NAT gene polymorphisms and susceptibility to Alzheimer's disease: identification of a novel NAT1 allelic variant

Background

Clefts of the lip, alveolus, and palate (CLPs) rank among the most frequent and significant congenital malformations. Leu10Pro and Arg25Pro polymorphisms in the precursor region and Thr263Ile polymorphism in the prodomain of the transforming growth factor β1 (TGF-β1) gene have proved to be crucial to predisposition of several disorders.

Methods

In this study, polymorphism analysis was performed by real-time polymerase chain reaction (LightCycler) and TGF-β1 levels determined by enzyme-linked immunosorbent assay.

Results

Only 2/60 Caucasian non-syndromic patients with CLP (3.3%) carried the Arg25Pro and another 2/60 patients (3.3%) the Thr263Ile genotypes, whereas, in a control group of 60 healthy Caucasian blood donors, these heterozygous genotypes were more frequent 16.7% having Arg25Pro (10/60; p < 0.035) and 10,0% having Thr263Ile (6/60), respectively. TGF-β1 levels in platelet-poor plasma of heterozygous Arg25Pro individuals were lower than those of homozygous members (Arg25Arg) in the latter group, but this discrepancy narrowly failed to be significant. Although polymorphisms in codon 10 and 25 were associated with each other, no difference was found between patients and controls concerning the Leu10Pro polymorphism.

Conclusions

The genetic differences in codons 25 and 263 suggest that TGF-β1 could play an important role in occurrence of CLP, however, functional experiments will be required to confirm the mechanisms of disturbed development.     

A prospective study of prenatal and childhood lead exposure and erythropoietin production

We test the hypothesis that chronic lead (Pb) exposure may be associated with an inability to maintain an adequate serum erythropoietin (EPO) concentration. From a longitudinal study of Pb exposure and infant and childhood development, we measured blood Pb (BPb) and serum EPO concentrations serially at ages 4.5, 6.5, 9.5, and 12 and tibia (cortical) Pb concentration at age 12. Pb-exposed children aged 4.5 and 6.5 produced increased concentrations of EPO to maintain normal Hgb concentrations. EPO production declined between ages 4.5 and 6.5. At ages 9.5 and 12, further diminution of the association was found. No association was found between tibia Pb and EPO. The continued decline in the slope of the relationship between EPO and BPb with age, after adjustment for hemoglobin, implies a gradually decreasing capacity to produce EPO.     

Reduced full-field electroretinogram (ERG) in a patient treated with methotrexate

PURPOSE: To examine retinal function in a patient with decreased vision possibly due to treatment with methotrexate. METHODS: Ophthalmological examination included testing of visual acuity (VA), fundus inspection, fundus photography, and kinetic perimetry. Retinal function was tested objectively with three electrophysiological methods: full-field electroretinography (ERG), multifocal electroretinography (mfERg) and also electro-oculography (EOG). RESULTS: A 13-year-old boy with psoriasis arthritis had been treated with methotrexate on a weekly basis for 8.5 years. After terminating treatment, his VA, which was reduced to 0.3 in both eyes initially, improved during the following 3 years but did not return to normal. No visual field defects were found with kinetic perimetry. The rod and cone responses in the full-field ERG were markedly reduced in b-wave amplitude initially, but grew slowly to nearly normal values 3 years later. After withdrawal of the drug, the mfERG demonstrated normal responses in the macular region. The Arden index in the EOG was normal. CONCLUSION: Chronic treatment with methotrexate may affect VA, and mat reversible reduce rod and cone function. In patients who use systemic medication and who vision is reduced, objective evaluation of retinal function with electrophysiological methods is recommended.     

