The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway

We studied the ability of the vigilance-promoting drug modafinil to modulate the anterograde and retrograde changes in tyrosine hydroxylase (TH) immunoreactivity and in dopamine (DA) stores in the nigro-neostriatal DA neurons, following a partial hemitransection of this ascending DA system, using a combined morphometrical, biochemical and behavioural analysis. Modafinil was given daily i.p. in doses of 10–100 mg/kg, starting 15 min after the lesion, and the partially hemitransected rats were killed 2 weeks later. Changes in TH-immunoreactive nerve cell bodies and nerve terminals induced by the partial hemitransection were studied in the substantia nigra and neostriatum in combination with image analysis. The substantia nigra and neostriatum were also subjected to biochemical analysis of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels. Modafinil treatment dose-dependently (10–100 mg/kg) counteracted the hemitransection-induced disappearance of nigral TH-immunoreactive nerve cell body profiles and neostriatal TH-immunoreactive nerve terminal profiles. A 2-week treatment with 100 mg/kg of modafinil also counteracted the hemitransection-induced depletion of DA stores in the neostriatum and the ventral midbrain. Moreover, the repeated daily treatment with modafinil (100 mg/kg) protected against the hemitransection-induced disappearance of striatal 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and noradrenaline levels. Striatal DA function was analysed by studying apomorphine-induced (1 mg/kg, s.c.) ipsilateral rotational behaviour 4 and 11 days after the operation. A marked dose-dependent reduction of ipsilateral rotational behaviour was demonstrated after the daily modafinil treatment in the partially hemitransected rats. In another model involving unilateral nigral microinjections of 6-hydroxydopamine, acute (one single dose) modafinil (100 mg/kg) did not affect the contralateral rotational behaviour induced by apomorphine (0.05 mg/kg s.c.), when given 30 min before the apomorphine. Taken together, morphological, neurochemical and behavioural evidence has been obtained that anterograde and retrograde changes induced in the DA stores and TH immunoreactivity of the nigro-neostriatal DA neurons by a partial hemitransection are counteracted by modafinil in a dose dependent way with 100 mg/kg producing a significant protective action against impairment of DA transmission. The results of this study open up the possibility that modafinil may protect against the anterograde and retrograde degeneration of nigrostriatal DA neurons seen after mechanically induced injury.     

Eosinophil associated genes in the inflammatory bowel disease 4 region: Correlation to inflammatory bowel disease revealed

AIM: To study the association between inflammatory bowel disease (IBD) and genetic variations in eosinophil protein X (EPX) and eosinophil cationic protein (ECP).METHODS: DNA was extracted from ethylene diamine tetraacetic acid blood of 587 patients with Crohn’s disease (CD), 592 with ulcerative colitis (UC) and 300 healthy subjects. The EPX405 (G > C, rs2013109), ECP434 (G > C, rs2073342) and ECP562 (G > C, rs2233860) gene polymorphisms were analysed, by the 5’-nuclease allelic discrimination assay. For determination of intracellular content of EPX and ECP in granulocytes, 39 blood samples was collected and extracted with a buffer containing cetyltrimethylammonium bromide. The intracellular content of EPX was analysed using an enzyme-linked immunosorbent assay. The intracellular content of ECP was analysed with the UniCAP^® system as described by the manufacturer. Statistical tests for calculations of results were χ² test, Fisher’s exact test, ANOVA, Student-Newman-Keuls test, and Kaplan-Meier survival curve with Log-rank test for trend, the probability values of P < 0.05 were considered statistically significant.RESULTS: The genotype frequency for males with UC and with an age of disease onset of ≥ 45 years (n = 57) was for ECP434 and ECP562, GG = 37%, GC = 60%, CC = 4% and GG = 51%, GC = 49%, CC = 0% respectively. This was significantly different from the healthy subject’s genotype frequencies of ECP434 (GG = 57%, GC = 38%, CC = 5%; P = 0.010) and ECP562 (GG = 68%, GC = 29%,CC = 3%; P = 0.009). The genotype frequencies for females, with an age of disease onset of ≥ 45 years with CD (n = 62), was for the ECP434 and ECP562 genotypes GG = 37%, GC = 52%, CC = 11% and GG = 48%, GC = 47% and CC = 5% respectively. This was also statistically different from healthy controls for both ECP434 (P = 0.010) and ECP562 (P = 0.013). The intracellular protein concentration of EPX and ECP was calculated in μg/10⁶ eosinophils and then correlated to the EPX 405 genotypes. The protein content of EPX was highest in the patients with the CC genotype of EPX405 (GG = 4.65, GC = 5.93, and CC = 6.57) and for ECP in the patients with the GG genotype of EPX405 (GG = 2.70, GC = 2.47 and CC = 1.90). ANOVA test demonstrated a difference in intracellular protein content for EPX (P = 0.009) and ECP (P = 0.022). The age of disease onset was linked to haplotypes of the EPX405, ECP434 and ECP562 genotypes. Kaplan Maier curve showed a difference between haplotype distributions for the females with CD (P = 0.003). The highest age of disease onset was seen in females with the EPX405CC, ECP434GC, ECP562CC haplotype (34 years) and the lowest in females with the EPX405GC, ECP434GC, ECP562GG haplotype (21 years). For males with UC there was also a difference between the highest and lowest age of the disease onset (EPX405CC, ECP434CC, ECP562CC, mean 24 years vs EPX405GC, ECP434GC, ECP562GG, mean 34 years, P = 0.0009). The relative risk for UC patients with ECP434 or ECP562-GC/CC genotypes to develop dysplasia/cancer was 2.5 (95%CI: 1.2-5.4, P = 0.01) and 2.5 (95%CI: 1.1-5.4, P = 0.02) respectively, compared to patients carrying the GG-genotypes.CONCLUSION: Polymorphisms of EPX and ECP are associated to IBD in an age and gender dependent manner, suggesting an essential role of eosinophils in the pathophysiology of IBD.     

