Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China

Mutations in GBA gene have been reported to be in patients with Parkinson's disease (PD) from different ethnic populations, including Taiwanese Chinese. To explore whether mutation in GBA is also associated with PD in Mainland China, we have now a case control study. The occurrence of the GBA L444P mutation was analyzed in an independent cohort of PD patients and controls from Mainland China. This mutation was present in 20/616 (3.2%) of PD compared with 1/411 (0.2%) of controls (odds ratio, OR = 13.76, 95% Confidence interval, CI: 1.84–102.92, p = 0.001). All carriers harbored the heterozygous genotype. In a subset analysis, the frequency of this mutation was higher both in early onset (EOPD) and late onset PD (LOPD) than in controls. However, no difference in clinical characteristics, such as gender, age at onset, onset symptoms, Hoehn–Yahr stage and UPDRS, was found between L444P carriers and non-carriers. In addition, we also explored the potential relationship between GBA L444P mutation and LRRK2 G2385R and R1628P variants in patients with PD. But no association was found, either. In conclusion, our data suggest that the GBA L444P mutation plays an important role in the development of PD also in Han-Chinese patients from Mainland China.     

MAPT IVS1+124 C>G modifies risk of LRRK2 G2385R for Parkinson's disease in Chinese individuals

Variants of the MAPT gene have been suggested to be associated with Parkinson's disease (PD) and to modify the risk for leucine-rich repeat kinase 2 (LRRK2) Parkinsonism. However, this has not been confirmed in Asians with ethnicity-specific variants of MAPT and LRRK2. In this study, Asian-specific LRRK2 p.G2385R variant and IVS1+124 C>G, a functional single-nucleotide polymorphism located in the MAPT promoter region, were genotyped in 561 Chinese PD patients and 556 control subjects. Allelic and genotypic frequencies of the 2 variants were compared between cases and control subjects independently and in combination. As a result, the LRRK2 p.G2385R variant alone was associated with an increased risk for PD (Odds ratio, 1.86; 95% confidence intervals, 1.08–3.19; p = 0.014), whereas MAPT IVS1+124 C>G was not (p = 0.34). However, the coexistence of MAPT IVS1+124C>G significantly enhanced the LRRK2 G2385R-conferred risk for PD (Odds ratio, 2.30; 95% confidence intervals, 1.14–4.54; p = 0.012). These results provide further evidence supporting the interaction between MAPT and LRRK2 genes, which increases the susceptibility to PD in Chinese individuals.     

A 12-month randomized controlled trial of balance training in elderly women with osteoporosis: Improvement of quality of life

Objective

Physical and psychological incapacity, including fear of falling is related to decreased satisfaction with life in osteoporosis (OP). The impact of a balance exercise program on improving the quality of life is not well established. We have, therefore, investigated the effect of 12-month Balance Training Program in quality of life, functional balance and falls in elderly OP women.

Methods

Sixty consecutive women with senile OP were randomized into a Balance Training Group (BT) of 30 patients and no intervention control group (CG) of 30 patients. The BT program included techniques to improve balance over a period of 12 months (1 h exercise session/week and home-based exercises). The quality of life was evaluated before and at the end of the trial using the Osteoporosis Assessment Questionnaire (OPAQ), functional balance was evaluated by Berg Balance Scale (BBS). Falls in the preceding year were noted and compared to the period of study.

Results

The comparison of OPAQ variations (INITIAL–FINAL) revealed a significant improvement in quality of life in all parameters for BT compared to CG: well-being (1.61 ± 1.44 vs. −1.46 ± 1.32, p < 0001), physical function (1.30 ± 1.33 vs. −0.36 ± 0.82, p < 0.001), psychological status (1.58 ± 1.36 vs. −1.02 ± 0.83, p < 0.001), symptoms (2.76 ± 1.96 vs. −0.63 ± 0.87, p < 0.001), social interaction (1.01 ± 1.51 vs. 0.35 ± 1.08, p < 0.001). Of note, this overall benefit was paralleled by an improvement of BBS (−5.5 ± 5.67 vs. +0.5 ± 4.88 p < 0.001) and a reduction of falls in 50% in BT group vs. 26.6% for the CG (RR: 1.88, p < 0.025).

