Melatonin Ameliorates Atherosclerotic Plaque Vulnerability by Regulating PPARδ-Associated Smooth Muscle Cell Phenotypic Switching.

Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator-activated receptor delta (PPARδ) has been shown to modulate vascular smooth muscle cell (SMC) phenotypic switching, and, hence, atherosclerotic plaque stability. Melatonin reportedly plays a beneficial role in cardiovascular diseases; however, the mechanisms underlying improvements in atherosclerotic plaque vulnerability remain unknown. In this study, we assessed the role of melatonin in regulating SMC phenotypic switching and its consequential contribution to the amelioration of atherosclerotic plaque vulnerability and explored the mechanisms underlying this process. We analyzed features of atherosclerotic plaque vulnerability and markers of SMC phenotypic transition in high-cholesterol diet (HCD)-fed apolipoprotein E knockout (ApoE-/-) mice and human aortic SMCs (HASMCs). Melatonin reduced atherosclerotic plaque size and necrotic core area while enhancing collagen content, fibrous cap thickness, and smooth muscle alpha-actin positive cell coverage on the plaque cap, which are all known phenotypic characteristics of vulnerable plaques. In atherosclerotic lesions, melatonin significantly decreased the synthetic SMC phenotype and KLF4 expression and increased the expression of PPARδ, but not PPARα and PPARγ, in HCD-fed ApoE-/- mice. These results were subsequently confirmed in the melatonin-treated HASMCs. Further analysis using PPARδ silencing and immunoprecipitation assays revealed that PPARδ plays a role in the melatonin-induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPARδ-mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis.

Activation of heme oxygenase-1 by laminar shear stress ameliorates high glucose-induced endothelial cell and smooth muscle cell dysfunction.

High glucose (HG)-induced endothelial cell (EC) and smooth muscle cell (SMC) dysfunction is critical in diabetes-associated atherosclerosis. However, the roles of heme oxygenase-1 (HO-1), a stress-response protein, in hemodynamic force-generated shear stress and HG-induced metabolic stress remain unclear. This investigation examined the cellular effects and mechanisms of HO-1 under physiologically high shear stress (HSS) in HG-treated ECs and adjacent SMCs. We found that exposure of human aortic ECs to HSS significantly increased HO-1 expression; however, this upregulation appeared to be independent of adenosine monophosphate-activated protein kinase, a regulator of HO-1. Furthermore, HSS inhibited the expression of HG-induced intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and reactive oxygen species (ROS) production in ECs. In an EC/SMC co-culture, compared with static conditions, subjecting ECs close to SMCs to HSS and HG significantly suppressed SMC proliferation while increasing the expression of physiological contractile phenotype markers, such as α-smooth muscle actin and serum response factor. Moreover, HSS and HG decreased the expression of vimentin, an atherogenic synthetic phenotypic marker, in SMCs. Transfecting ECs with HO-1-specific small interfering (si)RNA reversed HSS inhibition on HG-induced inflammation and ROS production in ECs. Similarly, reversed HSS inhibition on HG-induced proliferation and synthetic phenotype formation were observed in co-cultured SMCs. Our findings provide insights into the mechanisms underlying EC-SMC interplay during HG-induced metabolic stress. Strategies to promote HSS in the vessel wall, such as continuous exercise, or the development of HO-1 analogs and mimics of the HSS effect, could provide an effective approach for preventing and treating diabetes-related atherosclerotic vascular complications.

Oxygen Vacancy-Rich Manganese Nanoflowers as Ferroptosis Inducers for Tumor Radiotherapy.

