Neuropsychological Activations and Networks While Performing Visual and Kinesthetic Motor Imagery.

This study aimed to answer the questions 'What are the neural networks and mechanisms involved in visual and kinesthetic motor imagery?', and 'Is part of cognitive processing included during visual and kinesthetic motor imagery?' by investigating the neurophysiological networks and activations during visual and kinesthetic motor imagery using motor imagery tasks (golf putting). The experiment was conducted with 19 healthy adults. Functional magnetic resonance imaging (fMRI) was used to examine neural activations and networks during visual and kinesthetic motor imagery using golf putting tasks. The findings of the analysis on cerebral activation patterns based on the two distinct types of motor imagery indicate that the posterior lobe, occipital lobe, and limbic lobe exhibited activation, and the right hemisphere was activated during the process of visual motor imagery. The activation of the temporal lobe and the parietal lobe were observed during the process of kinesthetic motor imagery. This study revealed that visual motor imagery elicited stronger activation in the right frontal lobe, whereas kinesthetic motor imagery resulted in greater activation in the left frontal lobe. It seems that kinesthetic motor imagery activates the primary somatosensory cortex (BA 2), the secondary somatosensory cortex (BA 5 and 7), and the temporal lobe areas and induces human sensibility. The present investigation evinced that the neural network and the regions of the brain that are activated exhibit variability contingent on the category of motor imagery.

Neuropsychological Evidence Underlying Counterclockwise Bias in Running: Electroencephalography and Functional Magnetic Resonance Imaging Studies of Motor Imagery.

We aimed to answer the question "why do people run the track counterclockwise (CCW)?" by investigating the neurophysiological differences in clockwise (CW) versus CCW direction using motor imagery. Three experiments were conducted with healthy adults. Electroencephalography (EEG) was used to examine hemispheric asymmetries in the prefrontal, frontal, and central regions during CW and CCW running imagery (n = 40). We also evaluated event-related potential (ERP) N200 and P300 amplitudes and latencies (n = 66) and conducted another experiment using functional magnetic resonance imaging (fMRI) (n = 30). EEG data indicated greater left frontal cortical activation during CCW imagery, whereas right frontal activation was more dominant during CW imagery. The prefrontal and central asymmetries demonstrated greater left prefrontal activation during both CW and CCW imagery, with CCW rotation exhibiting higher, though statistically insignificant, asymmetry scores than CW rotation. As a result of the fMRI experiment, greater activation was found during CW than during CCW running imagery in the brain regions of the left insula, Brodmann area 18, right caudate nucleus, left dorsolateral prefrontal cortex, left superior parietal cortex, and supplementary motor area. In the ERP experiment, no significant differences were found depending on direction. These findings suggest that CCW rotation might be associated with the motivational approach system, behavioral activation, or positive affect. However, CW rotation reflects withdrawal motivation, behavioral inhibition, or negative affect. Furthermore, CW rotation is understood to be associated with neural inefficiency, increased task difficulty, or unfamiliarity.

HM10660A, a long-acting hIFN-α-2b, is a potent candidate for the treatment of hepatitis C through an enhanced biological half-life.

Interferon-α (IFN-α) has been widely used for the treatment of infections due to the hepatitis C virus (HCV). Because of the short half-life of IFN-α in serum, it must be administered three times per week. To increase the half-life of IFN-α, the immunoglobulin G4 (IgG4) Fc fragment (HMC001) was conjugated with human IFN-α-2b to develop a long-acting IFN-α-2b, HM10660A. An analysis of the antiviral efficacy of HM10660A in a human hepatocyte-engrafted mouse model found that HM10660A reduced serum HCV titers more effectively than a commercially available peginterferon α-2a (PEGASYS®) and IFN-α-2b. Pharmacokinetic (PK) and pharmacodynamic (PD) studies of HM10660A using monkeys demonstrated that the half-life of HM10660A was approximately 2-fold longer than commercially available peginterferon α-2a, which is approved for a once-weekly regimen. Moreover, the IFN-mediated induction profiles of neopterin and 2', 5'-oligoadenylate synthase (OAS) in normal cynomolgus monkeys indicated that HM10660A had enhanced antiviral activity and a prolonged duration of action compared with peginterferon α-2a. Considering the improved PK and PD properties, HM10660A can most likely be dosed every two or four weeks, providing superior antiviral efficacy and convenience for patients with HCV.

LAPS-FSH: a new and effective long-acting follicle-stimulating hormone analogue for the treatment of infertility.