Conclusion

The long-term Balance Training Program of OP women provides a striking overall health quality of life improvement in parallel with improving functional balance and reduced falls.     

NO-mediated activation of Src kinase during hypoxia in the cerebral cortex of newborn piglets

The present study aims to investigate the mechanism of Src kinase activation during hypoxia and tests the hypothesis that the hypoxia-induced activation of Src kinase, as determined by Src kinase phosphorylation, in the cerebral cortical membranes of newborn piglets is mediated by NO derived from neuronal nitric oxide synthase (nNOS). Fifteen piglets were divided into normoxic (Nx, n = 5), hypoxic (Hx, n = 5) and hypoxic-treated with nNOS inhibitor I (Hx-nNOSi) groups. Hypoxia was induced by decreasing FiO₂ to 0.06 for 1 h. nNOS inhibitor I (selectivity >2500 vs eNOS and >500 vs iNOS) was administered (0.4 mg/kg, i.v.) 30 min prior to hypoxia. Cortical membranes were isolated and phosphorylation of Src kinase was determined by Western blot analysis. Src kinase activity was determined by radioactive assay using immunopurified enzyme. Membrane proteins were separated by 12% SDS–PAGE and probed with anti-phospho (pTyr⁴¹⁸)-Src kinase antibody. Protein bands were detected, analyzed by densitometry and expressed as absorbance (OD × mm²). Density (OD × mm²) of phosphorylated Src kinase was 111.7 ± 21.1 in Nx, 234.5 ± 23.8 in Hx (p < 0.05 vs Nx) and 104.7 ± 18.1 in Hx-nNOSi (p < 0.05 vs Hx, p = NS vs Nx). Src kinase activity (pmol/mg protein/ h) was 2472 ± 75 in Nx, 4556 ± 358 in Hx (p < 0.05 vs Nx) and 2259 ± 207 in Hx-nNOSi (p < 0.05 vs Hx, p = NS vs Nx). The data show that pretreatment with nNOS inhibitor prevents the hypoxia-induced increase in tyrosine phosphorylation and the activity of Src kinase. We conclude that the mechanism of hypoxia-induced increased activation of Src kinase is mediated by nNOS derived NO. We propose that NO mediated inhibition of protein tyrosine phosphatases SH-PTP-1 and SH-PTP-2 leads to increased tyrosine phosphorylation and activation of Src kinase in the cerebral cortex of newborn piglets.     

No association of the LRRK2 genetic variants with Alzheimer's disease in Han Chinese individuals

The leucine-rich repeat kinase–2 (LRRK2) gene has been regarded as 1 of the most common genetic causes of Parkinson's disease (PD). We hypothesized that LRRK2-susceptible allele(s) for PD might pose a risk for Alzheimer's disease (AD). In this study, we screened 12 LRRK2 gene variants in 2 independent cohorts from southwestern China (341 AD patients and 435 normal individuals) and eastern China (297 AD patients and 384 normal individuals), to discern the potential association between this gene and AD. No variant was identified to be associated with AD in either case-control sample. As both of the cohorts were of Han Chinese origin, we combined the LRRK2 variant data for the 2 sample sets together (a total of 638 AD patients and 819 normal individuals) and still found no association between the LRRK2 gene and AD, suggesting that LRRK2 gene variants may not affect the development of AD in Han Chinese individuals.     

Psychological insulin resistance in geriatric patients with diabetes mellitus

Objective

To determine the extent to which geriatric patients with diabetes mellitus experience psychological insulin resistance (PIR).

Methods

A total of 67 unselected geriatric patients with diabetes (mean age 82.8 ± 6.7 years, diabetes duration 12.2 [0.04–47.2] years, 70.1% female) were recruited in a geriatric care center of a university hospital.A comprehensive geriatric assessment (CGA) was performed including WHO-5, Hospital Anxiety and Depression Scale (HADS), Mini Mental State Examination (MMSE) and Barthel-Index. We assessed PIR using the Barriers of Insulin Treatment Questionnaire (BIT) and the Insulin Treatment Appraisal Scale in a face-to-face interview.

