Hueng-Chuen Fan

Current Status of the Immunomodulation and Immunomediated Therapeutic Strategies for Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and CD4+ T cells form the core immunopathogenic cascade leading to chronic inflammation. Traditionally, Th1 cells (interferon-γ-producing CD4+ T cells) driven by interleukin 12 (IL12) were considered to be the encephalitogenic T cells in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Currently, Th17 cells (Il17-producing CD4+ T cells) are considered to play a fundamental role in the immunopathogenesis of EAE. This paper highlights the growing evidence that Th17 cells play the core role in the complex adaptive immunity of EAE/MS and discusses the roles of the associated immune cells and cytokines. These constitute the modern immunological basis for the development of novel clinical and preclinical immunomodulatory therapies for MS discussed in this paper.

Hematoma Shape, Hematoma Size, Glasgow Coma Scale Score and ICH Score: Which Predicts the 30-Day Mortality Better for Intracerebral Hematoma?

Purpose To investigate the performance of hematoma shape, hematoma size, Glasgow coma scale (GCS) score, and intracerebral hematoma (ICH) score in predicting the 30-day mortality for ICH patients. To examine the influence of the estimation error of hematoma size on the prediction of 30-day mortality. Materials and Methods This retrospective study, approved by a local institutional review board with written informed consent waived, recruited 106 patients diagnosed as ICH by non-enhanced computed tomography study. The hemorrhagic shape, hematoma size measured by computer-assisted volumetric analysis (CAVA) and estimated by ABC/2 formula, ICH score and GCS score was examined. The predicting performance of 30-day mortality of the aforementioned variables was evaluated. Statistical analysis was performed using Kolmogorov-Smirnov tests, paired t test, nonparametric test, linear regression analysis, and binary logistic regression. The receiver operating characteristics curves were plotted and areas under curve (AUC) were calculated for 30-day mortality. A P value less than 0.05 was considered as statistically significant. Results The overall 30-day mortality rate was 15.1% of ICH patients. The hematoma shape, hematoma size, ICH score, and GCS score all significantly predict the 30-day mortality for ICH patients, with an AUC of 0.692 (P = 0.0018), 0.715 (P = 0.0008) (by ABC/2) to 0.738 (P = 0.0002) (by CAVA), 0.877 (P<0.0001) (by ABC/2) to 0.882 (P<0.0001) (by CAVA), and 0.912 (P<0.0001), respectively. Conclusion Our study shows that hematoma shape, hematoma size, ICH scores and GCS score all significantly predict the 30-day mortality in an increasing order of AUC. The effect of overestimation of hematoma size by ABC/2 formula in predicting the 30-day mortality could be remedied by using ICH score.

Association between Gastroenterological Malignancy and Diabetes Mellitus and Anti-Diabetic Therapy: A Nationwide, Population-Based Cohort Study

Background The relationship between diabetes mellitus (DM) and cancer incidence has been evaluated in limited kinds of cancer. The effect of anti-diabetic therapy (ADT) on carcinogenesis among diabetic patients is also unclear. Materials and Methods Using population-based representative insurance claims data in Taiwan, 36,270 DM patients and 145,080 comparison subjects without DM were identified from claims from 2005 to 2010. The association between the top ten leading causes of cancer-related death in Taiwan and DM was evaluated. Whether ADT altered the risk of developing cancer was also investigated. Results Incidence of cancer at any site was significantly higher in patients with DM than in those without (p<0.001). The risk of carcinogenesis imparted by DM was greatest in gastroenterological malignancies (liver, pancreas, and colorectal cancer) as well as lung, breast and oral cancer (p<0.001). Among the oral types of ADT, metformin decreased the risk of lung and liver cancer, but had less effect on reducing the risk of colorectal cancer. α-glucosidase inhibitor decreased the risk of developing liver, colorectal, and breast cancer. Apart from intermediate-acting insulin, rapid-acting, long-acting, and combination insulin treatment significantly reduced the overall cancer risk among all DM patients. In subgroup analysis, long-acting insulin treatment significantly decreased the risk of lung, liver, and colorectal cancer. Conclusion Our results supported the notion that pre-existing DM increases the incidence of gastroenterological cancer. ADT, especially metformin, α-glucosidase inhibitor, and long-acting insulin treatment, may protect patients with DM against these malignancies. It is crucial that oncologists should closely collaborate with endocrinologists to provide an optimal cancer-specific therapy and diabetic treatment to patients simultaneously with cancer and DM.

Protein kinase C isoforms in atherosclerosis: Pro- or anti-inflammatory?

