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Background and Purpose: Various clinical and neuroimaging predictive factors have been identified for the recovery of upper extremity (UE) motor function after stroke. However, few studies have addressed factors related to the recovery of lower extremity (LE) motor function after stroke or performed direct comparisons of UE and LE motor recovery in the same set of patients. In this study, predictive factors for UE and LE motor recovery after stroke were investigated using clinical and neuroimaging characteristics., Methods: Forty-two subacute ischaemic stroke patients underwent structural and functional magnetic resonance imaging data acquisition and cognitive/behavioral assessments using the Fugl-Meyer assessment, the National Institutes of Health Stroke Scale (NIHSS) and the Mini-Mental State Examination (MMSE) 2 weeks after stroke onset. Neuroimaging factors, including corticospinal tract (CST) fractional anisotropy, lesion volume, CST lesion load and interhemispheric homotopic functional connectivity, were extracted. The outcome of motor function was assessed by Fugl-Meyer assessment scores 3 months after onset., Results: Early clinical and neuroimaging factors for predicting motor recovery were noticeably different for UE and LE. UE motor function recovery was related to age, NIHSS, MMSE, CST lesion load, lesion volume, ipsilesional CST integrity and interhemispheric homotopic functional connectivity. In contrast, LE motor recovery was related to ipsilesional and contralesional CST integrity and MMSE. Specifically, LE recovery showed a strong relationship to the preservation of cognitive function compared with motor impairment., Conclusions: Our results indicate that different mechanisms underlie UE and LE motor recovery after stroke. LE motor recovery seems to be more intensively modulated by cognitive functions than UE., (© 2020 European Academy of Neurology.)

Background and Purpose: A common single nucleotide polymorphism, Val66Met, in the human brain-derived neurotrophic factor (BDNF) gene has a potential role in the pathogenesis and treatment of stroke. The relevance of the BDNF Val66Met polymorphism to long-term stroke outcomes was examined, specifically with respect to changes in corticospinal integrity., Methods: Thirty-five stroke patients with unilateral motor weakness were genotyped within 2 weeks after onset (T1), and changes in the integrity of the ipsilesional corticospinal tract (CST) as well as alterations in motor function at 1 month (T2) and 3 months after onset (T3) were tracked., Results: On the basis of the Fugl-Meyer assessment upper extremity score, carriers of the Met allele (Val/Met and Met/Met) showed poorer motor outcomes at T2 and T3 compared to carriers of only the Val allele (Val/Val). For both BDNF allele types, patients exhibited characteristic degeneration of the CST compared to healthy controls. There were no differences between the two genotypes with respect to time-dependent changes in diffusion-tensor-imaging-derived parameters of the CST. However, the two groups showed different relationships between motor outcomes and directional diffusivities according to the elapsed time after onset. Poorer motor function was associated with lower axial diffusivity values for the Val/Val genotype group in the sub-acute phase (T1 and T2) but with higher radial diffusivity values for the Val/Met and Met/Met genotype group in the early chronic phase (T3)., Conclusions: Motor recovery in stroke patients may be affected by the BDNF Val66Met polymorphism, possibly through its effects on distinct pathological processes underlying corticospinal degeneration., (© 2015 EAN.)

To compare the prevalence of extrapyramidal syndrome (EPS) between the first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), the co-prescribing rate of anti-Parkinson drugs (APDs) of each antipsychotic drug was analyzed using population database. Fourteen antipsychotics had been prescribed during the 5-year study period. Among the SGAs, quetiapine had the lowest crude co-prescribing rate of APDs (27.09%), whereas risperidone had the highest rate (66.50%). Among the FGAs, thioridazine and loxapine had the lowest (60.99%) and highest rates (96.35%), respectively. The rankings of the co-prescribing rate of APDs among antipsychotics, in increasing order, were quetiapine, clozapine, olanzapine, thioridazine, zotepine, chlorpromazine, risperidone, sulpiride, clotiapine, flupentixol, haloperidol, zuclopentixol, trifluoperazine, and loxapine. The results indicate that the risk of EPS appears to be lower in SGAs than in FGAs; however, the considerably high rate of EPS in some of the newer generation of antipsychotics warrants clinical attention.