Results

Insulin-naïve patients (INP) showed higher PIR scores than patients already on insulin therapy (BIT-sum score: 4.3 ± 1.4 vs. 3.2 ± 1.0; p < 0.001). INP reported in the BIT increased fear of injection and self-testing (2.4 ± 2.4 vs. 1.3 ± 0.8; p = 0.016), expect disadvantages from insulin treatment (2.7 ± 1.6 vs. 1.9 ± 1.4; p = 0.04), and fear of stigmatization by insulin injection (5.2 ± 2.3 vs. 3.6 ± 2.6; p = 0.008). Fear of hypoglycemia, however, did not differ significantly (6.3 ± 2.8 vs. 5.1 ± 3.1; p = 0.11). Depression was not shown to be a barrier to insulin therapy.

Conclusion

INP with diabetes have a significantly more negative attitude toward insulin therapy in comparison to patients already on insulin.

Practice implications

Systematic assessment of barriers of insulin therapy, individualized diabetes treatment plans and information of patients may help to overcome such negative attitudes, leading to quicker initiation of therapy, improved adherence to treatment and a better quality of life.     

Mechanism of tyrosine phosphorylation of procaspase-9 and Apaf-1 in cytosolic fractions of the cerebral cortex of newborn piglets during hypoxia

Previous studies have shown that cerebral hypoxia results in increased activity of caspase-9 in the cytosolic fraction of the cerebral cortex of newborn piglets. The present study tests the hypothesis that hypoxia results in increased tyrosine phosphorylation of procaspase-9 and apoptotic protease activating factor-1 (Apaf-1) and the hypoxia-induced increased tyrosine phosphorylation of procaspase-9 and Apaf-1 is mediated by nitric oxide. To test this hypothesis, 15 newborn piglets were divided into three groups: normoxic (Nx, n = 5), hypoxic (Hx, n = 5) and hypoxic treated with nNOS inhibitor I (Hx + nNOS I 0.4 mg/kg, i.v., 30 min prior to hypoxia) [16]. The hypoxic piglets were exposed to an FiO₂ of 0.06 for 1 h. Tissue hypoxia was documented by ATP and phosphocreatine (PCr) levels. Cytosolic fractions were isolated and tyrosine phosphorylated procaspase-9 and Apaf-1 were determined by immunoblotting using specific anti-procaspase-9, anti-Apaf-1 and anti-phosphotyrosine antibodies. ATP levels (μmoles/g brain) were 4.3 ± 0.2 in the Nx and 1.4 ± 0.3 in the Hx and 1.7 ± 0.3 in Hx + nNOS I group (p < 0.05 vs. Nx) groups. PCr levels (μmoles/g brain) were 3.8 ± 0.3 in the Nx and 0.9 ± 0.2 in the Hx and 1.0 ± 0.4 in the Hx + nNOS I (p < 0.05 vs. Nx) group. Density (OD × mm²) of tyrosine phosphorylatd procaspase-9 was 412 ± 8 in the Nx, 1286 ± 12 in the Hx (p < 0.05 vs. Nx) and 421 ± 10 in the Hx + nNOS I (p < 0.05 vs. Hx) group. Density of tyrosine phosphorylated Apaf-1 was 11.72 ± 1.11 in Nx, 24.50 ± 2.33 in Hx (p < 0.05 vs. Nx) and 16.63 ± 1.57 in Hx + nNOS I (p < 0.05 vs. Hx) group. We conclude that hypoxia results in increased tyrosine phosphorylation of procaspase-9 and Apaf-1 proteins in the cytosolic compartment and the hypoxia-induced increased tyrosine phosphorylation of procaspase-9 and Apaf-1 is mediated by nNOS derived nitric oxide. We propose that increased interaction between the tyrosine phosphorylated procaspase-9 and Apaf-1 molecules lead to increased activation of procaspase-9 to caspase-9 in the hypoxic brain that initiates programmed neuronal death.     

