Contribution of glucocerebrosidase mutation in a large cohort of sporadic Parkinson's disease in Taiwan.

BACKGROUND AND PURPOSE: The association between glucocerebrosidase (GBA) mutations and Parkinson's disease (PD) is attracting increased attention worldwide. In patients of Chinese ethnicity, other than the common L444P mutation, a few mutations have been reported. However, the contribution of GBA to PD can be answered only by a thorough investigation of its mutations in a unique large population. METHODS: We enrolled 1747 participants: 967 PD patients and 780 healthy individuals. We screened entire GBA coding regions and exon-intron boundaries in 30 randomly chosen PD patients, followed by testing five variants (L444P, D409H, R120W, L174P, and Q497R) in all participants. The G2385R and R1628P in LRRK2 had been previously studied in almost all participants. RESULTS: In total, 36 patients (3.72%) carried a heterozygous mutant GBA allele (27 L444P, 7 RecNciI, and 2 D409H). Only two controls (0.26%) carried heterozygous GBA mutation (1 L444P and 1 RecNciI). In PD group, the mean age at onset in carriers was younger than in non-carriers. The difference in percentage of mutation frequencies between patients and controls was highly significant for the L444P mutation (P < 0.0001). One L444P carrier was also associated with LRRK2 G2385R variant, but no atypical Parkinsonism was observed. CONCLUSIONS: The present study ascertains that L444P mutation in GBA gene may contribute to an earlier onset of development of PD in Han/Chinese population. Following LRRK2 variants, GBA is the second most frequent mutations indicated for sporadic PD development in the Han/Chinese population. These GBA carriers are associated with an earlier onset of Parkinsonism.

[Risk factors for surgical site infection after emergency abdominal surgery: a multicenter cross-sectional study in China].

Objective: Surgical site infection (SSI) is the most common infectious complication after emergency abdominal surgery (EAS). To a large extent, most SSI can be prevented, but there are few relevant studies in China. This study mainly investigated the current situation of SSI occurrence after EAS in China, and further explored risk factors for SSI occurrence. Methods: Multi-center cross-sectional study was conducted. Clinical data of patients undergoing EAS in 33 hospitals across China between May 1, 2019 and June 7, 2019 were prospectively collected, including perioperative data and microbial culture results from infected incisions. The primary outcome was the incidence of SSI after EAS, while the secondary outcomes were postoperative hospital stay, ICU occupancy rate, length of ICU stay, hospitalization cost, and mortality within postoperative 30 days. Univariate and multivariate logistic regression models were used to analyze the risk factors of SSI after EAS. Results: A total of 660 EAS patients aged (47.9±18.3) years were enrolled in this study, including 56.5% of males (373/660). Forty-nine (7.4%) patients developed postoperative SSI. The main pathogen of SSI was Escherichia coli [culture positive rate was 32.7% (16/49)]. As compared to patients without SSI, those with SSI were more likely to be older (median 56 years vs. 46 years, U=19 973.5, P<0.001), male [71.4% (35/49) vs. 56.1% (343/611), χ(2)=4.334, P=0.037] and diabetes [14.3% (7/49) vs. 5.1% (31/611), χ(2)=5.498, P=0.015]; with-lower preoperative hemoglobin (median: 122.0 g/L vs. 143.5 g/L, U=11 471.5, P=0.006) and albumin (median: 35.5 g/L vs. 40.8 g/L, U=9452.0, P<0.001), with higher blood glucose (median: 6.9 mmol/L vs. 6.0 mmol/L, U=17 754.5, P<0.001); with intestinal obstruction [32.7% (16/49) vs. 9.2% (56/611), χ(2)=25.749, P<0.001], with ASA score 3-4 [42.9% (21/49) vs. 13.9% (85/611), χ(2)=25.563, P<0.001] and with high surgical risk [49.0% (24/49) vs. 7.0% (43/611), χ(2)=105.301, P<0.001]. The main operative procedure resulting in SSI was laparotomy [81.6%(40/49) vs. 35.7%(218/611), χ(2)=40.232, P<0.001]. Patients with SSI experienced significantly longer operation time (median: 150 minutes vs. 75 minutes, U=25 183.5, P<0.001). In terms of clinical outcome, higher ICU occupancy rate [51.0% (25/49) vs. 19.5% (119/611), χ(2)=26.461, P<0.001], more hospitalization costs (median: 44 000 yuan vs. 15 000 yuan, U=24 660.0, P<0.001), longer postoperative hospital stay (median: 10 days vs. 5 days, U=23 100.0, P<0.001) and longer ICU occupancy time (median: 0 days vs. 0 days, U=19 541.5, P<0.001) were found in the SSI group. Multivariate logistic regression analysis showed that the elderly (OR=3.253, 95% CI: 1.178-8.985, P=0.023), colorectal surgery (OR=9.156, 95% CI: 3.655-22.937, P<0.001) and longer operation time (OR=15.912, 95% CI:6.858-36.916, P<0.001) were independent risk factors of SSI, while the laparoscopic surgery (OR=0.288, 95% CI: 0.119-0.694, P=0.006) was an independent protective factor for SSI. Conclusions: For patients undergoing EAS, attention should be paid to middle-aged and elderly patients and those of colorectal surgery. Laparoscopic surgery should be adopted when feasible and the operation time should be minimized, so as to reduce the incidence of SSI and to reduce the burden on patients and medical institutions.

