MiR-134 expression and changes in inflammatory cytokines of rats with epileptic seizures.

OBJECTIVE: To investigate the expression of miR-134 and the change of inflammatory cytokines in seizure rats and to explore its relationship. MATERIALS AND METHODS: A rat model of seizures was made by an intraperitoneal injection with kainic acid. ELISA kit for detection of seizures in rats was used. The changes of inflammatory cytokines (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and the hippocampal neuronal cell growth were observed. The expression of miR-134 in brain tissue and serum samples of model group and control group was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) quantitative determination. RESULTS: After the intraperitoneal injection of kainic acid, the rat model of seizure was successfully established. Compared with the control group, the neuronal cells in the hippocampus of the model group showed evident pathological changes. Inflammatory cytokines in seizures rats showed that the increase of IL-2, IL-6, and TNF-α were larger, but the increase of IL-1 and IFN-γ was not obvious. The results of the RT-PCR quantitative analysis showed that the expression of miR-134 in brain tissue and serum of epilepsy rats was lower than that of the control group (p<0.05). CONCLUSIONS: The expression of miR-134 would be down by the increasing of inflammatory cytokines in the epileptic seizure.

Serum YKL-40, a prognostic marker in patients with large-artery atherosclerotic stroke.

BACKGROUND AND PURPOSE: Inflammation comprises important aspects of large-artery atherosclerosis (LAA) stroke pathophysiology. YKL-40 is a new and emerging biomarker that is associated with both acute and chronic inflammations. Elevated serum concentrations of YKL-40 have been reported in patients with atherosclerosis and other cardiovascular diseases. This study investigates whether serum YKL-40 concentrations on admission can predict 3-month clinical outcomes after LAA stroke. METHODS: We recruited control patients (n=85) and those with LAA stroke (n=141) according to the TOAST classification system. The modified Rankin scale at 3 months after stroke was used to evaluate the prognosis. The prognostic accuracy was assessed by the receiver operating characteristic curve. RESULTS: Serum YKL-40 level was significantly higher for LAA patients than for controls (P<.001). Patients with poor outcomes (n=36) had significantly increased serum YKL-40 concentrations on admission (P=.01). High YKL-40 levels predicted poor functional outcome (OR=6.47, P=.02). Moreover, the combination of YKL-40 level and the NIHSS score could improve the prognostic accuracy of the NIHSS in predicting functional outcome (combined areas under the curve, 0.87; 95% CI, 0.80-0.94; P<.001). CONCLUSIONS: The level of serum YKL-40 is a significant and independent biomarker to predict the clinical outcome of LAA stroke.

Brown-Séquard syndrome: a rare manifestation of decompression sickness.

Neurological decompression sickness (DCS) is a rare condition that commonly leads to spinal cord injury. We report the case of a 30-year-old man who developed left-sided weakness and numbness after diving to a maximum depth of 15 m with a total dive time of 205min (10 repetitive dives). To the best of our knowledge, only six cases diagnosed as Brown-Séquard syndrome caused by DCS have been reported in the literature. Divers should be aware of the risk factors of DCS before diving and clinicians should make the diagnosis of spinal cord DCS based primarily on clinical symptoms, not on magnetic resonance imaging findings.

Increased risk of dementia among chronic osteomyelitis patients.

Inflammatory processes may trigger neuroinflammation and cerebrovascular dysfunctions, further provoking dementia. The role of chronic osteomyelitis (COM), a disorder characterized by persistent inflammation, in dementia development has not been fully explored. This study investigates whether COM increases the risk of dementia. Taiwanese National Health Insurance (NHI) inpatient claims were used to identify 17,238 patients newly diagnosed with COM from 2000 to 2008, and 68,944 age- and gender-matched patients without COM were randomly selected for comparison. Risks of dementia associated with COM and comorbidities, including hypertension, diabetes, stroke, hyperlipidemia, and depression, were evaluated using data from the end of 2011. Dementia risk was 1.6-fold higher (95% confidence interval [CI]: 1.4-1.83) in the COM cohort than in the control group, calculated using the multivariable Cox model. Age-specific analysis indicated that the adjusted hazard ratios (aHRs) of dementia for COM patients decreased with age, with an aHR of 3.65 (95% CI: 1.5-8.9) for patients <55 years old, which gradually decreased to 1.43 (95% CI: 1.23-1.66) for patients ≥ 70 years old. Dementia risk increased with COM severity, with an aHR of 5.48 (95% CI: 4.43-6.79) for patients with severe COM. For those without comorbidities, dementia risk was 1.73-fold (95% CI: 1.37-2.17) higher in the COM cohort than in the control group. This study is the first to find that COM is an inflammatory disorder associated with an increased risk of dementia, particularly among younger people.