Glial activation in the spinal ventral horn caudal to cervical injury

Microglia and astrocytes play complex roles following spinal cord injury (SCI), contributing to inflammatory processes that both exacerbate injury and promote functional recovery by supporting neuro-protection and neuroplasticity. The crossed phrenic phenomenon (CPP) is an example of respiratory plasticity in which C₂ cervical hemisection (C₂HS) strengthens crossed-spinal synaptic pathways to phrenic motor neurons ipsilateral to injury. We hypothesized that microglia and astrocytes are activated in the phrenic motor nucleus caudal and ipsilateral to C₂HS, suggesting their potential for involvement in the CPP. To test this hypothesis, an incomplete cervical spinal hemisection (C₂ lateral injury; C₂LI) was performed, and rats were allowed to recover for 1, 3, 14 or 28 days before collecting perfused spinal tissues. Microglia (via OX42) and astrocytes [via glial fibrillary acidic protein (GFAP)] were visualized with immunofluorescence microscopy in the C₄-C₅ ventral horn, the region encompassing most of the phrenic motor nucleus. OX42-occupied fractional area ipsilateral to injury increased with C₂LI (vs. sham) at 1 (12.5 ± 1.8%, p < 0.001), 3 (29.0 ± 1.9%, p < 0.001), 14 (26.1 ± 3.1%, p < 0.001) and 28 (19.2 ± 2.0%, p < 0.001) days post-C₂LI. GFAP-occupied fractional area also increased with C₂LI at 3 (24.4 ± 3.2%, p < 0.001) and 14 (16.8 ± 8.3%, p = 0.012) days, but not at 1 (6.2 ± 3.9%, p = 0.262) or 28 (10.6 ± 3.9%, p = 0.059) days post-C₂LI. Thus, microglia and astrocytes are activated in the phrenic motor nucleus caudal to C₂LI, suggesting that they play a role in functional deficits and/or recovery following spinal injury.     

Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial progressive neurodegenerative disease. Recently, two studies reported inconsistent results on a possible involvement of the NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, 6p25-p24) as a candidate gene for the risk of developing AD and/or Parkinson's disease (PD). We analyzed the distribution of the rs760678 SNP polymorphism in 735 Italian subjects: 214 unrelated sporadic late-onset AD patients (LOAD, 64.5% females, mean age-at-onset 71.8 ± 5.2 years), 135 early-onset AD patients (EOAD, 57.3% females, mean age-at-onset 57.5 ± 5.5 years) and 386 healthy controls (68.9% females, mean age 83.4 ± 17.9 years; SD). We observed a statistically significant difference between LOAD patients and controls according to genotypes (P = 0.016) and allele frequency (P = 0.007); CC genotype was more frequent in LOAD cases (44.4%) than controls (36.0%). No difference after stratification of the data in terms of gender and status of the APOE ?4 allele was observed. In conclusion, our data do support an implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E (APOE) ?4 allele in the risk of developing AD.     

Genetic associations with acute stress-related changes in eating in the absence of hunger

Background

Acute psychological stress is associated with eating in the absence of hunger.

Objective

To investigate if BclI and FTO polymorphisms are associated with eating in the absence of hunger as a result of acute psychological stress.

Methods

FTO (rs9939609) and BclI were genotyped in 98 subjects (BMI = 23.9 ± 3.3 kg/m²). In a randomized crossover design, the ‘eating in absence of hunger’ protocol was measured as a function of acute stress vs. a control task and of STAI (State Trait Anxiety Index) state scores.

Results

In comparison with the FTO T allele, the A allele was associated with an increased feelings of hunger after food intake in the stress (11 ± 10 vs. 18 ± 15, p < 0.01) and control condition (12 ± 9 vs. 16 ± 12, p < 0.05), even though food intake was not different. For the first time, it was observed that in comparison to the BclI C/C genotype, the BclI G/G genotype was associated with higher STAI states scores at 0, 10, and 20 min after the stress condition (30.8 ± 6.4 vs. 36.3 ± 8.2; 28.3 ± 5.5 vs. 32.3 ± 7.5; 27.7 ± 6.1 vs. 31.2 ± 7.5, p < 0.05). Additionally, the BclI G/G genotype was associated with a larger difference in energy intake between the stress and control condition, in comparison with the BclI C/C genotype (136.6 ± 220.4 vs. 29.4 ± 176.3 kJ, p < 0.04).