A longitudinal study of Taiwanese sialidosis type 1: an insight into the concept of cherry-red spot myoclonus syndrome.

BACKGROUND AND PURPOSE: Sialidosis type 1 (ST-1) is a neurodegenerative disorder with limited long-term follow-up report. This study is to document the chronological profile of ST-1. METHODS: We perform serial analysis of 17 Taiwanese patients with ST-1 focusing on evolution of clinical features, electrophysiological findings, genetic studies, and neuroimage examinations. RESULTS: All patients had a mutation at 554A-->G in exon 3 of the NEU1 gene causing Ser182Gly substitution. Fifteen patients were homozygous. Two patients were heterozygous with novel mutations, 956C-->T causing Ala319Val in one and 163C-->T causing Gln55stop codon in the other. The neuraminidase activity was markedly decreased in all 11 available patients. Only three patients (17.6%) manifested the macular cherry-red spot. The majority of patients (82.3%) developed full-blown manifestation of myoclonus, ataxia, and seizures within 5 years. Abnormal somatosensory evoked potentials with giant cortical waves were found in all patients. Prolonged P100 peak latency of the visual evoked potentials (VEPs) were found in 16 patients (94.1%) in the early stage even without visual symptoms. CONCLUSION: ST-1 in Taiwanese population illustrates distinct characteristics of phenotype with infrequent cherry-red spot. We suggest to screen the NEU1 mutations in patients presenting action myoclonus with abnormal VEPs, even without macular cherry-red spots.

Adaptive variation in fall cold hardiness of aspen from northwestern Ontario.

We investigated adaptive variation in fall cold hardiness development based on the electrical conductivity of tissue diffusates (EC) among 20 aspen provenances from northwestern Ontario. Provenance accounted for over 40% of the total variation in cold injury for seven dates from September through November in three provenance trials. Principal component analysis was performed to summarize the combinations of results for all sampling sites, dates and temperatures (traits). Principal component (PC)-1 represented fully developed cold hardiness differences among provenances; PC-2 represented differences in the timing of the onset of cold hardiness development; and PC-3 represented a site-related difference in cold hardiness development. Heat sum in early summer and late summer precipitation together were the best predictors of absolute degree of cold hardiness (PC-1), whereas temperatures for mid- to late summer were best for predicting onset of cold hardiness development (PC-2). In a second study, we assessed the efficacy of chlorophyll fluorescence (CF) as a simpler technique for determining the cold hardiness of aspen stem samples. Fall cold hardiness of stem samples of 12 of the original 20 provenances was estimated by CF, and the results were evaluated by a visual scoring (VS) method. Correlations between EC and CF measurements from the two studies were moderately strong based on the extent of cold hardiness in October of each year, but were negative for September dates because of a later onset of cold hardiness in the EC study year. Although the EC and CF methods gave similar cold hardiness values for stem samples from 12 provenances, the CF method may be preferred to the EC or VS method for species with chlorophyllous stems because of its greater ease of use.

Up-regulation of long non-coding RNA SNHG1 contributes to proliferation and metastasis in laryngeal squamous cell carcinoma.

