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The political dynamics of the national law shows that the existence of the Islamic law has ups and downs following the existing social dynamic and political configuration. It needs serious efforts to dig up and socialize as many as possible noble values contained in the Islamic law. The ways to dig up the values, among others, are to understand philosophical aspects of the Islamic law as mirrored from the kulli (sharia law) serving as the basis of its thought, the goals of the Islamic law (maqashid al-syariat) including their wisdom (hikmah al-tasyri’), and also the concept of human beings according to Islam. The Islamic law as the source of values for rules of laws that will be made, is implemented using how the values of the laws are obtained and then poured down into the national law. The majority of Muslim and Islamic prominent leaders seem to consider that the implementation of the Islamic law may be accommodated without any formal legislation as Islamic law, but by merely integrating principles of the Islamic law into the national law. Such an integration into the national law is probably made especially under the framework of the national law development.

Pandrah Weir, built-in 1987, serves the Pandrah Technical Irrigation Area in Bireuen District, Aceh Province, with an area of 1.203 Ha. Its old infrastructure has experienced various damage that can decrease the irrigation system performance. The Pandrah irrigation system's previous performance assessment by both the MASSCOTE approach and Rapid Appraisal Procedure (RAP) evaluation suggested a service level of 3.05 (useful classification). This study assessed the effect of the variables on the Pandrah irrigation system's performance with Structural Equation Modeling (SEM) operated by the AMOS program. The four leading indicators were irrigation service, Water User Farmers Association (P3A), operator Human Resources (H.R.), and irrigation operation modernization. The refinement of irrigation system performance analysis using SEM showed that results of the four irrigation system performance indicators, namely: 0.082 (p=0.768), 0.090 (p=0.273), 0.419 (p=0.287), and 0.606 (p=0.039) for irrigation service, P3A indicator, irrigation operation modernization, and H.R. respectively. Based on the evaluation of the four indicators of irrigation system performance, it is concluded that the Pandrah irrigation system's performance is good. This performance assessment provides a clear picture of irrigation water services, H.R., P3A being an initial assessment for priorities, planning, and scheduling to start modernization programs for irrigation system operations. Irrigation modernization aims to facilitate the operation and maintenance by improving the irrigation system. This modernization means that irrigation planning, irrigation operation, maintenance, and monitoring systems have been carefully calculated before proposing a new irrigation network. The success of monitoring activities requires the use of information technology.

Mandor Village has developed as a tradisional gold mining area since years ago. It involved activities that have led to extreme land condition and the release of mining residues, i.e., mercury, to the soils. The study examined the potential of soil bacteria as mercury bioremediation agent based on their population and activity in former mines with different ages. The bacterial population was measured by isolating soil bacteria on solid media using the pour plate method, and the colonies were enumerated during the incubation. The Nutrient Agar (NA) medium was used to obtain the total population, whereas the Salt Base Solution (SBS) was to determine the presence of mercury-tolerant bacteria. The addition of HgCl2 affected the number of the colonies. The colony only grew until the concentration of HgCl2 reached 5 mg/l, and the total colony was larger in older mines. The observation of bacterial activity showed that biotransformation performance was lower when the concentration of mercury was the same as its natural presence in soils (0.1-0.5 mg/l) compared with higher mercury level (1 mg/l). The research showed that lower mercury concentrations in nature reduced the natural ability of bacteria to transform pollutants. This study provides information that can assist the development of a technological approach to control mercury pollution in former traditional gold mines in an environmentally friendly manner using indigenous soil bacteria.

The manufacturing industry sector is an economic sector that provides the largest contribution to the national economy so that the performance of the manufacturing industry greatly affects overall economic performance. Industrial sector investment is currently required to be located within industrial estates in order to improve efficiency, organize space, manage the environment and optimize the multiplier effects on other economic sectors. This study aims to analyze the multiplier effects of increased investment in the manufacturing industry sector in industrial estate on the performance of the transport/logistics sector. The analysis model uses the Social Accounting Matrix (SAM) Model, which is an effect multiplier analysis. The results of the research show that the increase in investment in the manufacturing industry sector located in the industrial area provides a multiplier effect on improving the performance of the transportation/logistics sector in the form of increased transportation/logistics sector revenues.