Conclusion

In concordance with previous studies, the FTO A allele is related to a lower feeling of hunger after a standardized meal. For the first time, the BclI G/G genotype is shown to be associated with increased sensitivity to psychological stress, and increased eating in the absence of hunger after stress.

Practice implications

Interventions to reduce body weight should consider the subjects’ genetic background.     

Exercise improves cardiovascular control in a model of dislipidemia and menopause

The present study investigated the effects of exercise training on arterial pressure, baroreflex sensitivity, cardiovascular autonomic control and metabolic parameters on female LDL-receptor knockout ovariectomized mice. Mice were divided into two groups: sedentary and trained. Trained group was submitted to an exercise training protocol. Blood cholesterol was measured. Arterial pressure (AP) signals were directly recorded in conscious mice. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses to AP changes. Cardiovascular autonomic modulation was measured in frequency (FFT) and time domains. Maximal exercise capacity was increased in trained as compared to sedentary group. Blood cholesterol was diminished in trained mice (191 ± 8 mg/dL) when compared to sedentary mice (250 ± 9 mg/dL, p < 0.05). Mean AP and HR were reduced in trained group (101 ± 3 mmHg and 535 ± 14 bpm, p < 0.05) when compared with sedentary group (125 ± 3 mmHg and 600 ± 12 bpm). Exercise training induced improvement in bradycardic reflex response in trained animals (−4.24 ± 0.62 bpm/mmHg) in relation to sedentary animals (−1.49 ± 0.15 bpm/mmHg, p < 0.01); tachycardic reflex responses were similar between studied groups. Exercise training increased the variance (34 ± 8 vs. 6.6 ± 1.5 ms² in sedentary, p < 0.005) and the high-frequency band (HF) of the pulse interval (IP) (53 ± 7% vs. 26 ± 6% in sedentary, p < 0.01). It is tempting to speculate that results of this experimental study might represent a rationale for this non-pharmacological intervention in the management of cardiovascular risk factors in dyslipidemic post-menopause women.     

HLA rs3129882 variant in Chinese Han patients with late-onset sporadic Parkinson disease

Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (χ² = 6.446, p = 0.040 for genotypic distribution; χ² = 5.762, p = 0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population.     

Differential effects of endothelins on histological and ultrastructural changes and trypsinogen activation in the secretagogue-induced acute pancreatitis in rats

The role of endothelins in acute pancreatitis remains obscure. To assess the effects of endothelins (ETs) in early (4 h) caerulein-induced acute pancreatitis (AP) in rats, ET-1, ET-2 and ET-3 (0.5 or 1.0 nmol/kg) were applied twice with i.p. caerulein (2×40 μg/kg) at 1 h interval. Histological and ultrastructural examinations of pancreases and the assay of trypsinogen activation in whole homogenate were performed. All ETs, especially ET-1 at the higher dose, decreased inflammatory cell infiltration despite an increase in the edema score. The vacuolization and necrosis of acinar cells were slightly increased after the lower dose of ET-1 and ET-2. Ultrastructural changes were generally improved after the higher dose of ETs. Trypsinogen activation increased from 4.8±1.3% in control to 18.4±3.8% in AP (p<0.01). It was attenuated to 6.4±1.3% (p<0.01) by the higher dose of ET-1 and to 8.8±1.5% (p<0.05) by the lower dose of ET-3. In summary, ETs, especially ET-1 at the higher dose, were found to have some beneficial effects on morphological changes and trypsinogen activation in the pancreas in early caerulein-induced AP.     

Tyrosine phosphorylation of neuronal nitric oxide synthase (nNOS) during hypoxia in the cerebral cortex of newborn piglets: The role of nitric oxide