Atherosclerosis is a pathologic condition caused by chronic inflammation in response to lipid deposition in the arterial wall. There are many known contributing factors such as long-term abnormal glucose levels, smoking, hypertension, and hyperlipidemia. Under the influence of such factors, immune and non-immune effectors cells are activated and participate during the progression of atherosclerosis. Protein kinase C (PKC) family isoforms are key players in the signal transduction pathways of cellular activation and have been associated with several aspects of the atherosclerotic vascular disease. This review article summarizes the current knowledge of PKC isoforms functions during atherogenesis, and addresses differential roles and disputable observations of PKC isoforms. Among PKC isoforms, both PKCβ and PKCδ are the most attractive and potential therapeutic targets. This commentary discusses in detail the outcomes and current status of clinical trials on PKCβ and PKCδ inhibitors in atherosclerosis-associated disorders like diabetes and myocardial infarction. The risk and benefit of these inhibitors for clinical purposes will be also discussed. This review summarizes what is already being done and what else needs to be done in further targeting PKC isoforms, especially PKCβ and PKCδ, for therapy of atherosclerosis and atherosclerosis-associated vasculopathies in the future.

Polymorphisms of the β2-Adrenergic Receptor Correlated to Nocturnal Asthma and the Response of Terbutaline Nebulizer

BACKGROUND Inhaled β(2)-adrenergic receptor (β(2)-AR) agonists are the mainstay of treatment of acute asthma. Polymorphisms of the β(2)-AR, especially codons 16, 27, and 164, may affect the functions of the receptor. This study was conducted to investigate whether different polymorphisms of the β(2)-AR are related to the treatment responses of an inhaled β(2)-AR agonist in children with nocturnal and nonnocturnal asthma in Taiwan. METHODS The nocturnal asthma group consisted of 27 children (mean age of 10.3±2.4 years), and the nonnocturnal asthma group consisted of 24 patients (mean age of 9.9±3.0 years). Allele-specific polymerase chain reaction was performed to determine 16, 27, and 164 loci alleles of β(2)-AR genetic polymorphisms, and peak expiratory flow (PEF) was measured before and 1 hour after inhalation of 0.2mg/kg/dose of terbutaline to determine the treatment response in these patients. RESULTS The polymorphisms of β(2)-AR 27 but not 16 or 164 were significantly associated with the response to terbutaline nebulizer (p<0.05). The polymorphism of β(2)-AR 16 was associated with nocturnal asthma (p=0.027). The Gly16 allele was more prevalent in the nocturnal asthma group (9/27; 33.3%) than in the nonnocturnal asthma group (3/24; 12.5%). Arg16 allele was less prevalent in the nocturnal asthma (3/27; 11.1%) than in the nonnocturnal asthma group (10/24; 41.7%). There was also a linkage disequilibrium found between β(2)-AR 16 (Arg/Arg) and β(2)-AR 27 (Gln/Gln). CONCLUSION These findings suggest that polymorphisms of β(2)-AR 16 are related to nocturnal asthma and polymorphisms of β(2)-AR 27 are associated with the variable responses to the inhaled terbutaline in children with nocturnal and nonnocturnal asthma.

Potential of Neural Stem Cell-Based Therapy for Parkinson's Disease.

Neural stem cell (NSC) transplantation is an emerging strategy for restoring neuronal function in neurological disorders, such as Parkinsons disease (PD), which is characterized by a profound and selective loss of nigrostriatal dopaminergic (DA) neurons. Adult neurogenesis generates newborn neurons that can be observed at specialized niches where endothelial cells (ECs) play a significant role in regulating the behavior of NSCs, including self-renewal and differentiating into all neural lineage cells. In this minireview, we highlight the importance of establishing an appropriate microenvironment at the target site of NSC transplantation, where grafted cells integrate into the surroundings in order to enhance DA neurotransmission. Using a novel model of NSC-EC coculture, it is possible to combine ECs with NSCs, to generate such a neurovascular microenvironment. With appropriate NSCs selected, the composition of the transplant can be investigated through paracrine and juxtacrine signaling within the neurovascular unit (NVU). With target site cellular and acellular compartments of the microenvironment recognized, guided DA differentiation of NSCs can be achieved. As differentiated DA neurons integrate into the existing nigrostriatal DA pathway, the symptoms of PD can potentially be alleviated by reversing characteristic neurodegeneration.

Concomitant use of acyclovir and intravenous immunoglobulin rescues an immunocompromised child with disseminated varicella caused multiple organ failure.

