Familial aggregation of parkinsonism in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Distinct genetic forms of frontotemporal dementia.

BACKGROUND: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. METHODS: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. RESULTS: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. CONCLUSION: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease.

Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology.

Frontotemporal dementia and parkinsonism linked to chromosome 17 have been associated with mutations in the microtubule associated protein tau (MAPT or tau) gene. This disorder is characterized by a large spectrum of neuronal and glial tau lesions in different brain regions. Pick bodies were found in a family with hereditary Pick's disease with the G272V mutation and in several families with other tau mutations in exons 9 and 11-13. The biochemical composition of Pick bodies varies between these mutations. Until recently, no detailed biochemical characterization of G272V brain material was done owing to unavailability of fresh frozen brain material. We now report a detailed study using the immunohistochemistry, western blots and electron microscopy of two brains with the G272V mutation that recently became available. Both brains showed severe neuronal loss in the temporal cortex, whereas in the frontal cortex the loss was less; and abundant Pick bodies in the dentate gyrus of the hippocampus, and caudate nucleus. The Pick bodies consisted exclusively of three-repeat (3R) isoforms, as was demonstrated by isoform-specific antibodies and supported by western blot analysis of sarkosyl-insoluble tau. These observations confirm that this family diagnosed with hereditary Pick disease meets all the criteria for this condition, including the presence of Pick bodies that are unphosphorylated at Ser262 and contain twisted filaments with long periodicity consisting only of 3R tau.

Iron(II)-catalyzed enhancement of ultrasonic-induced degradation of diethylstilbestrol (DES).

The oxidation of the endocrine disruptor, diethylstilbestrol (DES) in aqueous media by ultrasound is significantly enhanced by Fe(II) catalyst. The observed enhancement is likely the result of increased levels of hydroxyl radicals from the iron-promoted reduction of the hydrogen peroxide produced during ultrasonic irradiation. The degradation is effective over a range of concentrations and is consistent with pseudo first-order kinetics. Relatively high concentrations of hydrogen peroxide, ~450 mM, are present in solution under our experimental conditions after 1 h of ultrasonic irradiation (665 kHz). The concentration of H2O2 in solution decreased with the addition of Fe(II) along with an increase in the degradation of DES. Hydrogen peroxide alone does not appreciably degrade DES. Our results demonstrate ultrasonic-induced degradation of DES can be accelerated with the addition of Fe(II). The combination of ultrasonic irradiation and Fe(II)-promoted conversion of H2O2 to hydroxyl radical may provide a valuable strategy for the treatment of organic pollutants.

Removal of atrazine and four organophosphorus pesticides from environmental waters by diatomaceous earth-remediation method.

A new viable remediation technique based on the use of diatomaceous earth is proposed to improve the ecological system. Its ability to remove atrazine and the four organophosphorus pesticides parathion-methyl, chlorpyriphos, fenamiphos and methidathion from river and waste waters has been proven. A series of experiments including variable conditions, such as temperature, pH, contact time, pesticide concentration and adsorbent quantity, were performed to demonstrate the efficiency of pesticide removal from three different water samples. The batch experiments showed that diatomaceous earth was able to remove 95% of chlorpyriphos, 75% of methidathion and parathion-methyl and 55% of atrazine and fenamiphos from all types of waters tested. The individual adsorption of each pesticide on diatomaceous earth could be described by the Freundlich isotherm and a tentative adsorption mechanism was proposed. The Freundlich coefficient (Kf) and Freundlich constant (1/n) appeared to be closely related to the physicochemical properties (Kow, solubility) of the compounds. The actual results support the conclusion that diatomaceous earth has the potential to serve as an extractant in remediation techniques.

All-L-Leu-Pro-Leu-Pro: a challenging cyclization.

In this paper, we report the difficult synthesis of cyclo(Leu-Pro-Leu-Pro). While the cyclization of Leu-Pro-Leu-D-Pro did not cause problems, the all-L-peptide afforded cyclodimer rather than cyclotetrapeptide (cyclomonomer). A first attempt using our reversible backbone substitution methodology failed. However, we were successful in obtaining the desired cyclo(Leu-Pro-Leu-Pro) by decreasing the concentration. The ratio of cyclomonomer to cyclodimer was raised to 1:1.1 using BOP and 1:0.6 using HATU under our high dilution condition. The structures of the cyclopeptides were confidently assigned by electrospray ionization mass spectrometry and NMR.