Sequelae of chorioamnionitis

Chorioamnionitis correlates to preterm delivery prior to 30 weeks of gestation. In most studies, proxies of intrauterine infection (clinical chorioamnionitis, histological chorioamnionitis, intra-amniotic increase in cytokines) are associated with acute neonatal morbidity and mortality and, at least to some degree, with neurological impairments (periventricular leukomalacia, intraventricular hemorrhage, cerebral palsy, polymicrogyria), chronic lung disease, and involution of the thymus in the preterm infant. The connection to visual impairment and cognitive deficits is uncertain or unknown. Full-term babies exposed to intrauterine infection often present with depressed Apgar scores and neonatal encephalopathy, and are at markedly increased risk of developing cerebral palsy. The infectious/inflammatory mechanisms involved are incompletely understood, and the types of microbes, as well as the genetic characteristics of the host adaptive and innate immune response, need to be better characterized.     

Insufficient fluid and energy intake in hospitalised patients with hip fracture. A prospective randomised study of 80 patients

AIMS: Evaluate nutritional status and fluid and energy intake during the first ten days of hospitalisation in a selection of otherwise healthy patients with a hip fracture. METHODS: A prospective randomised controlled study of 80 patients. Nutritional status was assessed at inclusion. The energy and fluid intake was recorded and calculated daily whilst hospitalised. All patients were given ordinary hospital food and beverage. In the treatment group (n = 40) patients also received intraveneous supplementary nutrition (1000 kcal/day) for three days followed by oral supplementary nutrition (400 kcal/day) for seven days or until discharge. RESULTS: One third of patients were classified as malnourished in both groups. The average daily fluid intake/patient was 1300 ml in the control group compared to 1856 ml in the treatment group (P<0.0001). The average daily energy intake/patient was 916 kcal in the control group compared to 1296 kcal in the treatment group (P = 0.003). The mean difference between actual and needed daily fluid intake was -739 ml in the control group and +27 ml in the treatment group (P<0.0001). Corresponding numbers for energy intake was -783 kcal/day in the control group and -228 kcal/day in the treatment group (P = 0.0003). CONCLUSIONS: Malnutrition is common even in a selection of healthy patients with hip fractures. During hospital stay the fluid and energy intake was considerably lower than that needed in the control group. Supplementary nutritional intake for ten days increased the total fluid and energy intake in the treatment group to near needed levels.     