Varicella is a common and mild disease in healthy children. However, when patients are in immunocompromised conditions, such as receiving chemotherapy for cancer treatment, they are highly vulnerable and it can even prove lethal. Herein, we report a 14-year-old boy with acute lymphoblastic leukemia who was receiving chemotherapy for induction with vincristine, idarubicin, L-asparaginase, and prednisolone, presented with typical varicella skin lesions and varicella-zoster virus was detected in his serum by real-time polymerase chain reaction (PCR). His condition was advanced to multiple organs failure, including fulminant hepatitis, disseminated intravascular coagulation, and myocarditis despite acyclovir administration. After a combined therapy with intravenous acyclovir and high-dose intravenous immunoglobulin, his condition was dramatically improved. We suggest that IVIG may be used immediately with acyclovir when immunocompromised patients with varicella advanced to dissemination are identified.

Microsatellite alteration at chromosome 11 in primary human nasopharyngeal carcinoma in Taiwan

Nasopharyngeal carcinoma (NPC) is one of the common cancers in Taiwan but is rare in western countries. The development of NPC involves multiple genetic changes in tumorigenesis and progression of the disease. To better understand genetic alterations in chromosome 11 which occur in human (NPC), we examined tumor specimens and corresponding non-cancerous tissue from 30 cases of NPC, using five microsatellite polymorphic markers whose location has previously been defined. To determine the clinical characteristics of MSI(+) or LOH, we performed correlation analysis of the findings with clinicopathological parameters. Loss of heterozygosity (LOH) was identified in 18 (60%) of 30 cases on at least one of the five markers. A high frequency of LOH was found at the two loci: D11S912 (7/30, 23.33%) and D11S934 (6/30, 20.00%), both of which are located within 11q23-24. We also found that 14 specimens (14/30, 46.67%) exhibited microsatellite instability (MSI(+)). Five (5/30, 16.67%) specimens exhibited MSI(+) in the transformation growth factor beta receptor type II (TGF-beta RII) exon 3 which also exhibited on chromosome 11. LOH was found to be significantly correlated with the T (tumor size) value (P=0.022) of Hos system. MSI(+) showed a significant correlation with the N (lymph node) value of the UICC system (P=0.031). Our results suggest that multiple putative tumor suppressor genes on chromosome 11 play a role in the development of NPC. MSI(+) expression showed a predisposition to occur in the late stage of NPC while LOH tended to occur in early stages of NPC. The behavior of mutated TGF-beta RII exon 3, which appeared to serve as a dysfunction brake during nasopharyngeal carcinogenesis, may be a target gene in the defected mismatch repair system.

Current Proceedings of Childhood Stroke

Stroke is a sudden onset neurological deficit due to a cerebrovascular event. In children, the recognition of stroke is often delayed due to the low incidence of stroke and the lack of specific assessment measures to this entity. The causes of pediatric stroke are significantly different from that of adult stroke. The lack of safety and efficiency data in the treatment is the challenge while facing children with stroke. Nearly half of survivors of pediatric stroke may have neurologic deficits affecting functional status and quality of life. They may cause a substantial burden on health care resources. Hence, an accurate history, including onset and duration of symptoms, risk factors, and a complete investigation, including hematologic, neuroimaging, and metabolic studies is the key to make a corrective diagnosis. A prompt and optimal treatment without delay may minimize the damage to the brain.

The use of adjunctive traditional Chinese medicine therapy and survival outcome in patients with head and neck cancer: a nationwide population-based cohort study.

BACKGROUND Traditional Chinese medicine (TCM) is widely used in the treatment of patients with several types of cancer. However, no large-scale clinical studies have evaluated whether TCM is associated with better survival in patients with head and neck cancer (HNC). METHODS The Taiwan National Health Insurance Research Database was used to conduct a retrospective cohort study of patients with HNC between 2001 and 2011. The patients with HNC were separated into TCM users and non-users, and Cox regression models were applied to determine the association between the use of TCM and survival outcome. RESULTS The TCM and comparison cohorts comprised data for 2966 and 2670 patients, respectively. The mean age was 51.3 years in the TCM cohort and 51.7 years in the comparison cohort. Multivariate analysis demonstrated that the use of TCM was significantly associated with lower risk of all-cause mortality by 32% (adjusted hazard ratio, 0.68; 95% confidence interval, 0.62-0.75). Patients with longer TCM use had a lower mortality rate (P for trend < 0.001). CONCLUSIONS Our study showed that adjunctive therapy with TCM is associated with higher survival outcome. However, some limitations exist, such as the lack of information of cancer stage. In addition, causality cannot be assessed with this retrospective study. A randomized controlled trial to test the effect of adjunctive TCM therapy in HNC patients is needed.