Mechanical perturbations serve as extracellular signals to a variety of cells, including bone cells. Low-intensity pulsed ultrasound produces significant multifunctional effects that are directly relevant to bone formation and resorption. Ultrasound stimulation has been shown to accelerate bone-defect healing and trabecular bone regeneration. In this study, we use an in vitro bone cell culture model to investigate the effect of low-intensity pulsed ultrasound. The rat alveolar mononuclear cell-calvaria osteoblast coculture system was used in this study. Before treatment, the bone cells were cultured for 3 days to facilitate their attachment and differentiation. Then, ultrasound exposure (frequency = 1 MHz, intensity = 0.068 W/cm(2)) or sham exposure for 20 min per day was applied until the end of the experiment. Half of the culture media were obtained on the 4th, 5th, 6th, 7th, 8th, 9th, and 10th days for the analysis of cytokines and biochemical parameters. At the end of the experiment, cells were fixed and stained for identification and quantification of the osteoblast and osteoclast cells. After low-intensity pulse ultrasound stimulation, the osteoblast cell counts were significantly increased, whereas the osteoclast cell counts were significantly decreased. The total alkaline phosphatase amount in the culture medium was increased after 7 days of ultrasound stimulation, and tumor necrosis factor-alpha in ultrasound-stimulated bone cells was significantly increased after the 7th day of culture and reached 474.77% of the control medium on the 10th day of culture. The results of this study suggest that low-intensity ultrasound treatment may have a stimulatory effect on bone-healing processes., (Copyright 2001 John Wiley & Sons, Inc. J Biomed Mater Res 57: 449-456, 2001)

Cytokines produced by macrophages in the periprosthetic membranes surrounding joint replacements have been implicated as causal agents in osteolysis and prosthetic loosening. The present study characterizes the response of human peripheral blood monocytes to titanium particles. Monocytes were obtained from donated blood and were cultured in the presence of different-sized titanium particles. Exposure to titanium-aluminum-vanadium particles significantly changed the release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 (IL-1), whereas there was no significant effect on the release of prostaglandin E(2) (PGE(2)). When monocytes were cultured with particles, the titanium alloy particles induced significantly more release of TNF-alpha and less IL-1 secretion. Ciprofloxacin inhibited production of TNF-alpha, IL-6, IL-1, and PGE(2) in human monocytes exposed to titanium particles. In contrast to ciprofloxacin, indomethacin was not a potent inhibitor of TNF-alpha production but potentiated IL-6 production in titanium-stimulated monocytes. Indomethacin had no effect on the production of IL-1 and was a potent inhibitor of PGE(2) production in titanium-stimulated monocytes. Pentoxifylline had an inhibitor effect on TNF-alpha production in titanium-stimulated monocytes. Pentoxifylline potentiated IL-6 and IL-1 production in monocytes exposed to titanium particles and had a biphasic effect on the PGE(2) production. The results of this study support our hypothesis that human monocytes release bone resorption mediators after in vitro exposure to TiAlV alloy particles. The results also demonstrate the differences of bone-resorbing mediators in response to different wear particle size. The pharmacologic agents (ciprofloxacin, pentoxifylline, and indomethacin) that can modulate the release of bone resorbing mediators such as PGE(2), TNF-alpha, IL-1, and IL-6 release from human monocytes. The results help to elucidate the differences in cellular response to wear particles but may not be directly transposed to the human situation., (Copyright 2000 John Wiley & Sons, Inc.)

In an attempt to overcome the cytotoxicity problem of the glutaraldehyde-fixed tissues, a naturally occurring crosslinking agent (genipin) was used by our group to fix biological tissues. The study was intended to investigate the rate of tissue fixation by genipin. Glutaraldehyde was used as a control. In addition, the degrees of tissue fixation by genipin at different pHs (pH 4.0, pH 7. 4, pH 8.5, or pH 10.5), temperatures (4 degrees C, 25 degrees C, 37 degrees C, or 45 degrees C), and initial fixative concentrations (0.250%, 0.625%, or 1.000%) were examined. The results obtained revealed that the rate of tissue fixation by glutaraldehyde was significantly faster than that by genipin. The degree of tissue fixation by genipin may be controlled by adjusting its fixation duration or fixation conditions. The order in degree of tissue fixation by genipin at different pHs, from high to low, was: at nearly neutral pH (pH 7.4 or pH 8.5) > at basic pH (pH 10.5) > at acidic pH (pH 4.0). The degrees of tissue fixation by genipin at different temperatures were about the same, except for that at 4 degrees C. In contrast, the initial fixative concentration did not seem to affect the degree of tissue fixation by genipin, if only the amount of genipin in the fixation solution was sufficient to complete tissue fixation. The concentrations of genipin in the aqueous solutions at different pHs, temperatures, and initial fixative concentrations tended to decrease with time with or without the occurrence of tissue fixation. This indicated that genipin was not stable in the aqueous solution. The instability of aqueous genipin was more remarkable with increasing pH or temperature. The results obtained in this study may be used to optimize the fixation process for developing bioprostheses fixed by genipin., (Copyright 2000 John Wiley & Sons, Inc.)