OBJECTIVE: To investigate the expression of human long non-coding ribonucleic acid (RNA) small nucleolar RNA host gene 1 (SNHG1) in laryngeal carcinoma tissues, and to study the effect of SNHG1 on biological functions of laryngeal carcinoma HEp-2 cells. PATIENTS AND METHODS: The expression levels of SNHG1 in 20 pairs of laryngeal carcinoma tissues and para-carcinoma tissues were detected via Real-time fluorescence quantitative polymerase chain reaction (PCR). Laryngeal carcinoma cells were transfected with small interfering (si)-SNHG1 transiently using the RNA interference technique. The effects of si-SNHG1 on proliferation, apoptosis, invasion, and migration of laryngeal carcinoma HEp-2 cells were detected via cell counting kit-8 (CCK-8), colony formation assay, flow cytometry, and wound healing and Transwell assay, respectively. RESULTS: Results of PCR showed that the expression of SNHG1 in carcinoma tissues was increased compared with that in para-carcinoma tissues. Results of CCK-8 and colony formation assay revealed that SNHG1 knockdown could significantly inhibit the proliferation of laryngeal carcinoma HEp-2 cells. Flow cytometry showed that transfection with si-SNHG1 could promote the apoptosis of HEp-2 cells. Moreover, results of wound healing and Transwell assay showed that SNHG1 knockdown could inhibit invasion and migration of HEp-2 cells through inhibiting the epithelial-mesenchymal transition (EMT) process and expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 in cells. CONCLUSIONS: The expression of SNHG1 in laryngeal carcinoma tissues is significantly higher than that in para-carcinoma tissue. Patients with high expression of SNHG1 have a poor prognosis. SNHG1 knockdown in HEp-2 cells can inhibit cell proliferation, invasion, and metastasis, and can promote apoptosis.

Genetic and DAT imaging studies of familial parkinsonism in a Taiwanese cohort.

We here summarize the results of genetic investigations on a series of 82 parkinsonian patients from 60 families in Taiwan. We found 13 parkin patients in 7 families (12%), 2 PINK1 sibs from 1 family, and 1 LRRK2 patient from 1 family with I2012T mutation. We also identified SCA2 in 8 patients from 5 families (8%) and SCA3 in 3 patients from 1 family, all presenting with parkinsonian phenotype. In the available patients with parkin, PINK1, SCA2 and SCA3, the dopamine transporter (DAT) scan revealed that the reduction of uptake was primarily observed in the bilateral putamen, basically sharing a similar pattern with that in idiopathic Parkinson's disease. We concluded that the genetic causes contributed to about 25% of our series of familial parkinsonism. The parkin mutations and SCA2 were the most frequent genetic causes in our series with Chinese ethnicity. The results of DAT scan indicated that bilateral putamen was essentially involved in various genetically-caused familial parkinsonism.

[Effect of hydrogen peroxide on the lateral line hair cell regeneration of zebrafish].

Objective:To investigate effect of hydrogen peroxide (H2O2) in the lateral line hair cell growth and regeneration after damage on zebrafish. Method:Select 5 dpf zebrafish, each group of 10, randomly divided into A control group: the system of water culture. B H2O2 group: 10 µmol/L, 20 µmol/L H2O2 solution to replace three times a day. C neomycin group: treatment with system water after 1 h culture by 200 µmol/L neomycin. D neomycin + H2O2 group: 20 µmol/L H2O2 solution to replace three times a day after 200 µmol/L neomycin treatment for 1 h. E cisplatin group: treatment with system water after 3 h culture by 1 000 µmol/L cisplatin. F cisplatin + H2O2 group: 20 µmol/L H2O2 solution to replace three times a day after 1 000 µmol/L cisplatin treatment for 3 h. Each group in H2O2 treatment for 0 h, 24 h, 48 h was marked their hair cells by immunofluorescence method and count the P1, P7, P8 neuromasts under the fluorescence microscope. Repeat 3 times. Result:The number of hair cells on P1, P7, P8 three neuramasts among 5 to 7 dpf zebrafish were 9.364±0.901(n=11),9.645±0.598(n=15),9.922±0.862(n=13), no obvious difference (P>0.05); 10µmol/L, 20µmol/L H2O2 treated zebrafish for 48 h, the numbers were 11.540±0.741,11.905±0.607,compaired with the control group(10.841±0.389), P<0.05; neomycin+ H2O2 48 h and neomycin 48 h respectively were 10.600±0.689,8.767±0.603, P<0.01; cisplatin+ H2O2 48 h and cisplatin 48 h were 5.967±1.086,5.633±1.548, P>0.05. Conclusion:20 µmol/L H2O2 promotes the development of lateral line hair cells of zebrafish; H2O2 promotes the regeneration of the lateral line hair cells after injury of neomycin, but not cisplatin.

Decreased dopamine transporter binding in Machado-Joseph disease.