The combination of ferroptosis and innovative tumor therapy methods offers another promising answer to the problem of tumors. In order to generate effective ferroptosis in tumor cells, iron-based nanomaterials are commonly utilized to introduce foreign iron as a trigger for ferroptosis. However, this usually necessitates the injection of larger doses of iron into the body. These exogenous iron increases are likely to create concealed concerns for symptoms such as liver damage and allergy. Herein, an iron-free radiosensitizer is introduced, oxygen-vacancy-rich MnO2 nanoflowers (ovs-MnO2 ), that promotes ferroptosis and modifies the tumor microenvironment to assist radiotherapy. ovs-MnO2 with enriched oxygen vacancies on the surface induces the release of intracellular free iron (Fe2+ ), which functions as an activator of Fenton reaction and enhances the accumulation of intracellular reactive oxygen species. On the other hand, Fe2+ also triggers the ferroptosis and promotes the accumulation of lipid peroxides. Subsequently, the depletion of glutathione and accumulation of lipid peroxidation in tumor cells leads to the inactivation of glutathione peroxidase 4 (GPX4) and ferroptosis, thereby enhancing the therapeutic efficacy of radiotherapy. The nanoplatform provides a novel strategy for generating novel nanomedicines for ferroptosis-assisted radiotherapy.

Accuracy of Point-of-Care Blood Glucometers in Neonates and Critically Ill Adults.

PURPOSE: Inpatient glycemic management has become a common issue because of the increasing number of hospitalized patients with hyperglycemia. Point-of-care devices can enable timely inpatient glucose monitoring, which may lead to better outcomes. The accuracy of point-of-care testing in various clinical scenarios has been questioned, particularly in neonates and critically ill patients. This study aimed to evaluate the accuracy of the CONTOUR PLUS and CONTOUR PLUS ONE glucometers (new wireless systems that link to a smart mobile device) when used as point-of-care devices for blood glucose monitoring in neonates and critically ill adults in inpatient settings. METHODS: This cross-sectional study was conducted at a medical center in central Taiwan and enrolled patients admitted to the neonatal intensive care unit, sick child room, or respiratory intensive care unit between November 2020 and April 2021. Neonates with suspected infection or abnormal blood coagulation and adults who had abnormal blood coagulation, were pregnant, had received organ transplants, or had undergone massive blood transfusions were excluded. The accuracy of the glucometers was determined based on the following criteria of the International Organization for Standardization (ISO) standard: 15197:2013. FINDINGS: Overall, 114 neonates (mean age, 4.2 days [range, 0-28 days]; 65 boys [57.0%]) and 106 hospitalized critically ill adults (mean age, 68.2 years [range, 27-94 years]; 72 men [67.9%]) were enrolled in this study. The glucose values obtained with each glucometer had good precision, and all findings met the reference criteria of the within-lot results. All measurements of the neonates' venous blood by each glucometer met the accuracy criteria specified by ISO standard 15197:2013. Furthermore, 98.1% and 97.2% of the arterial blood glucose measurements for critically ill adults obtained with CONTOUR PLUS and CONTOUR PLUS ONE met the accuracy criteria, respectively. IMPLICATIONS: Both glucose management systems met the accuracy criteria for venous blood from neonates and arterial blood from critically ill adults. Thus, the use of these 2 point-of-care devices in inpatient settings, including for neonates and critically ill adults, can be recommended to minimize limitations associated with the clinical application of point-of-care testing in glucose management. The wireless connection may play a role in the subsequent development of institution-wide virtual glycemic management under the supervision of a team of endocrinologists.

Alleviating the hypoxic tumor microenvironment with MnO2-coated CeO2 nanoplatform for magnetic resonance imaging guided radiotherapy.