Increased risk of ischaemic stroke among patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Inflammatory processes including autoimmune diseases which ignite endothelial dysfunction and atherosclerosis may promote development of cardiovascular diseases including ischaemic stroke. This study aimed to evaluate whether multiple sclerosis (MS) increases stroke risk. METHODS: A national insurance claim data set of 22 million enrollees in Taiwan was used to identify 1174 patients with MS and 4696 randomly selected age- and gender-matched controls from 1 January 1997 to 31 December 2010. Both cohorts were followed up until the occurrence of stroke or censor. Relevant covariates, such as age, gender, hypertension, diabetes, hyperlipidaemia, coronary artery disease, congestive heart failure and pregnancy, were included for further survey. The hazard ratio (HR) of stroke was assessed using a Cox proportional hazards regression model. RESULTS: After adjusting for the relevant covariates, the MS cohort had an increased risk of stroke (adjusted HR = 12.1 for 1 year; adjusted HR = 4.69 for 2-5 years) compared with the control cohort within 5 years of follow-up. Amongst participants without comorbidities, the MS cohort was still at a greater stroke risk than the control cohort [HR 4.93, 95% confidence interval (CI) 2.85-8.55]. Moreover, in the population aged ≤40, MS was associated with a significantly increased risk of stroke (HR 12.7, 95% CI 3.44-46.7). CONCLUSIONS: Multiple sclerosis is declared to be associated with an increased risk in developing stroke, which requires closer attention to this group of patients for stroke prevention, especially in the younger population.

Helicobacter pylori infection increases subsequent ischemic stroke risk: a nationwide population-based retrospective cohort study.

BACKGROUND AND PURPOSE: The association of Helicobacter pylori infection (HP-I) with ischemic stroke (IS) incidence has been studied, but conflicting results have been reported. The purpose of this study was to investigate the association between chronic HP-I and the risk of acute IS by using data from the Taiwan National Health Insurance Research Database. METHODS: We identified17 332 patients with HP-I and 69 328 randomly selected age- and gender-matched controls from 1 January 2000 to 31 December 2010. Both cohorts were followed up until the occurrence of IS or until censored. The Cox proportional hazards model was used for assessing the association of HP-I with IS. RESULTS: Compared with the control cohort, patients diagnosed with HP-I exhibited a higher incidence rate of IS (14.8 vs. 8.45 per 1000 person years) and a hazard ratio (HR) of 1.52 (95% confidence interval [CI] = 1.40-1.65). The HRs for IS were 1.49 (1.37-1.62) in patients diagnosed with HP-I who had one admission, increasing to 2.26 (1.71-1.98) for those who had two or more admissions when adjusted for age, sex and comorbidities (P for trend < 0.0001). In addition, we observed a significantly positive association between nonembolic IS and increased admissions (P for trend < 0.0001) but negative association with embolic IS. CONCLUSION: Chronic HP-I is significantly associated with an increased risk of IS, particularly nonembolic IS. Anti-HP therapy may be beneficial to IS prevention.

Does maternal care evolve through egg recognition or directed territoriality?