Bioadhesives are used for tissue adhesion and hemostasis in surgery. A gelatin-resorcinol mixture crosslinked with formaldehyde (GRF glue) and/or glutaraldehyde (GRG) is used for this purpose. Although the bonding strength of the GRF glue to tissue is satisfactory, concerns about the cytotoxicity of formaldehyde are reported in the literature. It was suggested that the cytotoxicity problem of the GRF glue may be overcome by changing its crosslinking method. The study was therefore undertaken to assess the feasibility of using an epoxy compound (GRE glue), a water-soluble carbodiimide (GAC glue), or genipin (GG glue) to crosslink with a gelatin hydrogel as new bioadhesives. GRF glue and GRG glue were used as controls. The results of our cytotoxicity study suggested that the cellular compatibility of the GAC and GG glues was superior to the GRF, GRG, and GRE glues. The gelation time for the GG glue was relatively longer than the GRF and GRG glues, while no gelation time could be determined for the GAC glue. Additionally, it took approximately 17 h for the GRE glue to become adhesive. The GRF and GRG glues had the greatest bonding strengths to tissue among all test adhesives, while the bonding strengths of the GAC and GG glues were comparable. In contrast, there was almost no bonding strength to tissue for the GRE glue. However, the GRF and GRG glues were less flexible than the GAC and GG glues. Subsequent to the bonding strength measurement, each test adhesive was found to adhere firmly to the tissue surface and underwent cohesive failure during the bond breaking. In conclusion, the GRF and GRG glues may be used as tissue adhesives when their ability to bind tissue rapidly and tightly is required; the GAC and GG glues are preferable when the adhesive action must be accompanied with minimal cytotoxicity and stiffness; and the GRE glue is not suitable for bioadhesion in clinical applications., (Copyright 1999 John Wiley & Sons, Inc.)

Ultrasound has many medical applications. Previous animal and clinical studies have clearly shown a positive effect of ultrasound on the rate of osseous repair. The present in vitro study was designed to elucidate the specific response of bony tissue to ultrasound treatment. Bilateral femora were obtained from 36 mature male Wistar rats. A bone defect was created at the center of each distal metaphysis. The femora were maintained for either 7 or 14 days in in vitro tissue culture and received 15 min of ultrasound stimulation or a sham exposure. The ultrasound intensity used was either 320 or 770 mW/cm2. Healing of the bone defect was evaluated by histomorphological examination and by analysis for the synthesis and secretion of prostaglandin E2. The results showed that ultrasound stimulation can accelerate both defect healing and trabecular bone regeneration. All experimental femoral defects treated with ultrasound healed faster than the untreated cortical defects, but only the defects receiving 770 mW/cm2 reached a level that was significantly different. The healing rate for the 320-mW/cm2 stimulated defects was intermediate between that of the 770-mW/cm2 and sham-exposed defects. With ultrasound stimulation, prostaglandin E2 secretion by the experimental femora decreased significantly. Changes in the prostaglandin synthesis and concentration were found to correspond to changes in the amount of trabecular regeneration and to acceleration of bone healing. This highly controlled and well-studied model of ultrasound stimulation of bone healing in vitro can be used to further examine the biological mechanisms involved.

Aseptic loosening after total joint arthroplasty is a major problem in orthopedic surgery. Small particles from material wear have been reported as the main cause of implant failure. For this reason, investigation into possible wear particles from the materials used in the implant may lead to longevity after arthroplasty. Hydroxyapatite (HA) has been extensively investigated and reported as an excellent biomaterial with excellent biocompatibility. In this study, we used an in vitro osteoblast/osteoclast model to test the biocompatibility of various-sized HA particles. Primary osteoclasts/osteoblasts were co-cultured with different-sized HA particles (0.5-3.0 microm, 37-53 microm, 177-205 microm, and 420-841 microm) for 3 h, 1 day, 3 days, and 7 days. Cellular responses to the HA particles were evaluated by changes in cell counts and the secretion of transforming growth factor (TGF-beta1), alkaline phosphatase (ALP), tumor necrosis factor (TNF-alpha), prostaglandin (PGE2), and lactate dehydrogenase (LDH) in the supernatant of the culture media. The results showed that osteoblasts/osteoclasts co-cultured with HA particles smaller than 53 microm undergo the most significant changes. Cellular counts significantly decreased, and the changes were more obvious in the osteoblast population. There also was a significant decrease in TGF-beta1 concentration and a significant increase in PGE2 and LDH concentration, but there were no changes in the TNF-alpha or ALP titer. It can be concluded that larger HA particles may be quite compatible with bone cells while smaller-sized HA particles can both activate the osteoclasts and decrease the cell population of the osteoblasts. Justification for the additional expense incurred with the use of hydroxyapatite in primary total hip arthroplasty should be further evaluated.