The national family planning program in East Kalimantan needs to achieve a larger target on modern contraceptives. Despite the fertility decline, this program still facing increasing discontinuation rates. A better understanding of the factors behind the discontinuation of a modern method would help in improving programs. This study aims to analyze the determinants of discontinuation of modern contraceptive use. This was a cross-sectional study, the dataset came from Indonesia Demographic and Health Survey 2017 of East Kalimantan Province. The sample is all couples of childbearing age between 10–49 years with marital status who have used and are still using contraception (408 samples). Descriptive analyses were used to assess the reasons for discontinuation. Multiple logistic regression was used to estimate the likelihood of discontinuation by demographic characteristics and others. The proportion of respondents who continue using modern contraceptives was 51%, against 49% discontinuation. The reasons for discontinuation were the husband’s disapproval (31%) and health problems related to side effects (26.5%). In the multivariate analysis showed maternal age, women who live in urban areas, and women with birth planning near the future will have an opportunity to discontinue in modern contraceptives. It concluded that there is still high modern contraceptive discontinuation in East Kalimantan, therefore it needed for disseminating information through entertainment-education in social media, health workers better counseling services from also better tools, and include the male participation in family planning counseling. DETERMINAN YANG BERHUBUNGAN DENGAN PUTUS PAKAI KONTRASEPSI MODERN DI KALIMANTAN TIMUR: ANALISIS LANJUT SURVEI DEMOGRAFI DAN KESEHATAN INDONESIA 2017 Program keluarga berencana nasional di Kalimantan Timur perlu mencapai target yang lebih baik dalam penggunaan kontrasepsi modern. Meskipun terdapat penurunan fertilitas, namun program keluarga berencana masih menghadapi peningkatan angka putus pakai. Pemahaman yang lebih baik tentang faktor-faktor di balik putus pakai metode kontrasepsi modern akan membantu meningkatkan program. Penelitian ini bertujuan menganalisis faktor-faktor penentu putus pakai penggunaan kontrasepsi modern. Desain penelitian ini adalah cross-sectional, set data berasal dari Survei Demografi Kesehatan Indonesia 2017 untuk Provinsi Kalimantan Timur. Sampel adalah semua pasangan usia subur berusia 10–49 tahun dengan status perkawinan baik bagi yang pernah menggunakan dan masih menggunakan kontrasepsi, yaitu 408 sampel. Analisis deskriptif digunakan untuk menilai alasan putus pakai. Regresi logistik berganda digunakan untuk memperkirakan kemungkinan putus pakai berdasar atas karakteristik demografis dan lainnya. Proporsi responden yang masih terus menggunakan kontrasepsi modern adalah 51% dibanding dengan 49% putus pakai. Alasan penghentian adalah ketidaksetujuan suami (31%) dan masalah kesehatan yang berkaitan dengan efek samping (26,5%). Analisis multivariat menunjukkan usia ibu, wanita yang tinggal di daerah perkotaan, dan wanita dengan perencanaan kelahiran dalam waktu dekat akan memiliki kesempatan untuk berhenti menggunakan kontrasepsi modern. Dapat disimpulkan bahwa kejadian putus pakai kontrasepsi modern masih tinggi di Kalimantan Timur, oleh karena itu diperlukan diseminasi informasi melalui entertainment-education dalam sosial media, layanan konseling dari petugas kesehatan, serta alat bantu konseling yang lebih baik dan juga keikutsertaan pria dalam proses konseling.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide despite advances in cancer therapeutics. In several gynecological cancers, anti-Müllerian hormone receptor type 2 (AMHR2) mediates AMH-induced growth inhibition and is expressed at high levels. Furthermore, 5%-8% of NSCLCs exhibit high AMHR2 expression, suggesting that AMH may inhibit the progression of some lung cancers. However, the clinical relevance of AMHR2 expression and its role in lung cancer is not fully clarified., Methods: Immunostaining was performed on 79 surgical specimens of NSCLC. The Cancer Genome Atlas RNA-seq data for lung adenocarcinoma were analyzed, and gene ontology and gene set enrichment analyses were performed. In cellular experiments, AMHR2-overexpressing NSCLC cell lines were established, and the role of the AMH-AMHR2 pathway in cell proliferation with recombinant human AMH protein treatment was examined., Results: A total of 13 cases (16.5%) were positive for immunostaining in lung adenocarcinoma tissues; no positive signals were detected in lung squamous carcinoma tissues. Gene expression variation analysis using The Cancer Genome Atlas data showed that the expression of genes related to the cell cycle was downregulated in the AMHR2-high group. Cellular experiments showed that activation of the AMH-AMHR2 pathway suppressed cell proliferation., Conclusion: In lung adenocarcinoma tissues with high expression of AMHR2, activation of the AMH-AMHR2 pathway may suppress cell proliferation., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival has not improved significantly over the last decades because no major therapeutic breakthroughs have been achieved for over 15 years., Methods: We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies., Results: We identified SKP2 (encoding S-phase kinase-associated protein 2) and CKS1B (encoding CDC28 protein kinase regulatory subunit 1B) as the two most essential genes in that order in SCLC. Notably, SKP2 and CKS1B comprise the p27 binding pocket of the E3 ubiquitin ligase SCF SKP2 complex. Immunohistochemistry on tissue microarrays revealed that SKP2 was expressed in >95% of samples at substantially higher levels than that observed for commonly used neuroendocrine markers. As expected, SCLC cell lines were sensitive to SKP2 inhibition. Furthermore, SKP2 or CKS1B knockdown induced apoptosis in RB1 mutant cells, whereas it induced senescence in RB1 wild-type cells., Conclusion: Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between RB1-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the RB1 mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC., Competing Interests: Declaration of competing interest Ken Tajima received research funding from Novartis. Kazuhisa Takahashi received research funding from Chugai Pharm, MSD, Ono Pharm, and Bristol-Myers Squibb. Additionally, Kazuhisa Takahashi acknowledges donations from Eli Lilly Japan, Teijin Pharm, Chugai Pharm, Nippon Boehringer Ingelheim, Kyorin Pharm, Taiho Pharm, and Sanofi. The other authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Background and Objectives : Although statins are recommended for secondary prevention of acute ischemic stroke, some population-based studies and clinical evidence suggest that they might be used with an increased risk of intracranial hemorrhage. In this nested case-control study, we used Taiwan's nationwide universal health insurance database to investigate the possible association between statin therapy prescribed to acute ischemic stroke patients and their risk of subsequent intracerebral hemorrhage and all-cause mortality in Taiwan. Materials and Methods : All data were retrospectively obtained from Taiwan's National Health Insurance Research Database. Acute ischemic stroke patients were divided into a cohort receiving statin pharmacotherapy and a control cohort not receiving statin pharmacotherapy. A 1:1 matching for age, gender, and index day, and propensity score matching was conducted, producing 39,366 cases and 39,366 controls. The primary outcomes were long-term subsequent intracerebral hemorrhage and all-cause mortality. The competing risk between subsequent intracerebral hemorrhage and all-cause mortality was estimated using the Fine and Gray regression hazards model. Results : Patients receiving statin pharmacotherapy after an acute ischemic stroke had a significantly lower risk of subsequent intracerebral hemorrhage ( p < 0.0001) and lower all-cause mortality rates ( p < 0.0001). Low, moderate, and high dosages of statin were associated with significantly decreased risks for subsequent intracerebral hemorrhage (adjusted sHRs 0.82, 0.74, 0.53) and all-cause mortality (adjusted sHRs 0.75, 0.74, 0.74), respectively. Conclusions : Statin pharmacotherapy was found to safely and effectively reduce the risk of subsequent intracerebral hemorrhage and all-cause mortality in acute ischemic stroke patients in Taiwan.

