An increasing body of evidence suggests that bone marrow-derived myeloid cells play a critical role in the pathophysiology of pulmonary hypertension (PH). However, the true requirement for myeloid ...cells in PH development has not been demonstrated, and a specific disease-promoting myeloid cell population has not been identified. Using bone marrow chimeras, lineage labeling, and proliferation studies, we determined that, in murine hypoxia-induced PH, Ly6C
nonclassical monocytes are recruited to small pulmonary arteries and differentiate into pulmonary interstitial macrophages. Accumulation of these nonclassical monocyte-derived pulmonary interstitial macrophages around pulmonary vasculature is associated with increased muscularization of small pulmonary arteries and disease severity. To determine if the sensing of hypoxia by nonclassical monocytes contributes to the development of PH, mice lacking expression of hypoxia-inducible factor-1α in the Ly6C
monocyte lineage were exposed to hypoxia. In these mice, vascular remodeling and PH severity were significantly reduced. Transcriptome analyses suggest that the Ly6C
monocyte lineage regulates PH through complement, phagocytosis, Ag presentation, and chemokine/cytokine pathways. Consistent with these murine findings, relative to controls, lungs from pulmonary arterial hypertension patients displayed a significant increase in the frequency of nonclassical monocytes. Taken together, these findings show that, in response to hypoxia, nonclassical monocytes in the lung sense hypoxia, infiltrate small pulmonary arteries, and promote vascular remodeling and development of PH. Our results demonstrate that myeloid cells, specifically cells of the nonclassical monocyte lineage, play a direct role in the pathogenesis of PH.
The environmental yeast Cryptococcus neoformans is the most common cause of deadly fungal meningitis in primarily immunocompromised populations. A number of factors contribute to cryptococcal ...pathogenesis. Among them, inositol utilization has been shown to promote C. neoformans development in nature and invasion of central nervous system during dissemination. The mechanisms of the inositol regulation of fungal virulence remain incompletely understood. In this study, we analyzed inositol-induced capsule growth and the contribution of a unique inositol catabolic pathway in fungal development and virulence. We found that genes involved in the inositol catabolic pathway are highly induced by inositol, and they are also highly expressed in the cerebrospinal fluid of patients with meningoencephalitis. This pathway in C. neoformans contains three genes encoding
-inositol oxygenases that convert
-inositol into d-glucuronic acid, a substrate of the pentose phosphate cycle and a component of the polysaccharide capsule. Our mutagenesis analysis demonstrates that inositol catabolism is required for C. neoformans virulence and deletion mutants of
-inositol oxygenases result in altered capsule growth as well as the polysaccharide structure, including O-acetylation. Our study indicates that the ability to utilize the abundant inositol in the brain may contribute to fungal pathogenesis in this neurotropic fungal pathogen.
The human pathogen Cryptococcus neoformans is the leading cause of fungal meningitis in primarily immunocompromised populations. Understanding how this environmental organism adapts to the human host to cause deadly infection will guide our development of novel disease control strategies. Our recent studies revealed that inositol utilization by the fungus promotes C. neoformans development in nature and invasion of the central nervous system during infection. The mechanisms of the inositol regulation in fungal virulence remain incompletely understood. In this study, we found that C. neoformans has three genes encoding
-inositol oxygenase, a key enzyme in the inositol catabolic pathway. Expression of these genes is highly induced by inositol, and they are highly expressed in the cerebrospinal fluid of patients with meningoencephalitis. Our mutagenesis analysis indeed demonstrates that inositol catabolism is required for C. neoformans virulence by altering the growth and structure of polysaccharide capsule, a major virulence factor. Considering the abundance of free inositol and inositol-related metabolites in the brain, our study reveals an important mechanism of host inositol-mediated fungal pathogenesis for this neurotropic fungal pathogen.