BACKGROUND: Radiotherapy is a commonly used tool in clinical practice to treat solid tumors. However, due to the unique microenvironment inside the tumor, such as high levels of GSH, overexpressed H2O2 and hypoxia, these factors can seriously affect the effectiveness of radiotherapy. RESULTS: Therefore, to further improve the efficiency of radiotherapy, a core-shell nanocomposite CeO2-MnO2 is designed as a novel radiosensitizer that can modulate the tumor microenvironment (TME) and thus improve the efficacy of radiation therapy. CeO2-MnO2 can act as a radiosensitizer to enhance X-ray absorption at the tumor site while triggering the response behavior associated with the tumor microenvironment. According to in vivo and in vitro experiments, the nanoparticles aggravate the killing effect on tumor cells by generating large amounts of ROS and disrupting the redox balance. In this process, the outer layer of MnO2 reacts with GSH and H2O2 in the tumor microenvironment to generate ROS and release oxygen, thus alleviating the hypoxic condition in the tumor area. Meanwhile, the manganese ions produced by degradation can enhance T1-weighted magnetic resonance imaging (MRI). In addition, CeO2-MnO2, due to its high atomic number oxide CeO2, releases a large number of electrons under the effect of radiotherapy, which further reacts with intracellular molecules to produce reactive oxygen species and enhances the killing effect on tumor cells, thus having the effect of radiotherapy sensitization. In conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystem with radiosensitizing function. CONCLUSION: In conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystems with radiosensitizing function.

Selenadiazole derivative-loaded metal azolate frameworks facilitate NK cell immunotherapy by sensitizing tumor cells and shaping immuno-suppressive microenvironments.

The low sensitivity of tumor cells and immunosuppressive microenvironments lead to unsatisfactory efficacy of natural killer (NK) cell immunotherapy. In this work, we developed a safe and effective combination treatment strategy by integrating a selenadiazole derivative (PSeD)-loaded metal azolate framework (PSeD@MAF-4(R)) with NK cells derived from cancer patients against a xenograft human breast tumor model. Intriguingly, it was found that only PSeD@MAF-4(R) pretreatment on tumor cells exhibited synergistic effects with NK cells in inhibiting tumor cell growth by up-regulating NKG2D and its ligands to maximize the interactions between NK and MCF-7 cells. Moreover, PSeD@MAF-4(R) pretreatment could significantly enhance the degranulation of NK cells and regulate their secretions of pro- or anti-inflammatory cytokines (e.g. IL-6, IL-10, and TGF-ß). Furthermore, PSeD@MAF-4(R) could significantly enhance the penetration capability of NK cells into tumor spheroids. The combination treatment mainly induced G1 phase arrest and activated multiple caspase-mediated apoptosis of tumor cells. In vivo evidence showed that PSeD@MAF-4(R) combined with NK cells could highly efficiently combat breast tumor progression via inducing and activating innate immune cell (DC and NK cell) infiltrations within tumor tissues while shaping the suppressive tumor microenvironment by down-regulating the expression of TGF-ß. This developed strategy may provide important information for developing NK cell-based combination cancer immunotherapy with high efficacy and good safety profiles.

Depilatory creams increase the number of hair follicles, and dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-ß in mouse skin.

Besides using for hair removal, depilatory agents have been considered to be used as a penetration enhancer for transepidermal drug delivery. To examine the effect in hair follicles (HFs), two commercially available depilatory creams were tested on the dorsal skin of mice to monitor the effect deep into the skin structure. Fifteen male BALB/c mice were used in this study. Depilatory creams were applied to the dorsal skin of the same animal using shaved and untouched treatments as controls to minimize individual differences. Skin samples were collected at three days, one week and two weeks (n = 5 for each) after the treatment, and subjected for hematoxylin-eosin staining, and immunohistochemical analysis for proinflammatory cytokines. The morphological examination showed an increase in the thickness of epidermal layer of the depilatory cream-treated skin at early time points and in the subcutis at two weeks. Depilatory cream promoted entry of anagen phase and increased the number of hair follicles in the subcutis at one and two weeks. Immunohistochemistry showed elevated percentages of dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-ß. Shaving process increased the thickness of epidermis and dermis as depilatory creams did, but did neither induce the expression of proinflammatory cytokines in the dermal fibroblasts nor the number of HFs. The results suggested that the commercially available depilatory creams caused a transient minor inflammatory response of the skin and increased the levels of cytokines that might subsequently affect hair growth.