Subarachnoid hemorrhage (SAH) is a type of stroke caused by bleeding into the subarachnoid space. SAH is a medical emergency and requires prompt treatment to prevent complications such as seizures, stroke, or other brain damage. Treatment options may include surgery, medication, or a combination of both. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), a compound with anti-inflammatory and antioxidant properties, is currently being investigated as a potential treatment for various diseases, including chronic kidney disease and pulmonary arterial hypertension. In this study, the effects of CDDO on rats subjected to SAH were evaluated. Male Sprague-Dawley rats were divided into four groups ( n = 6/group): (1) control group, (2) SAH group, (3) SAH + low-dose CDDO (10 mg/kg injected into the subarachnoid space at 24 h after SAH) group, and (4) SAH + high-dose CDDO (20 mg/kg) group. CDDO improved SAH-induced poor neurological outcomes and reduced vasospasm in the basal artery following SAH. It also decreased the SAH-induced expression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 in both the cerebrospinal fluid and serum samples as determined by ELISA. A Western blot analysis confirmed an increase in the p-NF-κB protein level after SAH, but it was significantly decreased with CDDO intervention. Immunofluorescence staining highlighted the proliferation of microglia and astrocytes as well as apoptosis of the neuronal cells after SAH, and treatment with CDDO markedly reduced the proliferation of these glial cells and apoptosis of the neuronal cells. The early administration of CDDO after SAH may effectively mitigate neuronal apoptosis and vasospasm by suppressing inflammation.

In distal vascular lesions, such as the distal anterior inferior cerebellar artery or posterior inferior cerebellar artery (PICA) dissecting aneurysm, and dural arteriovenous fistula (dAVF) and arteriovenous malformation (AVM), super-selective catheterization and embolization using liquid agents, such as NBCA or Onyx liquid embolic system, is the preferred treatment.1 2 We used a flow-directed 1.5 Fr Marathon microcatheter (Medtronic, Minneapolis, MN, USA) for embolization because commonly used detachable coil-compatible microcatheters can be too short or rigid for superselection.3-6 We designed an in vitro coil compatibility test for the Marathon microcatheter and developed a 'free-running' technique (video 1). Using this technique, we trapped the distal PICA dissecting aneurysm and embolized the fistula points of dAVF precisely and safely without affecting adjacent normal structures, which can occur when applying liquid embolizing agents.1-3 After reviewing the case, we determined that this technique can also potentially be applied for implementing the pressure cooker technique7 and combining the management of AVM.4neurintsurg;jnis-2023-020893v1/V1F1V1Video 1Free-running technique via 1.5 Fr Marathon microcatheter., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Thymic squamous cell carcinoma and type B3 thymoma are primary neoplasms of the anterior mediastinum that are sometimes difficult to differentiate from one another histologically. However, only a few immunohistochemical markers are available for the differential diagnosis. The purpose of this study was to discover a novel marker for differentiating between thymic squamous cell carcinoma and type B3 thymoma., Methods: We used histological samples of thymic carcinomas (n = 26) and type B3 thymomas (n = 38) which were resected between 1986 and 2017. To search for candidates of differential markers, gene expression levels were evaluated in samples using promoter analysis by cap analysis of gene expression (CAGE) sequencing., Results: Promoter level expression of CALML5 genes was significantly higher in thymic carcinomas than in type B3 thymomas. We further validated the results of the CAGE analysis in all 26 thymic carcinomas and 38 type B3 thymomas by immunohistochemistry (IHC). CALML5 was strongly expressed in the cytoplasm in 19 of 26 cases with thymic carcinoma, whereas positivity at the protein level was shown in two of 38 type B3 thymomas. Thus, the sensitivity (73.1%) and specificity (94.7%) of CALML5 as markers for immunohistochemical diagnosis of thymic carcinoma were extremely high., Conclusion: We identified CALML5 as a potential marker for differentiating thymic squamous cell carcinoma from type B3 thymoma. It is assumed that future clinical use of CALML5 may improve the diagnostic accuracy of differentiating between these two diseases., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of PD-1/PD-L1 blockade treatment were measured in patients with advanced lung cancer between 2019 and 2020. The cachexia-related cytokines were identified by comparing the levels of circulating cytokines between cachectic and non-cachectic patients. Among 55 patients, 49.1% were diagnosed with cachexia at the beginning of PD-1/PD-L1 blockade therapy. Baseline levels of the circulating cytokines IL-6, IL-8, IL-10, IL-15, and IP-10 were significantly higher in cachectic patients. In contrast, the level of eotaxin-1 was lower in cachectic patients than in those without cachexia. Higher IL-6 at baseline and during treatment was associated with a greater risk of immune-related adverse events, while higher IL-10 at baseline was linked to worse overall survival. More importantly, increased eotaxin-1 after one cycle of PD-1/PD-L1 blockade treatment was associated with higher objective response and better overall survival. A blood-based, cachexia-related cytokine assay may yield potential biomarkers for the early prediction of clinical response to PD-1/PD-L1 blockade and provide clues for improving the outcomes of cachectic patients.

Willingness to pay (WTP) for booster doses of coronavirus disease 2019 (COVID-19) vaccines is an under studied research topic. Therefore, the current study aimed to investigate the WTP for the booster doses of COVID-19 vaccines and its predictors in Indonesia using an online survey distributed all over the provinces of this low-middle-income country. The WTP was evaluated using a basic dichotomous contingent valuation approach, and its associated determinants were evaluated using a linear regression model. Out of 2935 responders, 66.2% (1942/2935) were willing to pay for a booster dose of the COVID-19 vaccine. The majority of respondents (63.5%) were willing to pay within a price range of 100,000-500,000 Indonesian rupiah (IDR), i.e., USD 6.71-33.57. Being older than 40 years, having a higher educational level, having a higher income, knowing and understanding that booster doses were important, and having a vaccine status that is certified halal (permissible in Islamic law), were all associated with a higher WTP for the booster dose of COVID-19 vaccines. The study findings imply that the WTP for a booster dose of COVID-19 vaccination in Indonesia is lower compared to acceptance of vaccines provided free of charge. This WTP data can be utilized to develop a pricing scheme for the booster doses of COVID-19 vaccination in the country with potential benefits in other low-income countries. The government may be required to provide subsidies for the herd immunity vaccination process to proceed as anticipated. Furthermore, the public community must be educated on the importance of vaccination as well as the fact that the COVID-19 epidemic is far from being over.

