O(4) showed higher SAR (120 and 97 W/g of ferrite, respectively) than CoFe(2)O(4) (37 W/g of ferrite). In vitro study on BHK 21 cell lines showed dose-dependent cell viability for all the magnetic fluids. Threshold-biocompatible ferrite concentration for all the magnetic fluids was 0.1 mg/mL. Above 0.2 mg/mL, CoFe(2)O(4) was more toxic than the other magnetic fluids. On intravenous injection of different doses (50, 200, and 400 mg/kg body weight) of magnetic fluids in mice, no significant changes in hematological and biochemical parameters were observed for Fe(3)O(4) and MnFe(2)O(4). With CoFe(2)O(4), an increase in SGPT levels at a dose rate of 400 mg/kg body weight was observed, indicating its mild hepatotoxic effect. However, histology of different vital organs showed no pathological changes for all the three magnetic fluids. Further, long term in vivo evaluation of biocompatibility of the lauric acid-coated ferrites is warranted. This study shows that lauric acid-coated, superparamagnetic Fe(3)O(4) and MnFe(2)O(4) may be used for hyperthermia treatment and are to be preferred over CoFe(2)O(4).     

Ivermectin 1% (CD5024) for the treatment of rosacea

Introduction: Rosacea is a chronic and recurrent disease with a variety of cutaneous manifestations. The disorder is a centrofacial inflammatory dermatosis with significant financial, physical and psychological impacts. There are a number of topical, oral and systemic treatments available. Yet, treatment for rosacea remains difficult. The multifactorial nature of the disease combined with an incomplete understanding of the pathophysiology is challenging for providers and patients.

Areas covered: This article provides an in-depth review of rosacea treatment and emerging use of ivermectin 1% cream for papulopustular rosacea based on multiple clinical trials. The PubMed database was searched using the combination of keywords "ivermectin, rosacea, and papulopustular."

Expert opinion: Topical ivermectin 1% cream has emerged as a novel agent for treatment of papulopustular rosacea. The drug targets the Demodex mite which is increased in patients with rosacea. Though ivermectin 1% is a clinically efficacious medication, poor adherence continues to remain an issue due to topical application. Ultimately, the agent has the potential to be an effective drug when used as a single or combination agent. With the move to limit chronic antibiotic use, topical agents such as ivermectin 1% will continue to thrive as a specialized niche in the rosacea market.     

Effectiveness of behavior graded activity on exercise adherence and physical activity in hip and knee osteoarthritis – A systematic review

BackgroundOsteoarthritis (OA) has a major impact on daily life and often leads to avoidance of physical activity. A lack of regular physical activity in people with OA of the hip or knee is an important risk factor for further functional decline. Recently developed and evaluated exercise program called the behavioral graded activity (BGA) program acts as an approach to enhance adherence to exercises that lead to a more physically active lifestyle. The purpose of this systematic review is to identify Randomized Controlled Trials (RCT) on BGA interventions for hip and knee OA and to provide summary of current evidence.MethodsThe database searched with the keywords (knee osteoarthritis, hip osteoarthritis, behavior graded activity, behavior physical therapy, physical activity), in Cochrane Library (Cochrane Database of Systematic Reviews), PubMed, MEDLINE Plus, PEDro and CINAHL for studies published from January 2000 to May 2011. The randomized controlled trials included in the study assessed the effect of behavioral graded activity on hip and knee osteoarthritis.ResultsFour RCTs meeting the qualitative levels of evidence based on the grading system described by Tugwell and O'Shea (2004) and recommended by the Cochrane Musculoskeletal Group were considered for analysis and the results were projected.ConclusionThere is a silver level evidence that the BGA results in better exercise adherence and more physical activity than usual care in people with OA of the hip and knee, both in the short- and long-term.     

A novel 177Lu-labeled porphyrin for possible use in targeted tumor therapy

IntroductionPorphyrin and its derivatives exhibit inherent affinity for localization in tumors. Hence, porphyrin derivatives radiolabeled with suitable therapeutic radionuclides could be envisaged as potential agents for targeted tumor therapy. In this direction, a water-soluble porphyrin derivative, viz., 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin was synthesized in-house and radiolabeled with ¹⁷⁷Lu with an aim to prepare an agent for targeted tumor therapy. ¹⁷⁷Lu is an attractive radionuclide for the development of targeted radiotherapeutic agents owing to its suitable decay characteristics [T_1/2=6.73 d, E_β(max)=0.49 MeV, Eγ=208 keV (11%)], comparatively longer half-life and ease of production with high specific activity.Methods¹⁷⁷Lu was produced by irradiation of enriched Lu₂O₃ (64.3% ¹⁷⁶Lu) at a thermal neutron flux of 1×10¹⁴ n/cm².s for 14 d. The porphyrin was coupled to a suitable chelator, namely, p-aminobenzyl–1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid for complexation with ¹⁷⁷Lu. The radiolabeling was achieved by incubating 50 μg of the conjugate with ¹⁷⁷LuCl₃ (200 ng Lu) in acetate buffer (pH ～5) at 50°C for 1 h. The radiolabeled conjugate was characterized by high-performance liquid chromatography and its biological efficacy was studied in Swiss mice bearing fibrosarcoma tumors.Results¹⁷⁷Lu was obtained with a specific activity of ～550 TBq/g and radionuclidic purity of 99.98%. The ¹⁷⁷Lu-labeled porphyrin conjugate was obtained with 99% radiochemical purity and it exhibited good in vitro stability. Biodistribution studies revealed good tumor uptake (2.01% IA/g) within 3 h post injection (p.i.) with >94% injected activity exhibiting renal clearance. No significant accumulation of activity was observed in any of the vital organs/tissue. The tumor/blood and tumor/muscle ratios were 2.89 and 16.80, respectively, at 3 h p.i. and further increased till 2 days p.i. up to which the studies continued. Serial scintigraphic images recorded using a gamma camera exhibited significant accumulation of activity in tumor over background at 3 days p.i., and the activity was observed to be retained in the tumor till 14 d. Preliminary efficacy studies carried out in Swiss mice bearing fibrosarcoma tumors showed significant regression of the tumor growth in the treated animals.ConclusionBioevaluation and preliminary tumor regression studies provide supportive evidences toward the possible potential of the ¹⁷⁷Lu-labeled porphyrin for targeted tumor therapy.