An octimibate derivative, Oxa17, enhances cholesterol efflux and exerts anti-inflammatory and atheroprotective effects in experimental atherosclerosis.

Atherosclerotic cardiovascular diseases (ASCVDs), associated with vascular inflammation and lipid dysregulation, are responsible for high morbidity and mortality rates globally. For ASCVD treatment, cholesterol efflux plays an atheroprotective role in ameliorating inflammation and lipid dysregulation. To develop a multidisciplinary agent for promoting cholesterol efflux, octimibate derivatives were screened and investigated for the expression of ATP-binding cassette transporter A1 (ABCA1). Western blotting and qPCR analysis were conducted to determine the molecular mechanism associated with ABCA1 expression in THP-1 macrophages; results revealed that Oxa17, an octimibate derivative, enhanced ABCA1 expression through liver X receptors alpha (LXRα) activation but not through the microRNA pathway. We also investigated the role of Oxa17 in high-fat diet (HFD)-fed mice used as an in vivo atherosclerosis-prone model. In ldlr-/- mice, Oxa17 increased plasma high-density lipoprotein (HDL) and reduced plaque formation in the aorta. Plaque stability improved via reduction of macrophage accumulation and via narrowing of the necrotic core size under Oxa17 treatment. Our study demonstrates that Oxa17 is a novel and potential agent for ASCVD treatment with atheroprotective and anti-inflammatory properties.

Epigallocatechin-3-gallate exhibits immunomodulatory effects in human primary T cells.

T cells secrete several inflammatory cytokines that play a critical role in the progression of atherosclerosis. Although green tea epigallocatechin-3-gallate (EGCG) exerts anti-inflammatory and anti-atherosclerotic effects in animals, few studies have identified the mechanism underlying these effects in human primary T cells. This study investigated the pathway involved in EGCG modulation of cytokine secretion in activated human primary T cells. We pre-treated human primary T cells with EGCG (0.1, 1, 5, 10, and 20 µM) for 4 h and incubated them with or without phorbol 12-myristate 13-acetate and ionomycin (P/I) for 20 h. The cytokine production, activator protein (AP)-1 binding activity, and level of mitogen-activated protein kinase (MAPK) were assessed using enzyme-linked immunosorbent assay, electrophoretic mobility shift assay, and Western blotting, respectively. At 10 and 20 µM, EGCG decreased interleukin (IL)-2 levels by 26.0% and 38.8%, IL-4 levels by 41.5% and 55.9%, INF-γ levels by 31.3% and 34.7%, and tumor-necrosis factor (TNF)-α levels by 23.0% and 37.6%, respectively. In addition, the level of phosphorylated c-Jun N-terminal (p-JNK) and extracellular signal-regulated kinase (p-ERK) was decreased, but not the level of p-p38 MAPK. EGCG did not alter any of the total protein amounts, suggesting a selective effect on specific types of MAPKs in stimulated human T cells. EGCG tended to inactivate AP-1 DNA-binding activity. The P/I-induced production of IL-2, IL-4, INF-γ, and TNF-α by human T cells was suppressed by AP-1 inhibitor in a concentration-dependent manner. In conclusion, EGCG suppressed cytokine secretion in activated human primary T cells, and this effect was likely mediated by AP-1 inactivation through the ERK and JNK, but not p38 MAPK, pathways. These results may be related to the mechanisms through which EGCG inhibits immune- or inflammation-related atherogenesis.

