Screening of a Library of FDA-Approved Drugs Identifies Several Enterovirus Replication Inhibitors That Target Viral Protein 2C

Enteroviruses (EVs) represent many important pathogens of humans. Unfortunately, no antiviral compounds currently exist to treat infections with these viruses. We screened the Prestwick Chemical Library, a library of approved drugs, for inhibitors of coxsackievirus B3, identified pirlindole as a potent novel inhibitor, and confirmed the inhibitory action of dibucaine, zuclopenthixol, fluoxetine, and formoterol. Upon testing of viruses of several EV species, we found that dibucaine and pirlindole inhibited EV-B and EV-D and that dibucaine also inhibited EV-A, but none of them inhibited EV-C or rhinoviruses (RVs). In contrast, formoterol inhibited all enteroviruses and rhinoviruses tested. All compounds acted through the inhibition of genome replication. Mutations in the coding sequence of the coxsackievirus B3 (CV-B3) 2C protein conferred resistance to dibucaine, pirlindole, and zuclopenthixol but not formoterol, suggesting that 2C is the target for this set of compounds. Importantly, dibucaine bound to CV-B3 protein 2C in vitro, whereas binding to a 2C protein carrying the resistance mutations was reduced, providing an explanation for how resistance is acquired.     

Human Radiation Dosimetry of [<Superscript>18</Superscript>F]AV-1451(T807) to Detect Tau Pathology

Purpose

[¹⁸F]AV-1451 is a positron emission tomography (PET) radioligand for detecting paired helical filament tau. Our aim was to estimate the radiation dose of [¹⁸F]AV-1451 in humans.

Procedures

Whole-body PET scans were acquired for six healthy volunteers (three male, three female) for 128 min after injection of [¹⁸F]AV-1451 (268?±?31 MBq). Radiation doses were estimated using the OLINDA/EXM software.

Results

The estimated organ doses ranged from 7.81 to 81.2 μSv/MBq. The critical organ for radiation burden was the liver. Radiation doses to the reproductive and blood-forming organs were 14.15, 8.43, and 18.35 μSv/MBq for the ovaries, testes, and red marrow, respectively. The mean effective dose was 22.47?±?3.59 μSv/MBq.

Conclusions

A standard single injection of 185 MBq (5 mCi) results in an effective dose of 4.7 mSv in a healthy subject. Therefore, [¹⁸F]AV-1451 could be used in multiple PET scans of the same subject per year.

     

Conjoint bicondylar Hoffa fracture in an adult

Conjoint bicondylar Hoffa fracture is an extremely rare injury. Only one case has been reported previously in the pediatric age group. We describe this injury in a 17-year-old male who presented following a fall with direct impact on his semiflexed right knee. Plain radiographs were inadequate to define the exact pattern of injury. Computed tomographic (CT) scans demonstrated the coronal fracture involving both the femoral condyles which were joined by a bridge of intact bone. The patient was treated with open reduction and internal fixation using swashbuckler (modified anterior) approach. Union occurred within 3 months and at final followup (at 18 months) the patient had a good clinical outcome. The possible mechanism of injury is discussed.     

Experimental Evaluation of a New Single Wire Stainless Steel Fishscale Coronary Stent (Freedomª)