Over the past decade, a large number of biomaterials have been proposed as artificial bone fillers for repairing bone defects. The material most widely used in clinical medicine is hydroxyapatite. The aim of our investigation was to study the effect of hydroxyapatite size mechanism on osteoblasts. The osteoblasts were cultured in vitro with 0.1% (1 mg/mL) of various sized hydroxyapatite particles (0.5-3.0, 37-63, 177-250, and 420-841 microm) for 1 h, 3 h, 1 day, 3 days, and 7 days. The results showed that adding hydroxyapatite particles to osteoblast cultures can significantly affect osteoblast cell count. Osteoblast populations decreased significantly. Osteoblast mean surface areas also changed significantly. Transforming growth factor-beta1 (TGF-beta1) concentrations in culture medium decreased significantly with the addition of hydroxyapatite particles. Prostaglandin E2 (PGE2) concentrations in medium increased significantly. The changes in TGF-beta1 and PGE2 concentration were more significant and persisted longer in smaller-particle groups. The inhibitory effects of hydroxyapatite particles on osteoblast cell cultures were mediated by the increased synthesis of PGE2. Caution should be exercised before using a hydroxyapatite product which could easily break down into fine particles.

The pharmacokinetic interaction between buspirone and haloperidol was evaluated in schizophrenic patients in two different groups. In both groups, haloperidol doses (10-40 mg/day) remained constant for 6 weeks before the addition of buspirone 10 mg three times daily. Serial blood samples were obtained from the 11 patients in group I at baseline (before addition of buspirone) and after administration for 24 hours. The pharmacokinetic parameters of haloperidol were determined alone and with coadministration of buspirone. In group II, buspirone 10 mg three times daily was added to treatment with haloperidol in 27 patients. Blood samples were obtained before addition of buspirone and at weeks 2 and 6 of treatment with buspirone. Samples were obtained 10 to 12 hours after administration of the evening dose and before the morning dose. Haloperidol and its metabolite, reduced haloperidol (RH), were assayed by means of high-performance liquid chromatography with electrochemical detection. Significant changes in the pharmacokinetic parameters of haloperidol were not found in group I; a mean increase in the half-life (t1/2) of haloperidol from 21.5 to 28.1 hours was observed, but this finding was not statistically significant. Under steady-state conditions, plasma levels of haloperidol in the patients in group II did not change significantly from baseline to week 6. Plasma concentrations of RH remained unaltered in both groups. The results indicate that coadministration of buspirone does not markedly affect the pharmacokinetics or plasma concentrations of haloperidol.

Steady-state haloperidol and reduced haloperidol concentrations were measured in 250 schizophrenic patients from 4 ethnic groups: 39 Blacks, 66 Caucasians, 82 Chinese, and 63 Mexican Americans. The distribution of the reduced haloperidol to haloperidol concentration (RH/HL) ratios was bimodal in all ethnic groups, with the antimode determined by probit plot as 0.46, 0.51, 0.36, and 0.76, respectively. With these antimodes, the proportion of patients with low RH/HL ratios were 41%, 42%, 73%, and 57% in the four ethnic groups, respectively. Compared with the other three ethnic groups, in the Chinese patients the ratio was lower. The mean RH/HL ratio in the Chinese was 0.34 compared with 0.81 to 0.87 in the non-Chinese groups. In 53 patients who were treated with two or more haloperidol dosage regimens, steady-state haloperidol and reduced haloperidol drug concentrations obtained from the different regimens were positively correlated with the haloperidol dose (R = .79 and R = .62, respectively). Our data suggest not only the existence of a bimodal distribution in the RH/HL ratio, but also that the antimode separating the low and high ratio subgroups is different among the various ethnic groups.

The disposition of the atypical clozapine and its desmethyl metabolite were evaluated in fourteen male chronic patients. A single 100 mg dose of clozapine was administered and blood sampling performed over the following 72 hours. The mean (SD) oral clearance and half-life of clozapine were 55.4 (29.7) L/hr and 13.7 (9.9) hours, respectively. The mean (SD) AUC for clozapine and desmethylclozapine was 2389.9 (1406) and 751.1 (622.9) ng.hr/mL, respectively. The elimination of the metabolite is rate limited by its formation from cloza-pine. A wide interpatient variability in clozapine and desmethylclozapine pharmacokinetics was observed.

Cellular blue nevus can be clinically and histogenetically confused with malignant melanoma but remains a benign neoplasm of uncertain histogenesis. This paper reports the ultrastructural features of three cases of cellular blue nevus and emphasizes melanosomal alterations, including immature and granular forms, multiple layers of basement membrane around vessels, nerve fibers and tumor cells; endothelial fenestrations and banded structures within the nerve and outside in the stroma. A unifying concept of neural crest derived tumors is presented to better understand the histogenesis of cellular blue nevus.