Depilatory creams increase the number of hair follicles, and dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-β in mouse skin

Besides using for hair removal, depilatory agents have been considered to be used as a penetration enhancer for transepidermal drug delivery. To examine the effect in hair follicles (HFs), two commercially available depilatory creams were tested on the dorsal skin of mice to monitor the effect deep into the skin structure. Fifteen male BALB/c mice were used in this study. Depilatory creams were applied to the dorsal skin of the same animal using shaved and untouched treatments as controls to minimize individual differences. Skin samples were collected at three days, one week and two weeks (n = 5 for each) after the treatment, and subjected for hematoxylin-eosin staining, and immunohistochemical analysis for proinflammatory cytokines. The morphological examination showed an increase in the thickness of epidermal layer of the depilatory cream-treated skin at early time points and in the subcutis at two weeks. Depilatory cream promoted entry of anagen phase and increased the number of hair follicles in the subcutis at one and two weeks. Immunohistochemistry showed elevated percentages of dermal fibroblasts expressing interleukin-6, tumor necrosis factor-α, and tumor necrosis factor-β. Shaving process increased the thickness of epidermis and dermis as depilatory creams did, but did neither induce the expression of proinflammatory cytokines in the dermal fibroblasts nor the number of HFs. The results suggested that the commercially available depilatory creams caused a transient minor inflammatory response of the skin and increased the levels of cytokines that might subsequently affect hair growth.

A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction.

BACKGROUND AND PURPOSE: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. EXPERIMENTAL APPROACH: Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3 H labelling of cholesterol. LDL receptor knockout (Ldlr-/- ) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. KEY RESULTS: Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation. CONCLUSION AND IMPLICATIONS: Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.

Carvedilol Ameliorates Experimental Atherosclerosis by Regulating Cholesterol Efflux and Exosome Functions.

Carvedilol (Cav), a nonselective ß-blocker with α1 adrenoceptor blocking effect, has been used as a standard therapy for coronary artery disease. This study investigated the effects of Cav on exosome expression and function, ATP-binding cassette transporter A1 (ABCA1) expression, and cholesterol efflux that are relevant to the process of atherosclerosis. Human monocytic (THP-1) cell line and human hepatic (Huh-7) cells were treated with Cav, and cholesterol efflux was measured. Exosomes from cell culture medium or mice serum were isolated using glycan-coated recognition beads. Low-density lipoprotein receptor knockout (ldlr-/-) mice were fed with high-fat diet and treated with Cav. Cav accentuated cholesterol efflux and enhanced the expressions of ABCA1 protein and mRNA in both THP-1 and Huh-7 cells. In addition, Cav increased expression and function of exosomal ABCA1 in THP-1 macrophage exosomes. The mechanisms were associated with inhibition of nuclear factor-κB (NF-κB) and protein kinase B (Akt). In hypercholesterolemic ldlr-/- mice, Cav enhanced serum exosomal ABCA1 expression and suppressed atherosclerosis by inhibiting lipid deposition and macrophage accumulation. Cav halts atherosclerosis by enhancing cholesterol efflux and increasing ABCA1 expression in macrophages and in exosomes, possibly through NF-κB and Akt signaling, which provides mechanistic insights regarding the beneficial effects of Cav on atherosclerotic cardiovascular disease.

Pitavastatin Exerts Potent Anti-Inflammatory and Immunomodulatory Effects via the Suppression of AP-1 Signal Transduction in Human T Cells.

Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on T cell activation. This study evaluated the immunomodulatory capacities of three common statins, pitavastatin, atorvastatin, and rosuvastatin, in activated human T cells. The enzyme-linked immunosorbent assay (ELISA) and quantitative real time polymerase chain reaction (qRT-PCR) results demonstrated stronger inhibitory effects of pitavastatin on the cytokine production of T cells activated by phorbol 12-myristate 13-acetate (PMA) plus ionomycin, including interleukin (IL)-2, interferon (IFN)-γ, IL-6, and tumor necrosis factor α (TNF-α). Molecular investigations revealed that pitavastatin reduced both activating protein-1 (AP-1) DNA binding and transcriptional activities. Further exploration showed the selectively inhibitory effect of pitavastatin on the signaling pathways of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Our findings suggested that pitavastatin might provide additional benefits for treating hypercholesterolemia and ASCVD through its potent immunomodulatory effects on the suppression of ERK/p38/AP-1 signaling in human T cells.