UNLABELLED: The aim of this study was to use 99mTc-TRODAT-1 brain SPECT for investigation of the binding of dopamine transporter (DAT) in the nigrostriatal dopaminergic pathway of symptomatic Machado-Joseph disease (MJD) and to compare the results with the abnormal cytidylate, adenylate, and guanylate (CAG) expansion in the MJD1 gene and other clinical factors. METHODS: Ten symptomatic MJD patients (8 women, 2 men; age range, 20-71 y; mean age +/- SD, 36.4 +/- 10.6 y; mean duration of illness, 9.8 +/- 5.4 y) and 21 healthy volunteers (age range, 24-71 y; mean age, 47.6 +/- 20.1 y) were examined. Brain SPECT images were acquired 4 h after injection. The ratio of specific to nonspecific nigrostriatal 99mTc-TRODAT-1 binding was measured and compared with the clinical symptoms, duration of illness, and size of abnormal expanded CAG repeats. RESULTS: All nigrostriatal 99mTc-TRODAT-1 ratios were significantly lower in MJD patients than in healthy volunteers (P < 0.05). Discriminant function analysis of all MJD patients showed that the decreased binding of 99mTc-TRODAT-1 in the putamen was not significantly different from that in the caudate nucleus. Eight of 10 MJD patients had significantly decreased 99mTc-TRODAT-1 uptake. Of these 8, 2 had extrapyramidal signs and 6 had no obvious extrapyramidal signs. The other 2 patients, who had normal 99mTc-TRODAT-1 uptake, had no obvious extrapyramidal signs. CONCLUSION: Our findings indicate that 99mTc-TRODAT-1 brain SPECT is an appropriate method for evaluating damage to the nigrostriatal DAT in symptomatic MJD patients with and without extrapyramidal signs. The decreased binding of 99mTc-TRODAT-1 in the nigrostriatal dopaminergic pathway in symptomatic MJD patients correlates with the phenotype of extrapyramidal signs but not with the abnormal CAG repeat length, age at disease onset, or disease duration.

Concentrations of radionuclides of size fractionated fly-ash emissions from a thermal power plant using Taiwan coal.

Coal, fly ash and bottom ash samples were taken from a 300-MWe coal-fired power plant with a daily coal consumption of 2400 tons. A high volume sampler coupled with several mesh testing sieves was used to separate fly ash samples into different size fractions. Determination of the concentrations of 40K, 238U, 226Ra, 210Pb, 210Po, 228Th and 228Ra was carried out either by gamma or alpha spectrometry. For elements volatilized during combustion, their radionuclide concentrations decrease with increasing particle size. The enrichment factors for all radionuclides mentioned above were studied. Their values range from 31.0 for 210Po to 2.2 for 228Ra. Of all radionuclides studied, 210Po and 210Pb are the most volatile elements; therefore, an increase in the natural radiation level should first be indicated by an increase in these two nuclides.

Environmental risk factors of young onset Parkinson's disease: a case-control study.

While the cause of Parkinson's disease (PD) remains unknown, recent evidence suggests certain environmental factors, such as well water drinking, herbicides and pesticides exposure, and neurotoxins, may trigger the chain of oxidative reactions culminating in the death of dopaminergic neurons in substantia nigra to cause parkinsonism. Most studies to date focused on PD with old age onset. However, there is a peculiar group of parkinsonian patients, the young onset Parkinson's disease (YOPD), in whom the age of onset is before 40. It is intriguing to know whether earlier exposure to the putative neurotoxin(s) may contribute to the earlier onset. We therefore conducted this case-control study in which 60 PD patients, 30 YOPD patients and the same number of age- and sex-matched young controls were included. Using logistic regression, we found well water drinking and head injury were risk factors for the development of YOPD. When YOPD patients were compared with PD, we found head injury and exercise were the significant predictors. Keeping all other variables constant, head injury was a risk factor and exercise appeared to be a protective factor. We conclude early exposure to well water drinking and head trauma may trigger and expedite the appearance of parkinsonian features, but such acceleration may be prevented through regular exercise.

The optimal imaging time for [99Tcm]TRODAT-1/SPET in normal subjects and patients with Parkinson's disease.