Full-field ERG, multifocal ERG and multifocal VEP in patients with retinitis pigmentosa and residual central visual fields

PURPOSE: To evaluate (with three different electrophysiological methods) the residual retinal function in a selected group of patients with retinitis pigmentosa and remaining small central visual fields. METHODS: Fourteen patients from several different genetic subgroups, who had been followed with visual acuity and visual field testing for periods up to 32 years, were examined. Ophthalmological examination included full-field electroretinography (ERG), multifocal electroretinography (mfERG) and multifocal visual evoked potential (mfVEP). RESULTS: The ERGs were severely reduced in all patients. The mfERGs demonstrated the residual central retinal function in five of the patients. The mfVEPs showed measurable amplitudes centrally in most of the patients. The follow-up examinations demonstrated the slowly progressive course of the disease with preservation or only slight further loss of visual fields over a period of 7-32 years. CONCLUSION: Patients with retinitis pigmentosa may not always follow the typical natural course with progressive loss of visual fields, which may in some patients remain unaffected over several decades. Multifocal ERG and mfVEP may be clinically useful for evaluating remaining visual function in these patients.     

Doxorubicine-congestive heart failure-increased big endothelin-1 plasma concentration: reversal by amlodipine, losartan, and gastric pentadecapeptide BPC157 in rat and mouse

Overall, doxorubicine-congestive heart failure (CHF) (male Wistar rats and NMRI mice; 6 challenges with doxorubicine (2.5 mg/kg, i.p.) throughout 15 days and then a 4-week-rest period) is consistently deteriorating throughout next 14 days, if not reversed or ameliorated by therapy (/kg per day): a stable gastric pentadecapeptide BPC157 (GEPPPGKPADDAGLV, MW 1419, promisingly studied for inflammatory bowel disease (Pliva; PL 10, PLD-116, PL 14736)) (10 microg, 10 ng), losartan (0.7 mg), amlodipine (0.07 mg), given intragastrically (i.g.) (once daily, rats) or in drinking water (mice). Assessed were big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT) before and after 14 days of therapy and clinical status (hypotension, increased heart rate and respiratory rate, and ascites) every 2 days. Controls (distilled water (5 ml/kg, i.g., once daily) or drinking water (2 ml/mouse per day) given throughout 14 days) exhibited additionally increased BET-1 and aggravated clinical status, while enzyme values maintained their initial increase. BPC157 (10 microg/kg) and amlodipine treatment reversed the increased BET-1 (rats, mice), AST, ALT, CK (rats, mice), and LDH (mice) values. BPC157 (10 ng/kg) and losartan opposed further increase of BET-1 (rats, mice). Losartan reduces AST, ALT, CK, and LDH serum values. BPC157 (10 ng/kg) reduces AST and ALT serum values. Clinical status of CHF-rats and -mice is accordingly improved by the BPC157 regimens and amlodipine.     

CD95/Fas expression on peripheral blood T lymphocytes in patients with multiple sclerosis: effect of high-dose methylprednisolone therapy

Recent data indicate that the apoptotic process, mediated by the CD95/Fas cell surface receptor, is impaired in activated lymphocytes of patients with relapsing-remitting multiple sclerosis. Using flow cytometric-immunophenotyping, we analyzed the expression of CD95/Fas on peripheral blood CD4+ and CD8+ T lymphocytes (PBL) in 10 MS patients in relapse, and the effect of pulse corticosteroid therapy on the apoptosis of autoreactive lymphocytes. The proportions of CD8+ and CD8+CD95+ T lymphocytes were significantly higher in MS patients in relapse before than after pulse corticosteroid therapy. Conversely, the proportions of CD4+ and CD4+CD95+ T cells were significantly lower before than after therapy, but not significantly different from healthy persons. The different expression of CD95/Fas on peripheral blood CD8+ T lymphocytes in relapsing RRMS and in healthy controls suggests a possible involvement of apoptosis in the pathogenesis of MS. Our results also show that pulse corticosteroid therapy influences the CD95/Fas expression on CD8+ and CD4+ T lymphocytes in patients with RRMS.     

