The effect of peri-operative dexmedetomidine on the incidence of postoperative delirium in cardiac and non-cardiac surgical patients: a randomised, double-blind placebo-controlled trial.

Delirium occurs commonly following major non-cardiac and cardiac surgery and is associated with: postoperative mortality; postoperative neurocognitive dysfunction; increased length of hospital stay; and major postoperative complications and morbidity. The aim of this study was to investigate the effect of peri-operative administration of dexmedetomidine on the incidence of postoperative delirium in non-cardiac and cardiac surgical patients. In this randomised, double-blind placebo-controlled trial we included 63 patients aged ≥ 60 years undergoing major open abdominal surgery or coronary artery bypass graft surgery with cardiopulmonary bypass. The primary outcome was the incidence of postoperative delirium, as screened for with the Confusion Assessment Method. Delirium assessment was performed twice daily until postoperative day 5, at the time of discharge from hospital or until postoperative day 14. We found that dexmedetomidine was associated with a reduced incidence of postoperative delirium within the first 5 postoperative days, 43.8% vs. 17.9%, p = 0.038. Severity of delirium, screened with the Intensive Care Delirium Screening Checklist, was comparable in both groups, with a mean maximum score of 1.54 vs. 1.68, p = 0.767. No patients in the dexmedetomidine group died while five (15.6%) patients in the placebo group died, p = 0.029. For patients aged ≥ 60 years undergoing major cardiac or non-cardiac surgery, we conclude that the peri-operative administration of dexmedetomidine is associated with a lower incidence of postoperative delirium.

[18F]-florbetaben PET/CT Imaging in the Alzheimer's Disease Mouse Model APPswe/PS1dE9.

BACKGROUND: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aß), a pathological hallmark of Alzheimer's disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aß plaques. METHODS: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aß plaque load in cortex, hippocampus and cerebellum were analyzed. RESULTS: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. CONCLUSION: The findings suggest that histopathological characteristics of Aß plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

External radiation exposure, excretion, and effective half-life in 177Lu-PSMA-targeted therapies.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted therapy with 177Lu-PSMA-617 is a therapeutic option for patients with metastatic castration-resistant prostate cancer (mCRPC). To optimize the therapy procedure, it is necessary to determine relevant parameters to define radiation protection and safety necessities. Therefore, this study aimed at estimating the ambient radiation exposure received by the patient. Moreover, the excreted activity was quantified. RESULTS: In total, 50 patients with mCRPC and treated with 177Lu-PSMA-617 (mean administered activity 6.3 ± 0.5 GBq) were retrospectively included in a bi-centric study. Whole-body dose rates were measured at a distance of 2 m at various time points after application of 177Lu-PSMA-617, and effective half-lives for different time points were calculated and compared. Radiation exposure to the public was approximated using the dose integral. For the estimation of the excreted activity, whole body measurements of 25 patients were performed at 7 time points. Unbound 177Lu-PSMA-617 was rapidly cleared from the body. After 4 h, approximately 50% and, after 12 h, approximately 70% of the administered activity were excreted, primarily via urine. The mean dose rates were the following: 3.6 ± 0.7 µSv/h at 2 h p. i., 1.6 ± 0.6 µSv/h at 24 h, 1.1 ± 0.5 µSv/h at 48 h, and 0.7 ± 0.4 µSv/h at 72 h. The mean effective half-life of the cohort was 40.5 ± 9.6 h (min 21.7 h; max 85.7 h). The maximum dose to individual members of the public per treatment cycle was ~ 250 ± 55 µSv when the patient was discharged from the clinic after 48 h and ~ 190 ± 36 µSv when the patient was discharged after 72 h. CONCLUSIONS: In terms of the radiation exposure to the public, 177Lu-PSMA is a safe option of radionuclide therapy. As usually four (sometimes more) cycles of the therapy are performed, it must be conducted in a way that ensures that applicable legal requirements can be followed. In other words, the radiation exposure to the public and the concentration of activity in wastewater must be sub-marginal. Therefore, in certain countries, hospitalization of these patients is mandatory.

Role of choline PET/CT in guiding target volume delineation for irradiation of prostate cancer.