Imaging of dopamine transporters (DATs) in the brain using [99Tcm]TRODAT-1 showed excellent pharmacokinetics for estimation of transporter concentrations. It has been reported that there may be differences in the binding kinetics of DAT radiotracers to DATs between normal subjects and patients with Parkinson's disease (PD). The aim of this study was to determine an optimal time point for (99Tcm]TRODAT-1 brain single photon emission tomography (SPET) acquisition that provides stable target to non-target ratios reflecting the DAT concentration in the brain. Serial [99Tcm]TRODAT-1 brain SPET images 2, 3 and 4 h after intravenous injection of [99Tcm]TRODAT-1 (925 MBq) were performed in five healthy subjects and nine PD patients. Regions of interests were drawn, and caudate/occipital (C/O) and putamen/occipital (P/O) specific to non-specific [99Tcm]TRODAT-1 binding ratios were calculated. The C/O and P/O ratios in healthy subjects showed consistent increases with time, but in PD patients, the C/O and P/O ratios of [99Tcm]TRODAT-1 reached a stable level at 3 h post-injection. There was a statistically significant difference (P < 0.001) between PD and normal subjects at 4 h post-injection for both the C/O and the P/O ratios. In conclusion, we recommend the acquisition of [99Tcm]TRODAT-1 SPET images at 4 h post-injection, as at this time point the C/O and P/O ratios can be used to discriminate between PD patients and healthy subjects.

The biology of bilirubin production.

Heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, has been identified from the late 1960s. This enzyme has been shown to have many other roles in recent years. The inducible form is regulated by oxidative stress, inflammation, and heavy metals, among others, and is cytoprotective in many instance. Nonetheless, there are instances when HO-1 can be deleterious due to the release of iron from the reaction. Another important by-product, carbon monoxide, is a vasodilator and a neurotransmitter and has been implicated in signal transduction pathways. More recently, nonenzymatic, signaling roles of HO have been suggested. This may serve to regulate the endogenous activity of this enzyme when cellular heme levels are low.

Brain fluorodeoxyglucose positron emission tomography (¹8FDG PET) in patients with acute thallium intoxication.

OBJECTIVE: Thallium toxicity induces cellular injury through impaired Na-K-ATPase activity. The aim of this study was to investigate functional imaging and the long-term clinical-imaging correlations of thallium toxicity. MATERIALS AND METHODS: We measured thallium concentrations in blood, urine, stools, and hair of a 48-year-old woman and a 52-year-old man (patients 1 and 2) in the first 3 months after exposure to thallium containing water, and studied their neuropsychological functions. Using fluorodeoxyglucose positron emission tomography ((18)FDG PET) scans, we examined the brain involvement and correlated the image findings with the clinical presentations. RESULTS: On the 1st, 30th, and 61st days after exposure, the thallium concentrations in patient 1 were 2056, 311, and 7.5 µg/L in the blood, and 11400, 4570, and 36.4 µg/L in the urine. The concentrations in patient 2 were 956, 235, and 15.6 µg/L in the blood, and 11900, 2670, and 101 µg/L in the urine. On the 40th, 50th and 89th days after exposure, the thallium concentration in the stools were 21.6, 3.6, and 0.35 µg/g in patient 1, and 22.2, 3.2, and 0.37 µg/g in patient 2. Executive function, perceptual motor speed, and learning memory were initially abnormal but recovered particularly within the first year. The first (18)FDG PET studies of both patients disclosed a decreased uptake of glucose metabolism in the cingulate gyrus, bilateral frontal, and parietal lobes 2-5 months after exposure. The follow-up (18)FDG PET scan of patient 2 revealed a partial recovery. CONCLUSION: This study indicates that damage to the central nervous system after acute thallium poisoning may be reversible after a long-term follow-up. Brain (18)FDG PET demonstrated the brain involvement and was correlated with cognitive impairment.

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD.

(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser(257), and protein expression of active phospho-MKK4(Ser257) was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK(Thr183/Tyr185) and phospho-c-Jun(Ser63), downstream targets of phospho-MKK4(Ser257), was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun(Ser63), and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.

Analysis of the UCHL1 genetic variant in Parkinson's disease among Chinese.

The inverse association of the functional ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y variant with Parkinson's disease (PD) among Caucasian populations has been debated. We conducted a large-scale analysis to investigate the age-of-onset effect of the UCHL1 variant in PD among ethnic Chinese. Individual data sets from 5 centers comprising a total of 4088 study subjects were analyzed. In the univariate analysis, only data from 1 center showed a trend towards a protective effect among young subjects. However, in the combined analysis, no significant association between the UCHL1 variant and PD was detected (A allele frequency 0.531 vs. 0.528, p=0.87, OR 1.01, 95% CI 0.92-1.1). Among subjects less than 60 years old, the OR is 0.99 (95% CI 0.84-1.16, p=0.88). A multivariate logistic regression analysis showed that family history, UCHL1 variant and the interaction of UCHL1 variant and age at onset (p=0.816) were not significantly associated with PD.