Recent randomized clinical trials revealed a significant reduction in angiographic restenosis rates when adjunctive stenting was performed after conventional coronary balloon angioplasty. Current approved coronary stents are however hampered by their rigidity, limiting their trackability in tortuous vessels and furthermore, needing high pressure deployment for optimal vessel apposition. New coronary stents are currently under development, using more biocompatible metal alloys and/or designs which better align to the vessel wall at moderate deployment pressures. We evaluated the safety, efficacy, angiographic and histological effect of a new stainless steel fishscale designed stent (Freedoma, Global Therapeutics, Co., USA) in a porcine coronary and peripheral artery model. Implantation in the right coronary artery was successful in all 20 pigs. Control angiograms at 6 weeks follow-up demonstrated patent vessels and morphologic evaluation showed only a mild fibromuscular neointimal response resulting in an area stenosis of 28.7 +/- 0.18% and a mean neointimal hyperplasia of 0.18 +/- 0.25 mm. Comparison with the Palmaz-Schatza coronary stent in a porcine peripheral artery model demonstrated similar quantitative angiographic and morphologic vessel analysis results. Also the morphometric data were comparable. Area stenosis: Palmaz-Schatz: 37 +/- 0.24%, Freedom: 21 +/- 0.14%, p = 0.07. Mean neointimal hyperplasia: Palmaz-Schatz: 0.33 +/- 0.24 mm, Freedom: 0.18 +/- 0.08 mm, p = 0.08. CONCLUSION: Freedom coronary stent implantation in a porcine model resulted in a high procedural success without subacute thrombotic occlusions, despite no further anticoagulation nor antiplatelet therapy. Six weeks histopathological and morphometric evaluation demonstrated only a mild fibromuscular neointimal hyperplasia.     

Amygdalar shape analysis method using surface contour aligning,spherical mapping,and probabilistic subregional segmentation

The objective of this study was to develop a reliable method for the shape analysis of the amygdala, a structure that is important in gaining a better understanding of the limbic system in the human brain. The goal of this study was threefold; to develop (1) a robust method for aligning the contour of the amygdala; (2) a reproducible method for extracting surface parameters of the amygdala using a spherical mapping technique; and (3) a standardized approach for statistical assessment and visualization of shape alterations by applying the probabilistic maps of amygdalar subregions. This technique was validated by conducting an artificial phantom study and by assessing sex-related amygdalar shape differences using T1-weighted images from healthy volunteers. In the phantom study, the region with atrophy was detected successfully through the shape analysis process. In the human study, the average radii of the centromedial (CM) subregion in the left amygdala and laterobasal (LB), superficial (SF) and CM subregions in the right amygdala were different between sexes (t-tests, p = 0.02, 0.04, 0.04, and 0.002, respectively). In addition, focal regions with larger radii in amygdalae of men than those of women were found predominantly on the surfaces of bilateral SF and bilateral CM subregions, after the volumes of the amygdala had been scaled to the unit volume (1000 mm³) (Mann–Whitney U-test, false discovery rate corrected p < 0.05, clustered vertex points > 25). Regions with smaller radii in amygdalae of men were found predominantly on the anterior surfaces of the right LB and SF subregions (Mann–Whitney U-test, false discovery rate corrected p < 0.05, clustered vertex points > 25). This is generally in agreement with previous findings from animal studies. The current method may be used for measuring subtle local shape changes of the amygdala in various psychiatric or neurologic disorders.     

Full syndrome and subthreshold attention-deficit/hyperactivity disorder in a Korean community sample: comorbidity and temperament findings

Objective  The main objective of this study was to investigate the comorbid disorders and temperamental profiles of full syndrome and subthreshold attention-deficit/hyperactivity disorder (ADHD). Method  A sample of 2,493 students was randomly selected from six representative elementary schools in Seoul, Korea. Among 245 children with full syndrome and subthreshold ADHD diagnosed by the diagnostic interview schedule for children-4th version, parents of 185 subjects (mean age 9.0 ± 1.7 years) and of a random sample of 185 age- and gender-matched non-ADHD children have completed the parent’s version of the children behavior checklist (CBCL) and the juvenile temperament and character inventory (JTCI). Results  The prevalence rates of full syndrome and subthreshold ADHD were, respectively, 5.90% (95% confidence interval = 4.74–7.06) and 9.00% (95% confidence interval = 7.58–10.41). Subthreshold ADHD cases did not differ from full syndrome ADHD in any JTCI profile, showing high novelty seeking/low persistence/low self-directedness than controls. Subthreshold ADHD also showed increased risk for externalizing disorders and higher scores in eight CBCL scales (somatic complaints, anxious/depressed, social problems, attention problems, delinquent behaviors, aggressive behaviors, externalizing problems and total behavioral problems) compared to the controls. Conclusions  These results support the clinical relevance of subthreshold ADHD in Asian culture. Increased clinical awareness for children with subthreshold ADHD is needed.     

Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential

Splenectomized mice treated for 7 days with pegylated recombinant rat stem cell factor (rrSCF-PEG) showed a dose-dependent increase in peripheral blood progenitor cells (PBPC) that have enhanced in vivo repopulating potential. A dose of rrSCF-PEG at 25 micrograms/kg/d for 7 days produced no significant increase in PBPC. However, when this dose of rrSCF-PEG was combined with an optimal dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 200 micrograms/kg/d), a synergistic increase in PBPC was observed. Compared with treatment with rhG-CSF alone, the combination of rrSCF-PEG plus rhG-CSF resulted in a synergistic increase in peripheral white blood cells, in the incidence and absolute numbers of PBPC, and in the incidence and absolute numbers of circulating cells with in vivo repopulating potential. These data suggest that low doses of SCF, which would have minimal, if any, effects in vivo, can synergize with optimal doses of rhG-CSF to enhance the mobilization of PBPC stimulated by rhG-CSF alone.     

Intravascular Low Power Red Laser Light as an Adjunct to Coronary Stent Implantation Evaluated in a Porcine Coronary Model

BACKGROUND: It is believed that restenosis following coronary interventions is the result of endothelial denudation that leads to thrombus formation, vascular remodeling, and smooth muscle cell proliferation. We previously demonstrated that low power red laser light (LPRLL) irradiation enhances endothelial cell growth in vitro and in vivo and reduces restenosis in a small animal model. The present study investigated the effectiveness of intravascular LPRLL therapy in the reduction of restenosis following stenting in a porcine model. METHODS AND RESULTS: Stents were placed in the right coronary artery of domestic cross-bred pigs. After stent deployment, an additional inflation was performed with the laser-balloon. In group I (n = 18) no LPRLL was used; group II (n = 10) received LPRLL dosage of 10 mW for 1 minute; group III (n = 10) received LPRLL dosage of 34 mW for 1 minute. Quantitative coronary analysis of the stented vessel was performed before, immediately after stenting, and at 6 weeks. The pigs were sacrificed and histologic and planimetric analysis conducted. At 6 weeks, minimal luminal stent diameter was significantly narrower in the control group compared to the higher dose group (p < 0.05), late loss correlated inversely proportional to the dose used (r = 0.9; p < 0.03), these results were confirmed by morphometric analysis. Neointimal area was also significantly decreased in the higher dose group. CONCLUSIONS: Intravascular LPRLL contributes to reduction of angiographic restenosis and hyperplastic reaction in this animal model and seems to be dose dependent.     

Topographical distribution of cerebral cortical thinning in patients with mild Parkinson's disease without dementia

The pathology of Parkinson's disease (PD) is not confined to the brainstem regions, but spreads to involve the neocortical areas. Using surface‐based cortical thickness analysis, we studied the topographical distribution of cortical thinning in nondemented patients with mild PD. The high‐resolution magnetic resonance imaging (MRI) studies were performed in 48 patients with PD without dementia and 56 age‐matched healthy controls. Using the Freesurfer software, surface‐based analysis was done to find changes in cerebral cortical thickness in patients with PD. Compared to the controls, patients with PD showed significant cortical thinning in the temporal, inferior parietal, rostral frontal, and orbitofrontal cortical areas. Thinning of the cerebral cortex occurs even in nondemented patients with mild PD, and its topographical distribution was similar to that of the neocortical Lewy bodies. Further studies are needed to find pathological and clinical correlates of thinned cerebral cortex found in nondemented patients with mild PD. © 2010 Movement Disorder Society