Obtaining a booster dose of coronavirus disease 2019 (COVID-19) vaccine is required to maintain the protective level of neutralizing antibodies and therefore herd immunity in the community, and the success of booster dose programs depends on public acceptance. The aim of this study was to determine the acceptance of a booster dose of COVID-19 vaccine and its drivers and barriers in Indonesia. A cross-sectional survey was conducted in the provinces of Indonesia between 1 and 15 August 2022. Individuals who completed the primary series of the COVID-19 vaccine were asked about their acceptance of a booster dose. Those who refused the booster dose were questioned about their reasons. A logistic regression was used to determine the determinants associated with rejection of a booster dose of COVID-19 vaccine. A total of 2935 respondents were included in the final analysis. With no information on the efficacy and safety of the COVID-19 vaccine, 95% of respondents agreed to receive a booster dose if it were provided for free by the government. This acceptance was reduced to only 50.3% if the vaccine had a 75% efficacy with a 20% chance of side effects. The adjusted logistic regression analysis indicated that there were eight factors associated with the rejection of the booster dose: age, marital status, religion, occupation, type of the first two vaccines received, knowledge regarding the importance of the booster dose, belief that natural immunity is sufficient to prevent COVID-19 and disbelief in the effectiveness of the booster dose. In conclusion, the hesitancy toward booster doses in Indonesia is influenced by some intrinsic factors such as lack of knowledge on the benefits of the booster dose, worries regarding the unexpected side effects and concerns about the halal status of the provided vaccines and extrinsic determinants such as the effectiveness and safety of the vaccine. These findings suggest the need for more campaigns and promotions regarding the booster dose benefits to increase its acceptance.

Objective: The aim of this study was to assess the stigma associated with coronavirus disease - 2019 (COVID-19) among health care workers (HCWs) in Indonesia during the early phase of the pandemic., Methods: A cross-sectional study was conducted in 12 hospitals across the country in March, 2020. A logistic regression was employed to assess the association between stigma and explanatory variables., Results: In total, 288 HCWs were surveyed, of which 93.4% had never experienced any outbreaks. Approximately 21.9% of the respondents had stigma associated with COVID-19. HCWs who were doctors, had not participated in trainings related to COVID-19, worked in the capital of the province, worked at private hospitals, or worked at a hospital with COVID-19 triage protocols were likely to have no stigma associated with COVID-19., Conclusions: The stigma associated with COVID-19 is relatively high among HCWs in the early phase of the COVID-19 pandemic in Indonesia. Adequate dissemination of knowledge and adequate protection are necessary to reduce stigma among HCWs.

The 2022 multi-country monkeypox outbreak in humans has brought new public health adversity on top of the ongoing coronavirus disease 2019 (COVID-19) pandemic. The disease has spread to 104 countries throughout six continents of the world, with the highest burden in North America and Europe. The etiologic agent, monkeypox virus (MPXV), has been known since 1959 after isolation from infected monkeys, and virulence among humans has been reported since the 1970s, mainly in endemic countries in West and Central Africa. However, the disease has re-emerged in 2022 at an unprecedented pace, with particular concern on its human-to-human transmissibility and community spread in non-endemic regions. As a mitigation effort, healthcare workers, public health policymakers, and the general public worldwide need to be well-informed on this relatively neglected viral disease. Here, we provide a comprehensive and up-to-date overview of monkeypox, including the following aspects: epidemiology, etiology, pathogenesis, clinical features, diagnosis, and management. In addition, the current review discusses the preventive and control measures, the latest vaccine developments, and the future research areas in this re-emerging viral disease that was declared as a public health emergency of international concern.

Objectives: The Indonesian Ministry of Health launched isoniazid preventive therapy (IPT) in 2016, with general practitioners (GPs) at the frontline of this program. However, the extent to which GPs have internalized this program remains uncertain. The aim of this study was to identify the knowledge and attitudes of GPs towards the IPT program in Indonesia., Methods: This study used an online, self-administered questionnaire distributed via e-mail and social messaging services. A logistic regression model was employed to identify the explanatory variables influencing the level of knowledge and attitudes toward IPT among GPs in Indonesia. An empirical analysis was conducted separately for each response variable (knowledge and attitudes)., Results: Of the 418 respondents, 128 (30.6%) had a good knowledge of IPT. Working at a public hospital was the only variable associated with good knowledge, with an adjusted odds ratio (aOR) of 1.69 (95% confidence interval [CI], 1.02 to 2.81). Furthermore, 279 respondents (66.7%) had favorable attitudes toward IPT. In the adjusted logistic regression analysis, good knowledge (aOR, 0.55; 95% CI, 0.34 to 0.89), 1-5 years of work experience (aOR, 2.09; 95% CI, 1.21 to 3.60), and having experienced IPT training (aOR, 0.48; 95% CI, 0.25 to 0.93), were significantly associated with favorable attitudes., Conclusions: In general, GPs in Indonesia had favorable attitudes toward IPT. However, their knowledge of IPT was limited. GPs are an essential element of the IPT program in the country, and therefore, adequate information dissemination to improve their understanding is critical for the long-term viability and quality of the IPT program in Indonesia.

Indonesia is among the top three countries globally with the highest tuberculosis burden. During the past decades, Indonesian health authorities have struggled to improve tuberculosis care quality in health care facilities by optimizing the regulation and strengthening the private sector contributions. The coronavirus disease 2019 (COVID-19) pandemic has hardly affected the Indonesian health care system, including the National Tuberculosis Control Program. While the end of the COVID-19 pandemic in Indonesia is uncertain, the measure to control tuberculosis must not be weakened. Early identification and measurement of the problem size are essential to decide the most appropriate approach to maintain the sustainability of National Tuberculosis Control Program, particularly in health care facilities during the COVID-19 pandemic. This article points out the possible threats to the sustainability of TB care in Indonesia during the COVID-19 pandemic, including some approaches to overcome those problems., Competing Interests: All the authors declare that there are no conflicts of interest., (© 2022 The Author(s).)

Objectives: The aim of this study was to determine the level of coronavirus disease 2019 (COVID-19) risk perceptions in Indonesia and characterize predictors of perceptions., Methods: An online cross-sectional study was conducted. A questionnaire assessed perceived risk and collected independent variables, including sociodemographic data. A multivariable linear regression model was used to characterize the relationship between independent variables and perceived risk., Results: We included 1379 respondents in the final analysis with the mean and median of perceived risk score was 19.21% and 10.0%, respectively. Respondents aged between 21 and 30 years had the highest perceived risk, and those who were unmarried had 4.3% higher perceived risk compared with those who were married. Compared with the lowest monthly income group, those making Indonesian Rupiah (IDR) 6-10 million and more than IDR 10 million a month believed they had 4.2% and 8.8% higher risk, respectively. Citizens who lived in cities and health-care workers also had a higher perceived risk compared with those in the rural areas and non-health-care workers, respectively., Conclusions: Perceived risk of COVID-19 in Indonesia is relatively low, and this could hamper the adoption of preventive measures of COVID-19. Efforts to increase the awareness and perceived risk are important to prevent the pandemic from escalating.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial-mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK-AKT-GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance. IMPLICATIONS: This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM., (©2021 American Association for Cancer Research.)