The present study aims to investigate the mechanism of activation of nNOS during hypoxia and tests the hypothesis that the hypoxia-induced increased tyrosine phosphorylation of nNOS in the cerebral cortical membranes of newborn piglets is mediated by nNOS-derived nitric oxide (NO). Fifteen newborn piglets were divided into normoxic (Nx, n = 5), hypoxic (Hx, n = 5) and hypoxic-pretreated with nNOS inhibitor I (Hx-nNOSi) groups. Hypoxia was induced by an FiO₂ of 0.07 for 60 min. nNOS inhibitor I (selectivity > 2500 vs endothelial NOS and >500 vs inducible NOS) was administered (0.4 mg/kg, i.v.) 30 min prior to hypoxia. Cortical membranes were isolated and tyrosine phosphorylation of nNOS determined by Western blot. Membrane protein was immunoprecipitated with nNOS antibody, separated on 12% SDS-PAGE and blotted with anti-phosphotyrosine antibody. Protein bands were detected by enhanced chemiluminescence, analyzed by densitometry and expressed as absorbance (OD × mm²). Density (OD × mm²) of tyrosine phosphorylated nNOS was 51.66 ± 14.11 in Nx, 118.39 ± 14.17 in Hx (p < 0.05 vs Nx) and 45.56 ± 10.34 in Hx-nNOSi (p < 0.05 vs Hx, p = NS vs Nx). The results demonstrate that pretreatment with nNOS inhibitor prevents the hypoxia-induced increased tyrosine phosphorylation of nNOS. We conclude that the mechanism of hypoxia-induced increased tyrosine phosphorylation of nNOS is mediated by nNOS-derived NO.     

Matrix metalloproteinase-9 (MMP-9) expression and extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation in exercise-reduced neuronal apoptosis after stroke

Exercise preconditioning has been shown to reduce neuronal damage in ischemic/reperfusion (I/R) injury. ERK1/2 signaling in injury has been thought to modulate neuroprotection. In this study, we investigated the effects of ERK1/2 activation on the expression and activity of MMP-9 and downstream neuronal apoptosis. Adult male Sprague–Dawley rats were subjected to 30 min of exercise on a treadmill for 3 weeks. Stroke was induced by a 2-h middle cerebral artery (MCA) occlusion using an intraluminal filament. Apoptotic protein caspase-3 and neuronal apoptosis in cortex and striatum was determined by Western blot at 24 h reperfusion and TUNEL staining at 48 h reperfusion in 5 I/R injury groups: no treatment, MMP-9 inhibitor (doxycycline), pre-ischemic exercise, exercised animals undergone ERK1/2 inhibition (U0126), and dual inhibition of ERK1/2 and MMP-9 in exercised ischemic rats. Cerebral MMP-9 expression in ischemic rats with different treatment was determined at 6, 12 and 24 h reperfusion by real-time PCR for mRNA, Western blot for protein and zymography for enzyme activity. Exercise preconditioning significantly (p < 0.05) reduced apoptosis determined by caspase-3 and TUNEL. In non-exercised rats, doxycycline treatment had significant (p < 0.05) reductions in apoptosis after I/R injury. The dual ERK1/2–MMP-9 inhibited exercised animals had significantly (p < 0.05) reduced neuronal apoptosis that was similar to that seen in exercised ischemic rats. MMP-9 expression in I/R injury was significantly (p < 0.05) reduced in the exercised animals as compared to non-exercised controls. When ERK1/2 was inhibited, the reduced MMP-9 expression was reversed to the level seen in the non-exercised controls. This study has suggested that exercise-induced neuroprotection in I/R injury may be mediated by MMP-9 and ERK1/2 expression, leading to a reduction in neuronal apoptosis.     

Impact of laparoscopic surgery on thoracoabdominal mechanics and inspiratory muscular activity

Objective

To evaluate the effect of laparoscopic surgery on pulmonary volume distributions and inspiratory muscles activity. Respiratory consequences associated with postoperative pain were also evaluated.

Methods

This study enrolled 20 patients without lung disease performed spirometry and chest wall kinematic analyses (i.e., chest wall, upper and lower ribcage and abdominal volumes), and measured the activity of inspiratory muscular before and 2 days after laparoscopic surgery. Pain was also assessed.