Hypertensive encephalopathy mimicking brainstem tumour in psychiatric patient

Hypertensive encephalopathy is a syndrome consisting of headache, seizures, visual changes, and other neurologic disturbances in patients with elevated systemic blood pressure. Diagnosis based on clinical and radiological findings, which are not specific, may be difficult to establish. Furthermore, hypertensive encephalopathy may develop gradually even when blood pressure is lower than that of malignant hypertension. We present clinical, magnetic resonance imaging (MRI) and autopsy findings in a 43-year-old schizophrenic patient with unrecognised hypertensive encephalopathy, which was misinterpreted by MRI as a diffusely growing brain stem tumour. Increased blood pressure was recorded several times, but it was not properly controlled and treated either during his out-door psychiatric examinations or hospitalisation. At autopsy, generalised atherosclerosis, concentric hypertrophy of the left ventricle and arteriolonephrosclerosis were found in addition to microvascular fibrinoid necroses and thromboses in the brain and kidneys, which were almost certainly caused by arterial hypertension evolving from benign into malignant stage. We discuss the differential diagnosis and give a review of the literature.     

Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis

BACKGROUND: Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death. HYPOTHESIS: If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder. OBJECTIVE: To investigate the regional selectivity of dopamine terminal loss during the progression of PD. PARTICIPANTS: We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ). RESULTS: Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P<.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P<.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen. CONCLUSION: To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.     

N-methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: oxidative stress after acute and chronic administration

BACKGROUND: The underlying mechanisms of N-methyl-3,4-methylenedioxyamphetamine--MDMA--induced hepatotoxicity are still unknown. The aim of this study was to evaluate hepatic oxido-reductive status in the rats liver after the single and repeated administration of MDMA. METHODS: MDMA was dissolved in distilled water and administered in the doses of 5 mg, 10 mg, 20 mg, and 40 mg/kg. The animals from the acute experiment were treated per os with the single dose of the appropriate solution, through the orogastric tube. The animals from the chronic experiment were treated per os, with the doses of 5, 10, or 20 mg/kg of MDMA every day during 14 days. The control groups were treated with water only. Eight hours after the last dose, the animals were sacrificed, dissected, their livers were rapidly removed, frozen and stored at -70 degrees C until the moment of analysis. The parameters of oxidative stress in the crude mitochondrial fractions of the livers were analyzed. RESULTS: Superoxide dismutase (SOD) activity increased in the livers of the animals that were treated with single doses of MDMA. Chronically treated animals showed the increased SOD activity only after the highest dose (20 mg/kg). The content of reduced glutathione decreased in both groups, but the depletion was much more expressed after the single administration. Lipid peroxidation index increased in dose-dependent manner in both groups, being much higher after the single administration. CONCLUSION: The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.     

Alterations in electroretinograms and retinal morphology in rabbits treated with vigabatrin

PURPOSE: To determine whether long-term treatment with the anti-epileptic drug vigabatrin causes damage to rabbit retina. METHODS: Five rabbits were treated continuously with a daily dose of vigabatrin solution per orally during a period of 1-8 months. Two rabbits receiving water were used as controls. Repeated full-field electroretinograms (every two weeks) were assessed during this period. Vigabatrin serum concentration was repeatedly measured for securing successful drug administration. After termination of treatment the rabbits were sacrificed and the morphology of the sectioned retina was studied. RESULTS: In all rabbits treated with vigabatrin the serum analyses repeatedly demonstrated elevated drug concentration. Full-field electroretinograms demonstrated normal rod function in all treated rabbits, but reduced cone function in two of the five treated rabbits verified by 30Hz flicker stimulation. Morphologic studies of the sectioned retina demonstrated GFAP immunoactivity of the glial cells localized in the retinal periphery in all five treated rabbits, one of which had staining also in the centrally localized glial cells. The treated rabbits also demonstrated a weaker GAD staining in the IPL and less positive amacrine cells, compared to the controls. Only two treated rabbits had normal GABA staining while three had an enhanced GABA immunoreactivity and undistinguishable fibers in the IPL. In three out of five treated rabbits the Müller cells were short, stubby and fragmented, with swollen endfeet. CONCLUSION: This study demonstrates changes in histopathology caused by vigabatrin in an animal model, which has not been reported previously. We have found that vigabatrin orally administrated to rabbits does not affect rod function but may reduce cone function in the full-field electroretinogram, which is similar to the previously reported vigabatrin effect on the human ERG. The results indicate that vigabatrin may damage or influence, at least one cell type in the rabbit retina.