The mechanism that facilitates the evolution of maternal care is ambiguous in egg-laying terrestrial vertebrates: does the ability of mothers to recognize their own eggs lead them under some circumstances to begin providing care or can maternal care evolve from simply being in close proximity to the eggs (e.g. through territorial behaviour)? This question is difficult to answer because in most species, parental care is either absent altogether or present; in only a few species we have the opportunity to observe intraspecific variation in the expression of parental care. We studied a population of long-tailed skinks (Eutropis longicaudata) in which females have recently evolved maternal care from a noncaring state. Females on Orchid Island, Taiwan, remain with their eggs during incubation and when doing so, actively deter egg predation by egg-eating snakes (Oligodon formosanus); in all other populations, females lack post-ovipositional maternal care. Nest-guarding females on Orchid Island (i) showed antipredator behaviours only in the original nest site in which they laid eggs, even after we removed all of the eggs or substituted them with those of a conspecific; (ii) protect any eggs present inside the original nest site (even when the eggs belong to a conspecific); and (iii) develop this behaviour while gravid (i.e. prior to laying eggs). This supports the hypothesis that long-tailed skinks cannot recognize their own eggs, suggesting that maternal care is a directed form of territoriality only expressed towards egg-eating snakes and only during reproduction. Nest guarding is among the most primitive forms of parental care, and the recent evolution of this behaviour in a single population provides insight into one of the mechanisms by which parental care can originate in terrestrial vertebrates.

Efficient gene transfer using the human JC virus-like particle that inhibits human colon adenocarcinoma growth in a nude mouse model.

The JC virus (JCV) may infect human oligodendrocytes and consequently cause progressive multifocal leukoencephalopathy (PML) in patients with immune deficiency. In addition, the virus has also been detected in other human tissues, including kidney, B lymphocytes, and gastrointestinal tissue. The recombinant major structural protein, VP1, of JCV is able to self-assemble to form a virus-like particle (VLP). It has been shown that the VLP is capable of packaging and delivering exogenous DNA into human cells for gene expression. However, gene transfer is not efficient when using in vitro DNA packaging methods with VLPs. In this study, a novel in vivo DNA packaging method using the JCV VLP was used to obtain high efficiency gene transfer. A reporter gene, the green fluorescence protein, and a suicide gene, the herpes simplex virus thymidine kinase (tk), were encapsidated into VLPs in Escherichia coli. The VLP was used to specifically target human colon carcinoma (COLO-320 HSR) cells in a nude mouse model. Intraperitoneal administration of ganciclovir in the tk-VLP-treated mice greatly reduced tumor volume. These findings suggest that it will be possible to develop the JCV VLP as a gene delivery vector for human colon cancer therapy in the future.

Prognostic value of 18-FDG uptake in early stage NSCLC.

BACKGROUND: We assessed whether the standard uptake of 18-fluorodeoxyglucose (18-FDG) in non-small cell lung cancers (NSCLC) differed between stage I and non-stage I tumors. METHODS: We reviewed 163 patients with NSCLC who underwent surgical lymph node dissection after tumor resection in 2002-2003. Patients with clinical stage I NSCLC who were investigated with preoperative positron emission tomography integrated computed tomography (PET-CT) scans using 18-FDG uptake were included; those with N2 disease were excluded. We reviewed 55 patients with a mean follow-up of 68 months. RESULTS: We analyzed 36 patients with stage I (Group 1) and 19 patients with non-stage I NSCLC (Group 2; 8 stage II, 7 stage III and 4 stage IV). There were no statistical differences in sex, age, tumor size, histological type, location or tumor differentiation between the groups. Group 1 had lower maximum standard 18-FDG uptake values (SUVmax) than Group 2 (4.9 +/- 2.7 vs. 8.1 +/- 3.8; P = 0.001). Using multiple logistic regression, patients with higher preoperative SUVmax and serum carcinoembryonic antigen (CEA) levels showed advanced tumor stages postoperatively (SUVmax > 4.7, odds ratio 7.65; CEA > 3.5 ng/mL, odds ratio 8.39). High 18-FDG uptake was significantly associated with reduced median survival (62.69 months for SUVmax < 4.7 and 40.89 months for SUVmax > 4.7). CONCLUSIONS: High preoperative 18-FDG uptake of tumors was significantly associated with reduced overall patient survival. The SUVmax of the tumor and serum CEA levels demonstrated aggressive tumors and could be helpful preoperatively when considering patients for induction therapy or resection.

In-patient medical resource utilization for high-level cervical spinal cord injury without bone fracture in Taiwan.