Results

After laparoscopy, the patients demonstrated decreased volumes in all three thoracoabdominal compartments: abdomen (ABD), upper and lower rib cage (URC and LRC, respectively) compared with the pre-operative measurements: ABD = 0.38 ± 0.20 L vs. 0.55 ± 0.25 L; URC = 0.45 ± 0.18 L vs. 0.55 ± 0.21 L; and LRC = 0.31 ± 0.18 L vs. 0.41 ± 0.23 L; p < 0.05. A reduction in the inspiratory muscular activity after surgery was also observed (sternocleidomastoid: 10.6 ± 5.1 × 10⁻³ mV vs. 12.8 ± 6.3 × 10⁻³ mV; intercostals: 16.8 ± 12.4 × 10⁻³ mV vs. 25.1 ± 21.3 × 10⁻³ mV; p < 0.05). In addition, lower volumes during deep breathing were observed in patients who reported significant pain than those who did not (0.51 ± 0.17 L vs. 0.79 ± 0.29 L; p < 0.05, respectively).

Conclusion

Laparoscopic surgery reduces chest wall ventilation and inspiratory muscular activity during deep breathing. The effects appear to depend on the patient's reported pain level.     

Plasma levels of DJ-1 as a possible marker for progression of sporadic Parkinson's disease

DJ-1 is a multifunctional protein whose loss of function by gene mutations may play a causative role for familial Parkinson's disease (PD). A recent study has shown that the expression of this molecule is upregulated in both brains and cerebrospinal fluids (CSF) in various neurological disorders, including sporadic PD, Alzheimer's disease (AD) and stroke, raising a possibility that DJ-1 could be a potential biomarker for these diseases. In this context, the main objective of the present study was to determine if DJ-1 was increased in the plasma of PD patients. For this purpose, blood plasma samples collected from sporadic PD patients, dementia with Lewy bodies (DLB) and healthy age-matched controls were analyzed by immunoblotting and enzyme-linked immunosorbent assay. The results showed that the plasma DJ-1 levels in PD (n = 104) were higher than those in control (n = 80) (p < 0.05). Moreover, the plasma DJ-1 levels in the advanced stage of PD (n = 52, Yahr III–IV) were higher than those in the early stage of PD (n = 52, Yahr I–II) (p < 0.05), demonstrating that the plasma DJ-1 was correlated with the disease severity in PD. Plasma DJ-1 levels were also significantly higher in DLB (n = 30) compared with both controls and early stage of PD (p < 0.01). Taken together, these results suggest that the plasma DJ-1 could be a useful biomarker for the evaluation of the disease severity in PD and possibly in other Lewy body diseases.     

Mechanism of caspase-3 activation during hypoxia in the cerebral cortex of newborn piglets

We have previously shown that the activity and the expression of caspase-9 and caspase-3 were increased during hypoxia in the cerebral cortex of newborn piglets. The present study was conducted to test the hypothesis that the hypoxia-induced activation of caspase-3 in the cerebral cortex of newborn piglets is mediated by caspase-9. Twenty-two newborn piglets were randomly assigned to four groups: normoxic (Nx), normoxic pretreated with a selective caspase-9 inhibitor, Z-Leu-Glu(OMe)-His-Asp(OMe)-Fluoromethyl ketone (Z-LEHD-FMK) (Nx + LEHD), hypoxic (Hx), and hypoxic pretreated with Z-LEHD-FMK (Hx + LEHD). Cerebral tissue hypoxia was confirmed biochemically by measuring ATP and phosphocreatine. Caspase-9 and -3 activities were determined spectrofluorometrically. The expression of caspase-9 and -3 proteins was measured by Western blot analysis using active enzyme specific antibodies. Cytosolic caspase-9 activity (nmol/mg protein/h) was 3.70 ± 0.40 in Nx, 3.56 ± 0.31 in Nx + LEHD (p = NS versus Nx), 4.99 ± 0.64 in Hx (p < 0.05 versus Nx), and 3.73 ± 0.80 in Hx + LEHD (p < 0.05 versus Hx, p = NS versus Nx). Cytosolic caspase-3 activity (nmol/mg protein/h) was 7.80 ± 1.17 in Nx, 8.15 ± 0.87 in Nx + LEHD (p = NS versus Nx), 13.07 ± 0.78 in Hx (p < 0.05 versus Nx), and 10.05 ± 2.09 in Hx + LEHD (p < 0.05 versus Hx) The density (OD × mm²) of active caspase-9 protein was 18.52 ± 1.89 in Nx, 20.53 ± 1.12 in Nx + LEHD (p = NS versus Nx), 32.36 ± 5.03 in Hx (p < 0.05 versus Nx), and 19.94 ± 3.59 in Hx + LEHD (p < 0.05 versus Hx, p = NS versus Nx). The density (OD × mm²) of active caspase-3 protein was 55.87 ± 8.73 in Nx, 55.69 ± 8.18 in Nx + LEHD (p = NS versus Nx), 94.10 ± 12.05 in Hx (p < 0.05 versus Nx), and 56.12 ± 14.56 in Hx + LEHD (p < 0.05 versus Hx, p = NS versus Nx). These data show that administration of a selective caspase-9 inhibitor, Z-LEHD-FMK, prior to hypoxia prevents the hypoxia-induced increase in caspase-3 activity and the expression of active caspase-3 protein. We conclude that the hypoxia-induced activation of caspase-3 during hypoxia in the cerebral cortex of newborn piglets is mediated by caspase-9.     