Background: Zinc-finger E-box-binding homeobox 1 (ZEB1) is an important regulator of epithelial-mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR-200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT-mediated acquired resistance to gefitinib in EGFR-mutant non-small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear., Methods: PC9 and HCC827 NSCLC cell lines were treated with high concentrations of gefitinib, and surviving cells were referred to as "gefitinib-resistant persisters" (GRPs). ZEB1 knockdown or overexpression was performed to determine the biological significance of ZEB1 in the CSC features of GRPs, and animal models were studied for in vivo validation. Expression of ZEB1, BMI1, and ALDH1A1 was analyzed by immunohistochemistry in tumor specimens from NSCLC patients with acquired resistance to gefitinib., Results: GRPs had characteristic features of mesenchymal and CSC phenotypes with high expression of ZEB1 and BMI1, and decreased miR-200c, in vitro and in vivo. ZEB1 silencing attenuated the suppression of miR-200c, resulting in the reduction in BMI1 and reversed the mesenchymal and CSC features of GRPs. Furthermore, ZEB1 overexpression induced EMT and increased the levels of CD133- and BMI1-positive GRPs in vitro and gefitinib resistance in vivo. Finally, ZEB1, BMI1, and ALDH1A1 were highly expressed in tumor specimens from EGFR-mutant NSCLC patients with gefitinib resistance., Conclusions: ZEB1 plays an important role in gefitinib-resistant lung CSCs with EMT features via regulation of miR-200c and BMI1., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The aim of this study was to assess the magnitude of childhood vaccination disruption and to determine the predictors of delaying childhood vaccinations during the coronavirus disease 2019 (COVID-19) pandemic among Indonesian parents. We conducted a nationwide, online, cross-sectional study. A set of questionnaires assessed the disruption of childhood vaccinations and possible explanatory variables, including demographic characteristics, current underlying disease, exposure to and confidence in COVID-19 information, perceived risk, attitude and practice on vaccination, and COVID-19 prevention practice. A multivariable linear regression was used to characterize the relationship between explanatory variables and delayed childhood vaccination. We included 1137 respondents for analysis, of which 52.6% were males and 58.4% participants aged between 31 and 50-years old. Disruption of childhood vaccination service in local health facilities was reported in 42.2% (480/1137) of respondents and 13.3% (193/1137) of respondents explained that their children could not be vaccinated because a healthcare facility temporary stopped the vaccination service. Of all respondents, 312 (27.4%) delayed vaccinating their children for a compulsory vaccination shot. Factors associated with higher odds of delaying compulsory vaccinations for children were employment and chronic disease status, flu vaccination status in the past year, and prior COVID-19 infection. In conclusion, there was a significant disruption of childhood vaccination practices in Indonesia during the COVID-19 pandemic. This is not only due to healthcare closures but also due to parents' practice - delaying the compulsory childhood vaccination for their children. We urge the government to strengthen strategies to ensure childhood vaccination services are available to all children in the country during a pandemic., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Author(s).)

How countries, particularly low- and middle-income economies, should pay the coronavirus disease 2019 (COVID-19) vaccine is an important and understudied issue. We undertook an online survey to measure the willingness-to-pay (WTP) for a COVID-19 vaccine and its determinants in Indonesia. The WTP was assessed using a simple dichotomous contingent valuation approach and a linear regression model was used to assess its associated determinants. There were 1,359 respondents who completed the survey. In total, 78.3% (1,065) were willing to pay for the COVID-19 vaccine with a mean and median WTP of US$ 57.20 (95%CI: US$ 54.56, US$ 59.85) and US$ 30.94 (95%CI: US$ 30.94, US$ 30.94), respectively. Being a health-care worker, having a high income, and having high perceived risk were associated with higher WTP. These findings suggest that the WTP for a COVID-19 vaccine is relatively high in Indonesia. This WTP information can be used to construct a payment model for a COVID-19 vaccine in the country. Nevertheless, to attain higher vaccine coverage, it may be necessary to partially subsidize the vaccine for those who are less wealthy and to design health promotion materials to increase the perceived risk for COVID-19 in the country.

Indoor air pollution marked with decreased air quality below the set standard. The quality of indoor air is determined by ambient air quality as well as by a harmful substance resulting from the household activity. Indoor air pollution may cause several problems such as sick building syndrome, chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and is responsible for nearly two million death in developing countries. One of the interesting research topics to overcome the indoor air pollution problem is the application of indoor plants. Although there are no established criteria to specify the best indoor plant, several studies have revealed the capability of a particular indoor plant to remove the harmful substances. This paper summarizes important information about indoor air pollution and provides the evidence-based insight of indoor plant usefulness as an alternative way for indoor air remediation., (© 2020 Agus Dwi Susanto et al., published by De Gruyter, Berlin/Boston.)