STUDY DESIGN: Retrospective review of secondary data obtained from the Bureau of National Health Insurance (BNHI) on medical resource utilization in in-patient cervical spinal cord injury patients in Taiwan. OBJECTIVES: Since the start of the National Health Insurance Program in Taiwan in 1995, costs have continued to increase each year. High-level cervical spinal cord injury, a catastrophic illness, consumes a large amount of medical resources. Appropriate control of in-patient costs for these patients is mandatory. Analyses of the factors influencing the health-care costs of these patients are needed, so cost-containment policies can be established by the BNHI to conserve health-care resources. SETTING: Health-care institutions throughout Taiwan. METHODS: We obtained secondary data on a randomized basis for diagnostic codes 952.00, 952.01, 952.02, or 952.03 of the International Classification of Diseases, Ninth Revision, Clinical Modification from the BNHI files of annual in-patient expenses during the period from 1998 to 2000. There were 184 hospital admission records studied. RESULTS: The lengths of stay and in-patient costs were significantly different among different hospital types. Length of stay also was statistically different according to patient, gender, and age. The lengths of stay and in-patient costs were influenced by the hospital accreditation level and patient gender. Medical orders were influenced by patient age. CONCLUSIONS: Basic and selective diagnostics and therapeutics for high-level spinal cord injury without bone fracture should be established. Thus, patient needs for appropriate medical care will be met and overuse of medical resources will be prevented. Communication among doctors also should be strengthened.

Protein phosphorylation and signal transduction modulation: chemistry perspectives for small-molecule drug discovery.

Protein phosphorylation has been exploited by Nature in profound ways to control various aspects of cell proliferation, differentiation, metabolism, survival, motility and gene transcription. Cellular signal transduction pathways involve protein kinases, protein phosphatases, and phosphoprotein-interacting domain (e.g., SH2, PTB, WW, FHA, 14-3-3) containing cellular proteins to provide multidimensional, dynamic and reversible regulation of many biological activities. Knowledge of cellular signal transduction pathways has led to the identification of promising therapeutic targets amongst these superfamilies of enzymes and adapter proteins which have been linked to various cancers as well as inflammatory, immune, metabolic and bone diseases. This review focuses on protein kinase, protein phosphatase and phosphoprotein-interacting cellular protein therapeutic targets with an emphasis on small-molecule drug discovery from a chemistry perspective. Noteworthy studies related to molecular genetics, signal transduction pathways, structural biology, and drug design for several of these therapeutic targets are highlighted. Some exemplary proof-of-concept lead compounds, clinical candidates and/or breakthrough medicines are further detailed to illustrate achievements as well as challenges in the generation, optimization and development of small-molecule inhibitors of protein kinases, protein phosphatases or phosphoprotein-interacting domain containing cellular proteins.

Technetium-99m tetrofosmin single photon emission computed tomography to detect metastatic papillary thyroid carcinoma in patients with elevated human serum thyroglobulin levels but negative I-131 whole body scan.

AIM: The aim of this study was to evaluate the effectiveness of technetium-99m tetrofosmin (Tc-99m TF) single photon emission computed tomography (SPECT) of the neck and chest to detect metastatic lesions in papillary thyroid carcinoma (PTC) after near total thyroidectomy and radioiodine (I-131) treatment in patients who present with elevated serum human thyroglobulin (hTg) levels but negative I-131 whole body scan (WBS). MATERIALS AND METHODS: Twenty patients with PTC treated by near total thyroidectomy and I-131 treatments were included in this study. All 20 patients had negative I-131 WBS results and elevated hTg levels (hTg 2.0 microIU/ml) under thyroid-stimulating hormone (TSH) stimulation (TSH 30 microIU/ml). Nineteen of the 20 cases were confirmed to have metastases by operation/biopsy histopathological findings or clinical follow-up longer than 1 year by additional morphological imaging techniques. The remaining patient has been followed up closely and has been disease free for 10 months. Tc-99m TF SPECT was performed to detect metastatic lesions. RESULTS: Tc-99m TF SPECT demonstrated lesions in 11/19 patients; a sensitivity of 57.9%. Tc-99m TF SPECT failed to demonstrate lesions in eight patients including smaller lymph nodes and miliary lung metastases. CONCLUSIONS: We conclude that Tc-99m TF SPECT is a useful additional tool to detect metastatic lesions in PTC with elevated hTg but negative I-131 WBS. However, smaller lymph nodes and miliary lung metastases may be missed.