Spices and Atherosclerosis.

Cardiovascular disease is one of the leading causes of death and disability in the world. Atherosclerosis, characterized by lipid accumulation and chronic inflammation in the vessel wall, is the main feature of cardiovascular disease. Although the amounts of fruits and vegetables present in the diets vary by country, diets, worldwide, contain large amounts of spices; this may have positive or negative effects on the initiation and development of atherosclerosis. In this review, we focused on the potential protective effects of specific nutrients from spices, such as pepper, ginger, garlic, onion, cinnamon and chili, in atherosclerosis and atherosclerotic cardiovascular disease. The mechanisms, epidemiological analysis, and clinical studies focusing on a variety of spices are covered in this review. Based on the integrated information, we aimed to raise specific recommendations for people with different dietary styles for the prevention of atherosclerotic cardiovascular disease through dietary habit adjustments.

Dopamine Release Impairment in Striatum After Different Levels of Cerebral Cortical Fluid Percussion Injury.

To investigate the role of dopamine release in cognitive impairment and motor learning deficits after brain injury, different levels of traumatic brain injury (TBI) were made in rats by using fluid percussion at two different atmospheres (2 Psi and 6 Psi). Tonic and phasic bursting dopamine release and behavior tests followed at several time points. We used in vitro fast-scan cyclic voltammetry to survey dopamine release in the striatum and analyzed the rats' behavior using novel object recognition (NOR) and rotarod tests. Both tonic and bursting dopamine release were greatly depressed in the severely (6 Psi) injured group, which persisted up to 8 weeks later. However, in the 2 Psi-injured group, the suppression of bursting dopamine release occurred at 1∼2 weeks after injury, but there were no significant differences after 4 weeks. Tonic dopamine release was also diminished significantly at 1∼2 weeks after the injury; partial recovery could then be seen 4 weeks after injury. A significant deficiency in the fixed speed rotarod test and NOR test were noted in both 2 Psi and 6 Psi groups initially; however, the changes recovered in the 2 Psi group 2 weeks after injury while persisting in the 6 Psi group. In conclusion, striatal evoked dopamine release was affected by fluid percussion injury, with behavioral deficits showing differences as a function of injury severity. The severe fluid percussion injury (6 Psi) group showed more dopamine release defects, as well as cognitive and motor deficiencies. Recovery of dopamine release and improvement in behavioral impairment were better in the mild TBI group.

Remote effects on the striatal dopamine system after fluid percussion injury.

PURPOSE: To investigate the effects of traumatic brain injury (TBI) on the dopamine system in the brain at different distances from the impaction site, we compared the release, reuptake, metabolism, and release probability of dopamine on the sides of the brain ipsilateral and contralateral to the injury at different time points after varying severities of fluid percussion injuries. MATERIALS AND METHODS: Tonic (1-pulse evoked) and bursting (10-pulse evoked) dopamine release changes in the ipsilateral and contralateral sides of the striatum resulting from mild (2-Pa) and severe (6-Pa) levels of fluid percussion injury were analyzed at the acute (2h and 24h), subacute (1 and 2 weeks), and chronic stages (4, 6, and 8 weeks) after injury by using fast scan cyclic voltammetry to measure brain slices. The metabolic rate of striatal dopamine was surveyed using high-performance liquid chromatography. The microglia reaction was analyzed using immunohistochemistry at each stage. RESULTS: In 6-Pa injured animals, for both tonic and bursting dopamine release, reuptake and release probability were suppressed on both the ipsilateral and contralateral sides of the striatum from the acute to the chronic stage. These neuronal activities were also affected at the subacute stage on both sides of the striatum in 2-Pa injured animals. The turnover rate of dopamine was not affected in the 2-Pa injured animals but increased gradually during the chronic stage in the 6-Pa injured group. CONCLUSION: TBI suppresses dopamine release and reuptake and affects the metabolic rate and release probability of dopamine on the sides of the nigrostriatal system both ipsilateral and contralateral to the injury during both the acute and subacute stages after the injury.