Introduction: Several vaccine candidates are being clinically tested in response to the 2019 coronavirus disease (COVID-19) pandemic. This study was conducted to assess the acceptance of a 50 or 95% effective COVID-19 vaccine, when it becomes available in southeast Asia, among the general population in Indonesia. Methods: A cross-sectional online survey was conducted between March 25 and April 6, 2020. Participants were asked if they would accept a free vaccine which was 95 or 50% effective. Using a logistic regression model, we assessed the associations between sociodemographic characteristics, exposure to COVID-19 information, or perceived risk of infection with acceptance of a hypothetical COVID-19 vaccine. Results: Among 1,359 respondents, 93.3% of respondents (1,268/1,359) would like to be vaccinated for a 95% effective vaccine, but this acceptance decreased to 67.0% (911/1,359) for a vaccine with 50% effectiveness. For a 95% effective vaccine, being a healthcare worker and having a higher perceived risk of COVID-19 infection were associated with higher acceptance, adjusted odds ratio (aOR): 2.01; 95%CI: 1.01, 4.00 and aOR: 2.21; 95%CI: 1.07, 4.59, respectively; compared to civil servants, being retired was associated with less acceptance (aOR: 0.15; 95%CI: 0.04, 0.63). For a 50% effective vaccine, being a healthcare worker was also associated with greater acceptance, aOR: 1.57; 95%CI: 1.12, 2.20. Conclusion: Acceptance of a COVID-19 vaccine was highly influenced by the baseline effectiveness of the vaccine. Preparing the general population to accept a vaccine with relatively low effectiveness may be difficult., (Copyright © 2020 Harapan, Wagner, Yufika, Winardi, Anwar, Gan, Setiawan, Rajamoorthy, Sofyan and Mudatsir.)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder. Recent studies have suggested that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells influences development of pulmonary fibrosis, which is mediated by transforming growth factor β (TGF-β). Tumor necrosis factor α (TNF-α), an important proinflammatory cytokine in IPF, has been shown to enhance TGF-β-induced EMT. Nintedanib, a multiple tyrosine kinase inhibitor that is currently used to treat IPF, has been shown to suppress EMT in various cancer cell lines. However, the mechanism of EMT inhibition by nintedanib and its effect on TGF-β and TNF-α signaling pathways in alveolar epithelial cells have not been fully elucidated., Methods: A549 alveolar epithelial cells were stimulated with TGF-β2 and TNF-α, and the effects of nintedanib on global gene expression were evaluated using microarray analysis. Furthermore, Smad2/3 phosphorylation was assessed using western blotting., Results: We found that in A549 cells, TGF-β2 and TNF-α treatment induces EMT, which was inhibited by nintedanib. Gene ontology analysis showed that nintedanib significantly attenuates the gene expression of EMT-related cellular pathways and the TGF-β signaling pathway, but not in the TNF-α-mediated signaling pathway. Furthermore, hierarchical cluster analysis revealed that EMT-related genes were attenuated in nintedanib-treated cells. Additionally, nintedanib was found to markedly suppress phosphorylation of Smad2/3., Conclusion: Nintedanib inhibits EMT by mediating EMT-related gene expression and the TGF-β/Smad pathway in A549 alveolar epithelial cells., Competing Interests: Declaration of Competing Interest Kazuhisa Takahashi (K.T.) received research funding from Chugai Pharm, Ono Pharma, Taiho Pharm, Nippon Boehringer Ingelheim, AstraZeneca, Pfizer, MSD, and Lilly Japan. Motoyasu Kato (M.K.) received speaker honoraria from Nippon Boehringer Ingelheim. The remaining authors declare no conflict of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

In early December 2019, an outbreak of coronavirus disease 2019 (COVID-19), caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in Wuhan City, Hubei Province, China. On January 30, 2020 the World Health Organization declared the outbreak as a Public Health Emergency of International Concern. As of February 14, 2020, 49,053 laboratory-confirmed and 1,381 deaths have been reported globally. Perceived risk of acquiring disease has led many governments to institute a variety of control measures. We conducted a literature review of publicly available information to summarize knowledge about the pathogen and the current epidemic. In this literature review, the causative agent, pathogenesis and immune responses, epidemiology, diagnosis, treatment and management of the disease, control and preventions strategies are all reviewed., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Osimertinib (AZD9291) is a third-generation EGFR-tyrosine kinase inhibitor (TKI) that selectively inhibits the activating EGFR mutation and T790M mutation, and is currently used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC). However, acquired resistance to osimertinib is inevitable., Methods: We established osimertinib-resistant cells (PC9/T790M/AZDR and H1975/AZDR) derived from EGFR-mutant NSCLC cells harboring T790M mutation, and investigated the mechanism of acquired resistance to osimertinib by whole-exome sequencing and multiple phospho-receptor tyrosine kinase (RTK) array. A tumor specimen from an EGFR-mutant NSCLC patient with acquired resistance to osimertinib was also subjected to immunohistochemical analysis., Results: Whole-exome sequencing analysis demonstrated that genetic alterations, such as acquisition of EGFR C797S, loss of T790M mutation, MET amplification, or mutated KRAS, MEK, BRAF, PIK3CA, were not detected. Analysis of phospho-RTK array revealed that insulin-like growth factor-1 receptor (IGF1R) was activated in PC9/T790M/AZDR and H1975/AZDR cells. Knockdown of IGF1R by siRNA as well as inhibition of IGF1R activation by linstinib (IGF1R inhibitor) significantly restored the sensitivity to osimertinib. Immunohistochemical analysis revealed that the expression level of phosphorylated IGF1R was higher in the tumor specimen from the EGFR-mutant NSCLC patient with acquired resistance to osimertinib than in the specimen collected prior to the treatment., Conclusions: IGF1R activation could occur following treatment with osimertinib in EGFR-mutant NSCLC with T790M mutation, and might be one of the mechanisms underlying osimertinib resistance. Combined treatment of osimertinib and IGF1R inhibitor might be effective in overcoming the acquired resistance to osimertinib induced by IGF1R activation., Key Points: Significant findings of the study: Using osimertinib-resistant cells, we found that IGF1R activation induced by osimertinib treatment in EGFR-mutant NSCLC with T790M mutation is involved in resistance. Increased phosphorylation of IGF1R was observed in the tumor specimen from an EGFR-mutant NSCLC patient with acquired osimertinib resistance., What This Study Adds: IGF1R activation might be one of the mechanisms of osimertinib resistance. A combination therapy with osimertinib and an IGF1R inhibitor might be an optimal approach for overcoming the acquired resistance to osimertinib induced by IGF1R activation., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. F-box/WD repeat-containing protein 7 (FBXW7) is a ubiquitin ligase that regulates quiescence by targeting the c-MYC protein for ubiquitination. We previously reported that gefitinib-resistant persisters (GRPs) in EGFR-mutant non-small cell lung cancer (NSCLC) cells highly expressed octamer-binding transcription factor 4 (Oct-4) as well as the lung CSC marker CD133, and they exhibited distinctive features of the CSC phenotype. However, the role of FBXW7 in lung CSCs and their resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in NSCLC is not fully understood. In this study, we developed GRPs from the two NSCLC cell lines PC9 and HCC827, which express an EGFR exon 19 deletion mutation, by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high levels of CD133 and FBXW7, but low levels of c-MYC. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the FBXW7 gene significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. We also found that FBXW7 expression in CD133-positive cells was increased and c-MYC expression was decreased in gefitinib-resistant tumors of PC9 cells in mice and in 9 out of 14 tumor specimens from EGFR-mutant NSCLC patients with acquired resistance to gefitinib. These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC.