Spike-timing-related plasticity is preserved in Parkinson's disease and is enhanced by dopamine: Evidence from transcranial magnetic stimulation

We sought to investigate the effects of dopamine on motor cortical plasticity in Parkinson's disease (PD) using a novel interventional transcranial magnetic stimulation protocol that targets spike-timing-dependent plasticity (iTMS). Six patients (3F, mean age 62 years) with mild-moderate PD (mean disease duration 6 years, UPDRS-off 13, UPDRS-on 3, H&Y stage 2, daily levodopa dosage 450 mg) were studied off and on levodopa on separate days. Paired TMS pulses at resting motor threshold with an inter-stimulus interval of 1.5 ms were given over the hand area of the motor cortex for 20 min at 0.2 Hz. Single-pulse motor evoked potential (MEP) amplitude and visually cued simple reaction time (SRT) were measured before and after iTMS. When on levodopa, MEP amplitude increased to 278 ± 36% of baseline (p < 0.01), and when off levodopa to 157 ± 13% of baseline (p = 0.02). All patients showed a significantly greater increase in MEP amplitude when on levodopa than off levodopa (p = 0.01). SRT was reduced to 95% baseline after iTMS off levodopa (p = 0.02), but did not change on levodopa. These findings indicate that motor cortex plasticity to iTMS is preserved in mild-moderate PD. The effects of this spike-timing-related TMS protocol on cortical excitability were consistent and were enhanced by levodopa. The results support the important role of dopamine in regulating synaptic plasticity and justify a larger crossover study to assess the therapeutic effects of iTMS in PD.     

Plasma orexin A increases at emergence from sevoflurane-fentanyl anesthesia in patients undergoing ophthalmologic surgery

Central orexinergic and noradrenergic neurons are involved in the control of sleep and wakefulness. In addition, previous reports suggest that both neurons may have an important role to play in general anesthesia. In the present study, we have determined whether general anesthesia would affect plasma orexin A (OXA) and norepinephrine concentrations. Twelve patients scheduled for elective ophthalmic surgery under general anesthesia with sevoflurane, fentanyl and vecuronium were studied. Arterial blood was collected before and 1 and 2 h after induction of anesthesia and at emergence to measure plasma OXA, cortisol, norepinephrine and epinephrine concentrations. During anesthesia the inhalational concentration of sevoflurane was changed to maintain the bispectral index between 40 and 50. Plasma OXA, cortisol, norepinephrine and epinephrine did not change during anesthesia but significantly increased after emergence compared to pre-anesthesia (from 14.8 ± 1.7 to 21.4 ± 1.7 pM, p < 0.01, from 26.5 ± 5.2 to 52.8 ± 6.0 pM, p < 0.01, from 263 ± 46 to 513 ± 89 pM, p < 0.01, and from 1239 ± 120 to 1631 ± 203 pM, p < 0.01, respectively). There were significant correlations of plasma OXA with cortisol (r = 0.334, p < 0.05) and epinephrine (r = 0.292, p < 0.05) but not with norepinephrine. In conclusion we found that plasma OXA significantly increased at emergence from sevoflurane-fentanyl anesthesia and this was probably via activation of the hypothalamic-pituitary-adrenal axis.