Interleukin-6 and interleukin-8 in cervical fluid in a population of Swedish women in preterm labor: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm delivery

BACKGROUND: Intrauterine infection and inflammation in women with preterm labor are related to adverse perinatal outcome. Due to its subclinical nature, a correct diagnosis depends on retrieval of amniotic fluid. Amniocentesis is, however, not performed as a clinical routine because of its invasiveness. Hypothetically, cytokines in the cervical fluid may represent an alternative diagnostic approach. The aim was to examine cervical interleukin (IL)-6 and IL-8 in relation to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm birth in women in preterm labor. METHODS: Women with singleton pregnancies in preterm labor (<34 weeks of gestation) and intact membranes were included. Cervical (n = 91) and amniotic fluids (n = 56) were collected. Polymerase chain reaction for Ureaplasma urealyticum and Mycoplasma hominis and culture for aerobic and anaerobic bacteria were performed. IL-6 and IL-8 were analyzed with enzyme-linked immunosorbent assay. RESULTS: Non-lactobacillus-dominated biota was detected in cervical secretion in 25% (22/89) and the presence of micro-organisms in the amniotic fluid in 16% (9/56) of the patients. The presence of U. urealyticum in the cervical fluid (21/46) was associated with significantly higher levels of IL-6 in the secretion. IL-6 and IL-8 were significantly higher in cervical fluid of women with intra-amniotic infection and inflammation and in women who delivered < or =7 days and/or before 34 weeks of gestation. Cervical IL-6 > or = 1.7 ng/ml was related to intra-amniotic inflammation (relative risk: 2.67; range: 1.50-4.74) and had a sensitivity, specificity, positive predictive value, and negative predictive value of 58, 83, 75, and 69%, respectively, in the identification of intra-amniotic inflammation. Similar data were obtained for IL-8 > or = 6.7 ng/ml. CONCLUSIONS: High levels of cervical IL-6 and IL-8 are moderately predictive of intrauterine infection/inflammation and preterm delivery.     

The dioxin-like pollutant PCB 126 (3,3',4,4',5-pentachlorobiphenyl) affects risk factors for cardiovascular disease in female rats

Epidemiological studies suggest that exposure to persistent organic pollutants such as organochlorines might induce cardiovascular disorders and diabetes. Some of these organochlorines, such as dioxins and some dioxin-like PCBs, have been characterised as anti-estrogenic due to their inhibition of estrogenic-induced responses. In the present pilot study, 40 female rats were subjected to either exposure to the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) or vehicle, as well as ovariectomy (OVX) or sham operation in a 2×2 factorial design over 12 weeks to explore potential interactions between estrogen status and PCB 126 exposure on cardiovascular risk factors.

PCB 126 increased heart weight and serum cholesterol levels in both groups. PCB 126 increased blood pressure in the sham-operated animals only.

In conclusion, PCB 126 exposure in female rats resulted in effects on cardiovascular risk factors, such as serum cholesterol, blood pressure, and heart weight. Of these effects of PCB 126, the increase in blood pressure was dependent on estrogen status.     

Expression of cytokines and chemokines in cervical and amniotic fluid: relationship to histological chorioamnionitis.

OBJECTIVE: To correlate cervical and amniotic fluid cytokines and macrophage-related chemokines to the development of histological chorioamnionitis (HCA) in patients with preterm labor (PTL) and preterm prelabor rupture of the membranes (PPROM). STUDY DESIGN: Cervical and amniotic fluid interleukin (IL)-6, IL-8, IL-18, monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 from pregnant women (at 相似文献   

Reliability of gait performance tests in men and women with hemiparesis after stroke.

OBJECTIVE: To assess the reliability of 6 gait performance tests in individuals with chronic mild to moderate post-stroke hemiparesis. Design: An intra-rater (between occasions) test-retest reliability study. Subjects: Fifty men and women (mean age 58+/-6.4 years) 6-46 months post-stroke. METHODS: The Timed "Up & Go" test, the Comfortable and the Fast Gait Speed tests, the Stair Climbing ascend and descend tests and the 6-Minute Walk test were assessed 7 days apart. Reliability was evaluated with the intraclass correlation coefficient (ICC(2,1)), the Bland & Altman analysis, the standard error of measurement (SEM and SEM%) and the smallest real difference (SRD and SRD%). RESULTS: Test-retest agreements were high (ICC(2,1) 0.94-0.99) with no discernible systematic differences between the tests. The standard error of measurement (SEM%), representing the smallest change that indicates a real (clinical) improvement for a group of individuals, was small (< 9%). The smallest real difference (SRD%), representing the smallest change that indicates a real (clinical) improvement for a single individual, was also small (13-23%). CONCLUSION: These commonly used gait performance tests are highly reliable and can be recommended to evaluate improvements in various aspects of gait performance in individuals with chronic mild to moderate hemiparesis after stroke.     

Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years

This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p<0.01), while baseline Abeta(1-42) levels were lower (p<0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p<0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.