The safety and efficacy of stereotactic radiosurgery (SRS) in the brainstem is questioned by some over concern of violating historical brainstem SRS dose tolerance. Our purpose was to report on the clinical outcomes of patients treated at our institution with radiosurgery for brainstem metastases. Patients with metastatic tumors within or directly abutting the brainstem from 1992 to 2014 were analyzed. Patient and tumor characteristics, SRS parameters, and toxicity were recorded and analyzed for associations with local control and survival. Multivariate statistical analysis was performed using Cox proportional hazards modeling. One-hundred and eighty-nine (189) brainstem metastases from 161 patients were included in our analysis. Whole brain irradiation was administered prior to SRS in 52 % of patients. The median margin dose was 18 Gy prescribed to the 50 % isodose line. Median imaging follow up was 5.4 months and median survival was 5.5 months after SRS. At last follow up, local control was achieved in 87.3 % of brainstem lesions treated. There were 3 recorded events of grade 3-5 toxicity (1.8 %). On multivariate analysis, a margin dose ≥16 Gy was associated with improved local control (p = 0.049) and greater KPS score was associated with improved overall survival following SRS (p = 0.024). Patients with brainstem metastases who have limited intracranial disease and/or who have received whole brain irradiation should be considered for SRS. Margin doses of at least 16 Gy are associated with superior local control, and serious radiation toxicity in SRS for brainstem metastasis appears rare.

Several epidemiology studies suggest that host genetic factors play important roles in susceptibility, protection and progression of tuberculosis infection. Here we have reviewed the implications of some genetic polymorphisms in pathways related to tuberculosis susceptibility, severity and development. Large case-control studies examining single-nucleotide polymorphisms (SNPs) in genes have been performed in tuberculosis patients in some countries. Polymorphisms in natural resistance-associated macrophage protein 1 (NRAMP1), toll-like receptor 2 (TLR2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin-1 receptor antagonist (IL-1RA), IL-10, vitamin D receptor (VDR), dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), monocyte chemoattractant protein-1 (MCP-1), nucleotide oligomerization binding domain 2 (NOD2), interferon-gamma (IFN-γ), inducible nitric oxide synthase (iNOS), mannose-binding lectin (MBL) and surfactant proteins A (SP-A) have been reviewed. These genes have been variably associated with tuberculosis infection and there is strong evidence indicating that host genetic factors play critical roles in tuberculosis susceptibility, severity and development.

Background: The aims of this study were to evaluate the predictive value of admission Glasgow Coma Scale (GCS) scores, duration of unconsciousness, neurosurgical intervention, and countercoup lesion on the impairment of memory and processing speed functions six months after a traumatic brain injury (TBI) based on a structural equation modeling., Methods: Thirty TBI patients recruited from Neurosurgical Department at the Kaohsiung Medical University Hospital were administered the Wechsler Memory Scale-III (WMS-III) and the Wechsler Adult Intelligence Scale-III processing speed index to evaluate the memory and processing speed functions., Results: The study showed that GCS scores accounted for 40% of the variance in memory/processing speed. No significant predictive effects were found for the other three variables. GCS classification at the time of TBI seems to correspond moderately to the severity of memory/processing speed dysfunctions., Conclusions: The present study demonstrated that admission GCS score is a robust predictor of memory/processing speed dysfunctions after TBI. The results should be replicated with a large sample of patients with TBI, or be extended by examining other potential clinical predictors.

The WW domain-containing oxidoreductase (WWOX) functions as a tumor suppressor by interacting with various proteins in numerous important signaling pathways. WWOX silencing via homozygous deletion of its locus and/or promoter hypermethylation has been observed in various human cancers. However, the relationship between WWOX and tumors in the central nervous system has not been fully explored. In this study, the expression levels of WWOX protein in astrocytomas from 38 patients with different tumor grades were retrospectively analyzed by immunohistochemical staining. The results showed that 19 (50.0%) samples had highly reduced WWOX protein expression when compared with normal controls, while 14 (36.8%) and five (13.2%) cases exhibited moderate and mild decreases in WWOX expression, respectively. Reduction of the expression of WWOX protein correlated with patient age, supra-tentorial localization of the tumor and severity of the symptoms. Furthermore, loss of WWOX expression inversely correlated with survival time. No significant correlation was observed between the loss of WWOX expression and the gender of patients or the difference in pre-operative and post-operative karnofsky performance status scores. Surprisingly, there was no significant correlation between the loss of WWOX protein expression and overall tumor grades. Nevertheless, it was found that 63.6% (7/11) of the grade II astrocytomas had highly reduced WWOX expression and 36.4% (4/11) showed moderately reduced WWOX expression, while none of the samples exhibited mild reductions. Similar results were also found in grade III astrocytomas. The results from this small-size sample pilot study suggest that the loss of WWOX expression may be an early event in the pathogenesis of human astrocytoma., (© 2013 Japanese Society of Neuropathology.)

Delayed cerebral vasospasm is a main cause of morbidity and mortality as well as poor outcome in patients following aneurysmal subarachnoid hemorrhage (SAH). In this study, the effect of the bronchodilator KMUP-3 (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) on basilar artery narrowing, neurological outcome, and expression of rhoA/rho kinase II (ROCKII), rhoA, and protein kinase C (PKC) γ proteins were evaluated in a rat model of SAH. SAH was induced by double injection of autologous blood into the cistern magna on days 0 and 3. KMUP-3 was administered (0.3 mg/kg/day) by osmotic minipumps implanted subcutaneously (beginning day -3 in pretreatment group and at 1 h after the initiation of the first autologous blood injection in the treatment group). Neurological outcome was assessed by ambulation and placing/stepping reflex responses at 48 h after the second injection of autologous blood. Tissue morphology and protein expression were conducted on day 7 post-day 0 injection. Both KMUP-3 treatment regimens significantly improved neurological outcome and completely attenuated basilar artery narrowing as well as reduced the enhancement of ROCKII, rhoA, and PKCγ protein expression in rats subjected to SAH, compared with normal and untreated SAH rats. These results suggest that KMUP-3 may be a novel agent for the treatment of cerebral vasospasm following SAH.