Amantadine ameliorates dopamine-releasing deficits and behavioral deficits in rats after fluid percussion injury.

AIMS: To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery. MATERIALS AND METHODS: In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6 mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury. RESULTS: Sequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion. CONCLUSION: Chronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury.

The accumulation study of 9°Sr in fish from a fishpond of northern Taiwan.

Three kinds of fish from a natural fishpond in the north of Taiwan were collected and analyzed in this study. The three species were non-predatory Ctenopharyn odon idellus, predatory Aristichthys nobilis and predatory Mylopharyngodon piceus. The activity concentrations of (90)Sr in bone and edible flesh of fish, as well as in water and soil of fishpond were measured by using the radiochemical analysis. Additionally, the concentration of stable calcium in fish bone, [Ca]bone, and that of stable strontium in fish bone, [Sr]bone, were measured by ICP-AES. From the results, the concentration factors of (90)Sr, CF((90)Sr), in fish bone was no statistic difference between non-predatory and predatory fish. Besides, the accumulation of (90)Sr in the non-predatory fish remarkably decreased with increasing the fish weight. As for the predatory fish, they both showed no statistically significant correlations between the (90)Sr activity concentration and the fish weight. Regarding the activity concentrations of (90)Sr in fish bone, all the fish were observed positively correlated with the measured [Sr]bone.

[Good nursing: perspectives of patients and family].

This qualitative study aimed to explore patients' perspectives on good nursing for comparison with nurses' perspectives, as identified in a previous study. Purposive sampling was employed to recruit 53 patients and six family members from three medical centers and three regional hospitals, in northern, central, and southern Taiwan. The 59 participants were clustered into nine groups for focus-group interviews for data collection purposes, from March to June, 2003. Most of the participants were male (62.7%), and their mean age was 51.9 years (SD=15.6), with a range from 18 to 81 years old. All of the participants were hospitalized for at least three days and had the physical and mental strength to participate in a 60-90 minute group interview. The interviews were both hand-recorded and audio-taped on site, with permission from the participants, and then transcribed into verbatim narratives for data analysis. Content analysis was used to identify items in relation to good nursing/not-good nursing across narratives. The findings showed that four major categories of good nursing inductively emerged, including: (1) Providing professional nursing as a guardian angel, (2) Demonstrating professional skills with humanity, (3) Being accountable and competent, and (4) Showing self-improvement. The findings indicated that professional nursing competence is the essence of good nursing. Treating patients as relatives is also perceived as good nursing. In comparing the patients definitions of good nursing with those of nurses it was observed that there are similarities in terms of the main categories of the definitions. Patients, however, tend to use negative examples or normative moral terms, such as "should" or "ought to" to connote what is expected of good nursing and how good nursing is expressed in the context of patient-nurse interaction.

[Good nursing from the perspective of nurses].

This qualitative study used an in-depth interview method to explore nurses' perspectives on good nursing practices. A balanced stratified sampling approach was employed to recruit 83 nurses from 18 hospitals that were relatively evenly distributed around Taiwan. Fifteen nurses educated to the masters' level and well trained in the in-depth interview approach collected research data from January through May 2002. Interviews were audiotaped and transcribed in verbatim narratives. Content analysis was used to identify good nursing practices common across narratives. Four good nursing practice categories emerged inductively. These included (1) good decision making and execution, (2) dexterous professional skills, (3) good patient-nurse relationships, and (4) a mature self. Findings present quality nursing care as a relationship that combines professionalism and humanism. In order to provide better care, a nurse must incorporate knowledge from empirical research into his or her practice and internalize his or her value as a nurse. A discussion of the process of self-maturation acquisition and reflective learning offers new insights to guide the construction of nursing education curricula and activities for clinical nursing practice. Further research in good nursing is suggested.