Choline PET/CT has shown limitations for the detection of primary prostate cancer and nodal metastatic disease, mainly due to limited sensitivity and specificity. Conversely in the restaging of prostate cancer recurrence, choline PET/CT is a promising imaging modality for the detection of local regional and nodal recurrence with an impact on therapy management. This review highlights current literature on choline PET/CT for radiation treatment planning in primary and recurrent prostate cancer. Due to limited sensitivity and specificity in differentiating between benign and malignant prostatic tissues in primary prostate cancer, there is little enthusiasm for target volume delineation based on choline PET/CT. Irradiation planning for the treatment of single lymph node metastases on the basis of choline PET/CT is controversial due to its limited lesion-based sensitivity in primary nodal staging. In high-risk prostate cancer, choline PET/CT might diagnose lymph node metastases, which potentially can be included in the conventional irradiation field. Prior to radiation treatment of recurrent prostate cancer, choline PET/CT may prove useful for patient stratification by excluding distant disease which would require systemic therapy. In patients with local recurrence, choline PET/CT can be used to delineate local sites of recurrence within the prostatic resection bed allowing a boost to PET-positive sites. In patients with lymph node metastases outside the prostatic fossa and regional metastatic lymph nodes, choline PET/CT might influence radiation treatment planning by enabling extension of the target volume to lymphatic drainage sites with or without a boost to PET-positive lymph nodes. Further clinical randomized trials are required to assess treatment outcomes following choline-based biological radiation treatment planning in comparison with conventional radiation treatment planning.

Assessing prostate cancer growth with citrate measured by intact tissue proton magnetic resonance spectroscopy.

BACKGROUND: Annual PSA tests have led to a significant increase in the number of prostate cancer (PCa) cases diagnosed. This increased incidence has led to overtreatment of many patients, as current pathology often cannot distinguish latent from aggressive PCa. Studies have shown that the depletion of zinc in prostate cells correlated with cell-line growth rates, and may therefore relate to the progression of PCa. Furthermore, as zinc is normally an inhibitor of citrate oxidation, the reduction of zinc in PCa may cause a decrease in citrate secretion levels in the glandular epithelia of PCa patients. METHODS: Using high-resolution magic angle spinning proton magnetic resonance spectroscopy followed by quantitative histopathology, we investigate unit histo-benign prostate epithelial citrate concentrations in intact tissue samples obtained from 18 patients with pre-surgical PSA values less than 20 ng/ml. Using these data, we evaluate correlations between citrate concentrations and PSA velocities, densities and blood percent-free PSA. RESULTS: We observe different linear patterns between citrate concentrations and histo-benign glandular epithelia from patients of different PSA velocities. More importantly, we obtain a significant correlation between PSA velocity, density and percent-free PSA, and citrate concentrations in unit volume of histo-benign epithelial glands of the peripheral zone. CONCLUSIONS: Low levels of citrate in unit volume represent rapidly increasing PSA values, and, therefore, may be used as an indicator of fast-growing PCa. Thus, tissue samples obtained at the time of biopsy may be evaluated for their citrate concentrations for the prediction of PCa growth rates, allowing for the implementation of alternative treatment options and reducing overtreatment.

Qualitative and quantitative differences of cytoskeleton proteins in embryos produced in vitro, in vivo, and by somatic nuclear transfer.

The cytoskeleton, consisting of complex and dynamic systems of structural filaments, intermediate filaments and microtubules, is not only a structural element but also contributes to many cellular processes such as functional compartments, transportation, mitosis, secretion, formation of cell extensions, and intercellular communication. Suggestions in rat 2-cell embryos that abnormal distributions of cytoskeletal proteins occurred following the initiations of developmental arrest and our former studies showing reduced intercellular contact zones in cloned bovine embryos prompted us to conduct comparative studies on 8-cell stage bovine embryos from nuclear transfer (NT), in vitro, and in vivo production. Immunohistochemistry and Laser-Scanning-Microscopy facilitated detection of cytoskeleton proteins--alpha-tubulin, F-actin, beta-catenin, and the cell adhesion protein cadherin; image and cluster analysis were subsequently used to study the distribution pattern of the proteins, whereas Western blot was carried out for their qualitative and quantitative analysis. The maximum fluorescence intensity of stained alpha-tubulin was observed in the cloned and the in vitro embryos. A significant higher intensity of staining for F-actin was observed in the in vivo and in vitro embryos. In contrast, Western blot revealed no differences of actin, tubulin, and catenin between the three tested groups whereas a lower abundance of cadherin proteins in the cloned embryos was visible. The distribution of actin filaments in cloned embryos was more centric or one-sided and not peripheral whereas the stained spots of catenin were smaller in comparison to in vivo or in vitro produced embryos. These differences recorded in the distribution patterns may be associated with cell physiological processes related to an influenced actin-catenin-cadherin system. In conclusion, reduced intercellular contacts coupled with abnormal distribution of cytoskeletal proteins seem to play an important role in the developmental arrest encountered normally at the 8-cell stage in bovine cloned embryos.