Background: Axonal regeneration in peripheral nerves after injury is a complicated process. Numerous cytokines, growth factors, channels, kinases, and receptors are involved, and matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis subsequent to nerve injury. In this study, the effect of KMUP-1, an activator of large-conductance Ca(2+)-activated potassium channel, on functional recovery, myelinated axon growth, and immunoreactivity of MMP-9 was evaluated in rats subjected to sciatic nerve crush injury., Method: A total of 144 male Sprague-Dawley rats were divided into the following six groups (n = 24/group): group 1, sham-operated; group 2, sciatic nerve injury without treatment; group 3, injured and vehicle-treated; group 4, injured and treated with 1 mM KMUP-1 by topical application; group 5, injured and treated with 10 mM KMUP-1; group 6, injured and treated with 50 mM KMUP-1. Functional recovery was evaluated using walking track analysis at 1, 2, 3, and 4 weeks (n = 6/group at each time point) after injury. In addition, the number of myelinated axons and MMP-9 in the nerve was also examined., Findings: Animals subjected to sciatic nerve crush injury had decreased motor function, a reduced number of myelinated axons, and increased MMP-9 in the nerve. Treatment with KMUP-1 concentration-dependently improved functional recovery, increased the number of myelinated axons, and decreased MMP-9., Conclusions: These results suggest that KMUP-1 may be a novel agent for assisting peripheral nerve recovery after injury. The beneficial effect is probably due to known ability of the compound in activating the nitric oxide/cGMP/protein kinase G pathway.

Natural nanowires (NWs) of cellulose obtained from a marine animal tunicate display surprisingly high uniformity and aspect ratio comparable with synthetic NWs. Their layer-by-layer assembled (LBL) films show strong antireflection (AR) properties having an origin in a novel highly porous architecture reminiscent of a "flattened matchsticks pile", with film-thickness-dependent porosity and optical properties created by randomly oriented and overlapping NWs. At an optimum number of LBL deposition cycles, light transmittance reaches nearly 100% (lambda approximately 400 nm) when deposited on a microscope glass slide and the refractive index is approximately 1.28 at lambda = 532 nm. In accordance with AR theory, the transmittance maximum red-shifts and begins to decrease after reaching the maximum with increasing film thickness as a result of increased light scattering. This first example of LBL layers of cellulose NWs can be seen as an exemplary structure for any rigid axial nanocolloids, for which, given the refractive index match, AR properties are expected to be a common property. Unique mechanical properties of the tunicate NWs are also a great asset for optical coatings.

Endothelin-1 (ET-1) has been implicated in many neurological diseases, including subarachnoid hemorrhage (SAH) and cerebral ischemia. ET-1 is also proved to deteriorate the ischemia-reperfusion injury in many organs. Our previous studies demonstrated that the endothelin-converting enzyme (ECE) inhibitor, CGS 26303, possessed beneficial effects for the treatment of SAH and transient middle cerebral artery occlusion. In this study, we investigated the neuroprotective effect of CGS 26303 on the locomotor function and mRNA expression of heme-oxygenase-1 (HO-1) in rats subjected to a 15-min spinal cord ischemia. The results showed that pretreatment with CGS 26303 significantly preserved the locomotor function and decreased the paraplegia rate at Days 1 and 3 as compared with a saline-treated group. Furthermore, rats pretreated with CGS 26303 had a significant increase in the levels of HO-1 mRNA expression at Day 3 when compared with animals pretreated with saline after spinal cord ischemia and the sham operation group. These results suggest that CGS 26303 may have a promising neuroprotective effect in the spinal cord after ischemia-reperfusion injury, and beneficial result may be due to an adaptive mechanism involved by HO-1 overexpression.

A burgeoning body of evidence suggests that endothelin-1 (ET-1), the most potent endogenous vasoconstrictor yet identified, may be critical in the pathophysiology of various cardiovascular diseases. The ET system may also be implicated in the pathogenesis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Clinical studies have shown that the levels of ET-1 are increased in the cerebrospinal fluid (CSF) of patients following SAH, suggesting that ET-1-mediated vasoconstriction plays a major role in the development of vasospasm after SAH. The potential involvement of ETs in SAH-induced vasospasm has triggered considerable interest in developing therapeutic strategies that inhibit the biologic effects of ET. One promising approach to block the biosynthesis of ETs is suppressing the proteolytic conversion of the precursor peptide (big ET-1) to its vasoactive form (ET-1) using metalloprotease as endothelin-converting enzyme (ECE) inhibitor. To date, three types of ECE-1 inhibitors have been synthesized: dual ECE-1/neutral endopeptidase 24.11 (NEP) inhibitors, triple ECE-1/NEP/angiotensin-converting enzyme (ACE) inhibitors and selective ECE-1 inhibitors. The therapeutic effects of ECE-1 inhibitors on the prevention and reversal of SAH-induced vasospasm in animal studies are reviewed and discussed.

Endothelin-1, a potent vasoconstrictive peptide, has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). The goal of this study was to evaluate the effect of continuous intravenous infusion of a highly selective endothelin-converting enzyme-1 inhibitor, CGS 35066, on the prevention and reversal of cerebral vasospasm following SAH. New Zealand white rabbits were subjected to SAH by injecting autologous arterial blood into the cisterna magna. Infusion of CGS 35066 at dosages of 1, 3, or 10 mg/kg/ day was initiated either 1 hr and 24 hrs later in the prevention and reversal protocols, respectively. Animals were sacrificed by perfusion-fixation 48 hrs after SAH induction. The cross-sectional areas of basilar arteries were measured using computer-assisted videomicroscopy. Ultrastructural changes in basilar arteries were determined using electron microscopy. CGS 35066 significantly prevented and reversed the arterial narrowing after SAH in all three groups. The mean cross-sectional areas of arteries from animals in both the prevention and reversal protocol groups that received 10 mg/kg/day of CGS 35066 did not differ significantly from those of the healthy controls. Histological studies of the basilar artery in the 10 mg/kg/day treatment group did not show pathomorphological changes, such as corrugation of the endothelium seen at 2 days after SAH induction or vacuole formation in the endothelial cells noted in the vehicle-treated SAH group. These findings suggest that CGS 35066 is a promising therapeutic agent for the prevention and reversal of cerebral vasospasm after SAH. It also prevents the pathological changes in vascular walls due to SAH.