Abstract : Objectives : Workplace violence in the health sector is a worldwide concern. Physicians play an essential role in health-care teamwork ; thus, understanding how organizational factors ...influence workplace violence against physicians is critical. Methods : A total of 189 physicians from three public hospitals and one private hospital in Northern Taiwan completed a survey, and the response rate was 47.1%. This study was approved by the institutional review board of each participating hospital. The 189 physicians were selected from the Taipei area, Taiwan. Results : The results showed that 41.5% of the respondents had received at least one workplace-related physical or verbal violent threat, and that 9.8% of the respondents had experienced at least one episode of sexual harassment in the 3 months before the survey. Logistic regression analysis revealed that physicians in psychiatry or emergency medicine departments received more violent threats and sexual harassment than physicians in other departments. Furthermore, physicians with a lower workplace safety climate (OR=0.89 ; 95% CI=0.81-0.98) and more job demands (OR=1.15 ; 95% CI=1.02-1.30) were more likely to receive violent threats. Conclusions : This study found that workplace violence was associated with job demands and the workplace safety climate. Therefore, determining how to develop a workplace safety climate and ensure a safe job environment for physicians is a crucial management policy issue for health-care systems.
Background: This study investigated the survival and natural history of trisomy 13 in a series of patients, comparing the management and outcome before and after the implementation of Taiwan’s ...National Health Insurance program (NHI).
Methods: A total of 28 cases of trisomy 13 seen at Mackay Memorial Hospital, Taipei, Taiwan, from 1985 to 2004 were retrospectively reviewed. Survival and management before (12 cases) and after (16 cases) the implementation of National Health Insurance were compared, and structural defects, imaging findings, and cytogenetic results were analyzed. The cases that were diagnosed prenatally, and finally terminated, were excluded from this study. The diagnosis of trisomy 13 was based on the postnatal chromosome analysis.
Results: All patients except one with trisomy 13 translocation died in their first year because of severe malformations of the cardiovascular or central nervous system. The median survival was 9 days. After implementation of National Health Insurance, survival with trisomy 13 was significantly longer than before (P < 0.05). The three most common structural defects were abnormal auricular helices or low‐set ears (89%), cryptorchidism and abnormal scrotum of male (73%) and cleft lip and/or palate (71%). Using echocardiography, the most commonly detected heart defects were patent ductus arteriosus (68%), ventricular septal defect (50%) and atrial septal defect (50%), and eight cases (36%) had complex congenital heart defects. The most common brain lesion was lenticulostriate vasculopathy (22%), followed by holoprosencephaly (17%), brain edema (13%) and subependymal cyst (13%).
Conclusions: Early diagnosis and the survival patterns from the data collected should be used to inform parents and health‐care professionals to assist in decision making. Although most patients with trisomy 13 die within the first weeks after birth, it is important to recognize that a few may survive the first year. When counseling families, the long‐term survival prospects of trisomy 13 patients should be included.
An increasing body of evidence suggests that bone marrow derived myeloid cells play a critical role in the pathophysiology of pulmonary hypertension (PH). However, the true requirement for myeloid ...cells in PH development has not been demonstrated and a specific disease-promoting myeloid cell population has not been identified. Utilizing bone marrow chimeras, lineage labelling, and proliferation studies, we determined that, in murine hypoxia-induced PH, Ly6C
lo
non-classical monocytes are recruited to small pulmonary arteries and differentiate into pulmonary interstitial macrophages (IMØ). Accumulation of these non-classical monocyte-derived pulmonary IMØ around pulmonary vasculature is associated with increased muscularization of small pulmonary arteries and disease severity. To determine if the sensing of hypoxia by non-classical monocytes contributes to the development of PH, mice lacking expression of Hif1α in the Ly6C
lo
monocyte lineage were exposed to hypoxia. In these mice, vascular remodeling and PH severity were significantly reduced. Transcriptome analyses suggest that the Ly6C
lo
monocyte lineage regulates PH through complement, phagocytosis, antigen presentation, and chemokine/cytokine pathways. Consistent with these murine findings, relative to controls, lungs from PAH patients displayed a significant increase in the frequency of non-classical monocytes. Taken together, these findings show that, in response to hypoxia, non-classical monocytes in the lung sense hypoxia, infiltrate small pulmonary arteries, and promote vascular remodeling and the development of PH. Our results demonstrate that myeloid cells, specifically cells of the non-classical monocyte lineage play a direct role in the pathogenesis of PH.