Measurement of redox potential and steroid concentrations in the follicular fluid of growing and regressing follicles of mares.

The aim of this study was to prove if oxidation-reduction levels in the follicular fluid were new functional indices of follicular health and whether there was a high level of accordance with endocrinological parameters and with the growth stage as detected by ultrasound monitoring of individual follicles during the oestrous cycle in mares. Follicles were classified as growing and regressing follicles using ultrasonography. Altogether 48 follicles with a diameter from 20 to 56 mm were aspirated by transvaginal ultrasound guided follicular aspiration. Follicular concentration of oestradiol and progesterone in relation to the diameter of growing follicles showed correlations of r = 0.64 and r = 0.57, respectively. The redox potential derived index D2 varied from -448 to +431 in the collected fluids of the follicles. The accordance of the judgement of all follicles using both complexes of methods - endocrinological and ultrasonographic parameters vs. analysis of oxidation and reduction levels - reached 72.5%. This finding has shown that parameters of redox reactions do not correlate closely with the stage of follicular growth or regression as determined by in vivo scanning of ovaries or by assessment of follicular steroid concentrations. However, the measurement of redox potentials offers an opportunity to examine the whole process of metabolism in follicular cells and to forecast impairments of cellular performances. Changes of redox parameters in growing follicles enable an earlier prediction of their further development. The data demonstrate that growing and regressing follicles do not represent nonatretic, early atretic and atretic follicles, respectively.

Open gingival embrasures after orthodontic treatment in adults: prevalence and etiology.

The purposes of this study were to determine the prevalence of posttreatment open gingival embrasures in adult orthodontic patients and to examine the association of pretreatment maxillary incisor malalignment, posttreatment alveolar bone height, interproximal contact position, root angulation, crown shape, and embrasure area with open gingival embrasures. Posttreatment intraoral photographs of 337 adult orthodontic patients were evaluated to determine the prevalence of open gingival embrasures. A subsample of 119 patients was identified for measurement and divided into 2 groups: normal gingival embrasures and open gingival embrasures. Digital images of the pretreatment maxillary models and posttreatment maxillary central incisor periapical radiographs were made to measure the pretreatment and posttreatment variables. The prevalence of posttreatment open gingival embrasures in adult orthodontic patients was 38%. Pretreatment maxillary central incisor rotation and overlap were not statistically associated with posttreatment open gingival embrasures. A posttreatment alveolar bone-interproximal contact distance greater than 5.5 mm was associated with open gingival embrasures. Short and more incisally positioned posttreatment interproximal contacts were associated with open gingival embrasures. Open gingival embrasures were found to have more divergent root angulations and more divergent or triangular-shaped crown forms than normal gingival embrasures. Embrasure areas larger than 5.09 mm(2) were also correlated with open gingival embrasures. Increased alveolar bone-interproximal contact distance and increased root angulation demonstrated the greatest increase in the odds of an association with an open gingival embrasure. This investigation indicates that open gingival embrasures are common in adults who have undergone orthodontic treatment and that posttreatment variables are significant factors in open gingival embrasures.

Cell-autonomous expression of barley Mla1 confers race-specific resistance to the powdery mildew fungus via a Rar1-independent signaling pathway.

The barley Mla locus encodes 28 characterized resistance specificities to the biotrophic fungal pathogen barley powdery mildew. We describe a single-cell transient expression assay using entire cosmid DNAs to pinpoint Mla1 within the complex 240-kb Mla locus. The MLA1 cDNA encodes a 108-kD protein containing an N-terminal coiled-coil structure, a central nucleotide binding domain, and a C-terminal leucine-rich repeat region; it also contains a second short open reading frame at the 5' end that has a possible regulatory function. Although most Mla-encoded resistance specificities require Rar1 for their function, we used the single-cell expression system to demonstrate that Mla1 triggers full resistance in the presence of the severely defective rar1-2 mutant allele. Wheat contains an ortholog of barley Mla, designated TaMla, that is tightly linked to (0.7 centimorgan) but distinct from a tested resistance specificity at the complex Pm3 locus to wheat powdery mildew. Thus, the most polymorphic powdery mildew resistance loci in barley and wheat may have evolved in parallel at two closely linked homeoloci. Barley Mla1 expressed in wheat using the single-cell transformation system failed to trigger a response to any of the wheat powdery mildew Avr genes tested, indicating that AvrMla1 is not genetically fixed in wheat mildew strains.

EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency.

Infection of humans with Epstein-Barr virus (EBV) may cause infectious mononucleosis (IM). Analysis of single EBV-infected cells from tonsils of IM patients for rearranged immunoglobulin genes revealed two strategies of EBV for rapid and massive spread in the B cell compartment: the direct infection of many naive as well as memory and/or germinal center B cells and the expansion of the latter cells to large clones. In IM, the generation of virus-harboring memory B cells from naive B cells passing through a germinal center reaction likely plays no role. Members of clones can show distinct morphologies and likely also EBV gene expression patterns, and this ability implies a mechanism by which EBV-harboring cells can evade immune surveillance and establish a pool of persisting EBV-infected B cells.

Molecular single-cell analysis of the clonal relationship of small Epstein-Barr virus-infected cells and Epstein-Barr virus-harboring Hodgkin and Reed/Sternberg cells in Hodgkin disease.

Epstein-Barr virus (EBV) can be detected in the tumor cells of approximately 40% of cases of classical Hodgkin disease (cHD). Clonality studies suggest that infection of the neoplastic Hodgkin and Reed/Sternberg (HRS) cells occurs before tumor clone expansion. In EBV-positive cases, variable numbers of EBER-positive small B cells are sometimes also observed that immunohistologically differ from the neoplastic cells by lack of CD30 and latent membrane protein 1 expression. To analyze the clonal relationship between these EBV(+) cells and the HRS cells, single EBV-infected CD30(-) B cells, as well as HRS cells from 3 cases of EBV-positive cHD were micromanipulated, their immunoglobulin gene rearrangements amplified and then compared with each other. In 2 cases, all small EBV-infected cells were clonally unrelated to the HRS cells. In a third case, 2 of 29 small CD30(-) cells were found to carry HRS cell-specific rearrangements. Thus, small CD30(-) EBV-infected B cells in cHD belong to the HRS tumor clone rarely, if at all. In all cases, small clones unrelated to the HRS cell clones were identified among the small EBV(+) CD30(-) cells. The vast majority of small EBV(+) CD30(-) B cells was found to carry somatically mutated V region genes, indicating that in lymph nodes of patients with HD, like in the peripheral blood of healthy individuals, EBV persists in memory B cells.

Repeated follicle aspiration in mares: consequences for follicle growth and oocyte quality.

Cumulus-oocyte complexes (COCs) recovered from ovaries of mares killed at abattoirs or after in vivo collection have heterogeneous morphologies and meiotic competence as follicles of variable quality are used. It is thought that it should be possible to recover more uniform COCs, with respect to morphology and nuclear maturation, by repeated follicle aspiration. Therefore, the influence of repeated follicle aspiration on the number and diameter of follicles > or =5 mm in diameter, the morphology and recovery rate of COCs, and the chromatin configuration in oocytes was investigated. Repeated ultrasound-guided aspirations were performed on Warmblood mares (n=6) after either a normal cycle ('cyclic' sessions) or at 4-12 day intervals ('consecutive' sessions). In 88 follicle aspiration sessions, 1268 follicles were aspirated and 280 COCs were recovered: the mean number of follicles aspirated and the number of COCs obtained per session per mare were 14.4 and 3.2, respectively. The mean recovery rate was 22.1%; there was no significant difference in the recovery rate between cyclic and consecutive aspirations. However, the mean number of follicles aspirated was significantly different between cyclic and consecutive aspirations (15.3 versus 10.8, respectively) and, hence, fewer COCs were obtained in consecutive aspirations compared with cyclic aspirations (2.2 versus 3.5, respectively). The proportion of compact COCs was higher for consecutive than for cyclic aspirations (51.9 versus 28.8%, respectively; P < or = 0.02). Within consecutive sessions, the proportion of compact COCs decreased with increasing interval between aspirations. Moreover, the proportion of oocytes with a diffuse germinal vesicle chromatin configuration was higher in COCs collected in consecutive aspirations than in COCs collected in cyclic aspirations. Repeated follicle aspiration can be used to induce a more uniform follicular population and to provide more uniform COCs. The optimum interval between aspirations to provide the greatest number of meiotically competent oocytes must be determined.

The Mla (powdery mildew) resistance cluster is associated with three NBS-LRR gene families and suppressed recombination within a 240-kb DNA interval on chromosome 5S (1HS) of barley.