99mTc-TRODAT-1 SPECT in healthy and 6-OHDA lesioned parkinsonian monkeys: comparison with 18F-FDOPA PET.

Parkinson's disease (PD) is a degeneration of the nigrostriatal dopaminergic pathway, leading to a selective loss of dopamine in the striatum. 99mTc-TRODAT-1 is a recently developed radiotracer that selectively binds to the dopamine transporters, which are significant because loss of these transporters corresponds with a loss of dopaminergic neurons. The present investigation compared 99mTc-TRODAT-1 single photon emission computed tomography (SPECT) with 18F-FDOPA positron emission tomography (PET) in the evaluation of PD using a primate model. Three monkeys, including one 6-hydroxydopamine lesioned PD model and two controls, were examined by both 99mTc-TRODAT-1 SPECT and 18F-FDOPA PET. For the PD monkey, expression of parkinsonian behaviour and 18F-FDOPA PET were used to evaluate the severity of the lesion. 99Tc-TRODAT-1 was prepared from a lyophilized kit. After intravenous injection of the radiotracer, SPECT was acquired over 4 h using a dual-head camera equipped with ultra-high resolution fan-beam collimators. Both uptake measurement and visual assessment were performed. Data were compared with motor behaviour and PET imaging. The striatal uptake in both healthy and PD monkeys increased continuously during the study, although the gradient of increase was less prominent in the diseased monkey. The increased uptake in the controls appeared to become blunt around 4 h after injection. A profound decrease of 99Tc-TRODAT-1 uptake was found in the striatum of the PD monkey compared with the controls (0.91 vs 2.16). In the PD monkey, the decrease of striatal uptake contralateral to the more affected side of the body was more prominent compared to the ipsilateral side (0.77 vs 1.06). In addition, greater loss occurred in the contralateral side of the putamen (0.54 vs 1.04). Changes of uptake ratios in the striatum and its subnuclei of the PD monkey were significantly correlated with those measured from PET. The loss of striatal uptake appeared greater in SPECT than the corresponding PET with both visual and uptake analyses. In conclusion, our data in a limited series of cases indicate that 99Tc-TRODAT-1 with a conventional nuclear medicine camera system may provide a suitable tool in evaluating parkinsonism in a primate model.

Antiviral treatment responses in patients with chronic hepatitis C virus infection evaluated by a third generation anti-hepatitis C virus assay.

Antibodies to hepatitis C virus (HCV) may decrease or disappear after viral clearance in treated or spontaneously resolved infection. We evaluated the usefulness of serial antibody assays in predicting the antiviral treatment responses. One hundred and four chronic hepatitis C patients who received 24 weeks of interferon and ribavirin combination therapy were assayed with a third generation enzyme immunoassay anti-HCV. The mean titre of anti-HCV decreased by more than 50% (from 89.5 +/- 10.8 to 43.6 +/- 17.5) at 48 weeks post-treatment in patients with a sustained virological response, while in nonsustained virological responders and nonresponders, the titres remained over 85% of the pretreatment level at 48 weeks post-treatment. There was a divergence of anti-HCV titres between sustained and nonsustained virological responders during 6-9 months. By using the ratio of 9-month to 6-month titres as an index and receiver operator characteristic curve analysis with the cut-off point set at 90%, we could differentiate sustained virological responders from nonsustained virological responders with a sensitivity and specificity of 91.7% and 90.9%, respectively, 3 months after treatment. The titre of this third generation anti-HCV decreased progressively in sustained virological responders and this assay may be used to monitor and predict antiviral treatment responses.

Highly selective catalytic intermolecular reductive coupling of alkynes and aldehydes

Alkynes (internal and terminal) and aldehydes (aromatic and aliphatic) are reductively coupled in a single catalytic reaction to yield di- and trisubstituted allylic alcohols with high stereoselectivity and regioselectivity. In most cases, a 1:1 ratio of alkyne to aldehyde is sufficient for efficient coupling. The yield and regioselectivity are strongly dependent on the phosphine ligand, but the allylic alcohols formed are invariably the products of cis addition to the alkyne.