•Tonic and bursting dopamine release, reuptake and release probability were suppressed on both sides of striatum in 6-Pa injured animals.•The parameters were affected at the subacute stage on both ...sides of striatum in 2-Pa injured animals.•The turnover rate of dopamine was not affected in 2-Pa injured animals.•The increasing microglia amount was found on both sides of striatum at 1 day, 1 week, and 8 weeks after injury.
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.
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.
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.
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.
This paper proposes a passive optical brightening element design, a non-axisymmetric freeform lens (NAFL), arranged and assembled on a traditional traffic sign. NAFL is the first optical design which ...can effectively solve the traffic problem that direct sunlight affects the driver's inability to look directly at the traffic sign. The NAFL can converge the sunlight behind the traffic sign and diverge forward to 150 meters away. In this way, the NAFL array combinations on the traffic sign can directly rely on sunlight as image information pixels. According to the simulation, the optical efficiency of the NAFL can be as high as 81.5%. Besides, the angular tolerance is also analyzed to evaluate the working hours of the NAFL. Finally, we made the prototype and proved that such passive brightening components could effectively improve the traffic sign's visibility in harsh sunlight.
Aim : Chronic kidney disease (CKD) is associated with unfavorable outcomes in patients with ischemic stroke. One major metabolic derangement of CKD is dyslipidemia, which can be managed by statins. ...This study aimed to investigate whether the association of statins with post-stroke outcomes would be affected by renal function. Methods : We evaluated the association of statin therapy at discharge with 3-month outcomes according to the estimated glomerular filtration rate (eGFR) of 50,092 patients with acute ischemic stroke from the Taiwan Stroke Registry from August 2006 to May 2016. The outcomes were mortality, functional outcome as modified Rankin Scale (mRS), and recurrent ischemic stroke at 3 months after index stroke. Results : Statin therapy at discharge was associated with lower risks of mortality (adjusted hazard ratio aHR, 0.41 ; 95% confidence interval CI, 0.34 to 0.50) and unfavorable functional outcomes (mRS 3-5 ; aHR, 0.80 ; 95% CI, 0.76 to 0.84) in ischemic stroke patients. After stratification by eGFR, the lower risk of mortality associated with statins was limited to patients with an eGFR above 15 mL/min/1.73 m2. Using statins at discharge was correlated with a lower risk of unfavorable functional outcomes in patients with an eGFR of 60-89 mL/min/1.73 m2. Statin therapy in patients with an eGFR of 60-89 mL/min/1.73 m2 may be associated with a higher risk of recurrent ischemic stroke compared with nonusers (aHR, 1.29 ; 95% CI, 1.07 to 1.57). Conclusions : In patients with acute ischemic stroke, the associations of statins with mortality and functional outcomes was dependent on eGFR.
Desipramine (DP) is a tricyclic antidepressant used for treating depression and numerous other psychiatric disorders. Recent studies have shown that DP can promote neurogenesis and improve the ...survival rate of hippocampal neurons. However, whether DP induces neuroprotection or promotes the differentiation of neural stem cells (NSCs) needs to be elucidated. In this study, we cultured NSCs derived from the hippocampal tissues of adult rats as an in vitro model to evaluate the modulation effect of DP on NSCs. First, we demonstrated that the expression of Bcl-2 mRNA and nestin in 2 μM DP-treated NSCs were up-regulated and detected by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The results of Western blotting and immunofluorescent study confirmed that Bcl-2 protein expression was significantly increased in Day 3 DP-treated NSCs. Using the Bcl-2 small interfering RNA (siRNA) method, our results further showed that DP protects the lipopolysaccharide (LPS)- induced apoptosis in NSCs, in part by activating the expression of Bcl-2. Furthermore, DP treatment significantly inhibited the induction of proinflammatory factor interleukin (IL)-1β, IL-6, and tumor necrosis factor-á in the culture medium of LPS-treated NSCs mediated by Bcl-2 modulation. The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that DP significantly increased the functional production of serotonin (26 ± 3.5 ìM, DP-treated 96 h) and noradrenaline (50 ± 8.9 μM, DP-treated 96 h) in NSCs through activation of the MAPK/ERK pathway and partially mediated by Bcl-2. In conclusion, the present results indicate that DP can increase neuroprotection ability by inhibiting the LPS-induced inflammatory process in NSCs via the modulation of Bcl-2 expression, as confirmed by the siRNA method.
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