Although several long-acting follicle-stimulating hormone (FSH) therapies have been developed to enhance the ovarian response, a disadvantage of FSH therapy is its relatively short half-life, which requires women to receive one to two injections per day for almost 2 weeks. In the present study, we developed a novel FSH analogue by conjugating recombinant human FSH (rhFSH) and the constant region of the human immunoglobulin G4 fragment via non-peptidyl linkers. The efficacy of the FSH analogue was evaluated in vitro by cAMP level assessments, pharmacokinetic studies and a determination of ovarian weight and by comparing these findings with the results from other FSH analogues. In addition, the total number of antral and Graafian follicles was determined after 7 days of treatment with control, 6µgkg(-1) follitropin ß, 6, 12 or 42µgkg(-1) corifollitropin α or 3, 6 or 12µgkg(-1) long acting protein/peptide discovery-follicle-stimulating hormone (LAPS-FSH). As a result, the animals treated with 12µgkg(-1) LAPS-FSH produced additional and larger healthy follicles. These data demonstrate that LAPS-FSH promotes growth and inhibits atresia of the ovarian follicle compared with other available drugs, suggesting that our new drug enhances the efficacy and duration of treatment. It is expected that our new FSH analogue will result in a higher chance of pregnancy in patients who are unresponsive to other drugs.

Metabolite identification of a new tyrosine kinase inhibitor, HM781-36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry.

RATIONALE: HM781-36B (1-[4-[4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy]-piperidin-1-yl]prop-2-en-1-one hydrochloride) is a new anticancer drug to treat advanced solid tumors in clinical trial. In order to understand the behavior of HM781-36B in vitro and in vivo we validated an analytical method for HM781-36B and its major metabolites in plasma. METHODS: In vivo and in vitro metabolism of HM781-36B was studied in dog plasma, urine and feces as well as using human and dog liver microsomes with extraction by ethyl acetate or methyl tert-butyl ether, respectively, and successfully separated by high-performance liquid chromatography diode-array detection mass spectrometry (HPLC-DAD/MS). Ten metabolites were identified by LC/ESI-ion trap mass spectrometry (MS, MS(2) , MS(3) and MRM) and LC/Q-TOF-MS/MS for exact mass measurement. For accurate characterization of the major metabolites, authentic standards (M1, M2, M4, and M10) were synthesized. RESULTS: Ten metabolites of HM781-36B in an in vitro mixture were separated and identified by LC/ESI-MS(n) . The MS/MS spectral patterns of the parent drug and metabolites exhibited two characteristic ions (A- and B-type ions) attributed to the cleavage of the ether bond between the piperidine ring and the quinazoline ring, providing important information on the site of chemical conversion during the metabolism. Six hydroxylated derivatives including dehalogenation and demethylation, two N-oxide forms, a demethylated form and de-acryloylpiperideine metabolites were observed. CONCLUSIONS: The LC/ESI-ion trap MS(n) technique was effective in obtaining structural information and yielded diagnostic ions for the identification of diverse metabolites. The multiple metabolic pathways of HM781-36B were suggested in in vitro and in vivo samples and the dihydroxylation (M1) and demethylation (M2) appeared to be the major metabolites.

Serum immunoglobulin fused interferon-alpha inhibited tumor growth in athymic mice bearing colon 26 adenocarcinoma cells.

Interferon (IFN) has therapeutic potential for a wide range of infectious and proliferative disorders. However, the half-life of IFN is too short to have a stable therapeutic effect. To overcome this problem, serum immunoglobulin has been fused to IFN. In this study, the efficacy of serum immunoglobulin fused INFs (si-IFN1 and si-IFN2) was evaluated on athymic mice bearing colon 26 adenocarcinoma cells. Seven days after the implantation of tumor cells, each group of mice was injected once a week with si-IFN1 and si-IFN2 at two different concentrations (10 x : 30 microg/kg and 50 x : 150 microg/kg). A slight anti-tumoral effect was observed in all 10 x groups compared to the control. In the 50 x groups, however, si-IFN1 and si-IFN2 showed significant anti- tumoral effects compared to the control. To gain more information on the mechanisms associated with the decrease of tumor size, a Western blot assay of apoptosis-related molecules was performed. The protein expression of cytochrome c, caspase 9, 6, and 3 were increased by si-IFN1 and si-IFN2. These 2 IFNs also increased the expressions of p53, p21, Bax and Bad. Interestingly, si-IFN1 and si-IFN2 decreased the expression of VEGF-beta. Taken together, serum immunoglobulin fused IFNs increased therapeutic efficacy under current experimental condition.