Powdery mildew of barley, caused by Erysiphe graminis f. sp. hordei, is a model system for investigating the mechanism of gene-for-gene interaction between large-genome cereals and obligate-fungal pathogens. A large number of loci that confer resistance to this disease are located on the short arm of chromosome 5(1H). The Mla resistance-gene cluster is positioned near the telomeric end of this chromosome arm. AFLP-, RAPD-, and RFLP-derived markers were used to saturate the Mla region in a high-resolution recombinant population segregating for the (Mla6 + Mla14) and (Mla13 + Ml-Ru3) resistance specificities. These tightly linked genetic markers were used to identify and develop a physical contig of YAC and BAC clones spanning the Mla cluster. Three distinct NBS-LRR resistance-gene homologue (RGH) families were revealed via computational analysis of low-pass and BAC-end sequence data derived from Mla-spanning clones. Genetic and physical mapping delimited the Mla-associated, NBS-LRR gene families to a 240-kb interval. Recombination within the RGH families was at least 10-fold less frequent than between markers directly adjacent to the Mla cluster.

Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1).

Cerebral cavernous malformations (CCM) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. One locus for autosomal dominant CCM ( CCM1 ) maps to chromosome 7q21-q22. Recombination events in linked family members define a critical region of approximately 2 Mb and a shared disease haplotype associated with a presumed founder effect in families of Mexican-American descent points to a potentially smaller region of interest. Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene. Seven different KRIT1 mutations have been identified in 23 distinct CCM1 families. The identical mutation is present in 16 of 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 kindreds harbor other KRIT1 mutations. Identification of a common Mexican-American mutation has potential clinical significance for presymptomatic diagnosis of CCM in this population. In addition, these data point to a key role for the Krev-1/rap1a signaling pathway in angiogenesis and cerebrovascular disease.

Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.

We have characterized amyloid beta peptide (Abeta) concentration, Abeta deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Abeta deposition, Abeta-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Abeta, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Abeta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Abeta40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Abeta42. Abeta40 is known to be elevated in cerebrovascular amyloid deposits, and Abeta40 (but not Abeta42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Abeta, particularly soluble Abeta40. Previous experiments attempting to relate Abeta deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.

Efficient inactivation of viruses and mycoplasma in animal sera using UVC irradiation.

Transmission of viruses by animal sera represents a considerable risk for humans and animals particularly when the serum is used for the production of pharmaceutical products such as vaccines. Procedures applicable for inactivating large numbers of different viruses, both enveloped and non-enveloped, are therefore mandatory. For this purpose we have developed and validated UVC irradiation as the virus-inactivation procedure of choice for serum to be used in an industrial setting. Spiking experiments in foetal calf serum (FCS) were performed by independent contract laboratories and revealed constantly high clearance rates for various viruses such as bovine parvovirus, parainfluenza type III virus, bovine diarrhoea virus, foot-and-mouth disease virus and different forms of mycoplasmas. UVC-treated sera maintained their growth-promoting activities for various cell types (MRC-5, Vero, CHO). Conventional growth curves generated in the presence of 10% and 1% UVC-treated FCS differed only slightly from controls, indicating the lack of significant damage during UVC exposure. Experiments using a sensitive photometric-based acid phosphatase assay (APA), which correlates well with the more tedious cell counting procedure, confirmed these findings even in the presence of minimal serum requirements. UVC treatment of animal sera appears advantageous compared to currently recommended inactivation procedures, such as Gamma irradiation, for at least three reasons: (i) it possesses a high inactivation capacity for parvoviruses, a pathogen that cannot be destroyed easily by conventional methods; (ii) it causes no noticeable impairment in cell growth and (iii) it can be performed in a controlled manner at the production site.

Genetic predisposition plays a role in nigral cell death in Parkinson's disease.

Both genetic and environmental factors are involved in the etiology of Parkinson's disease (PD). The recent identification of specific autosomal genes that lead to variants of PD confirms that genetic factors are important. Identifying and confirming other genetic factors responsible for PD is a difficult task because PD is a complex disease, the results of multiple genetic and environmental factors leading to a final common pathology. This review will discuss how advances in human genetics will allow future unraveling of the complex interactions between genetics and environment in the etiology of PD.

Gene-toxin interaction as a putative risk factor for Parkinson's disease with dementia.

We had previously examined environmental, sociodemographic and clinical variables as predictors for Parkinson's disease with dementia (PD + D) and found that lower educational attainment, greater motor impairment and advanced age at disease onset were more common in PD + D than in subjects with Parkinson's disease without dementia (PD-D). We now explore the hypothesis that genetic traits coupled with nongenetic factors may raise the risk of development of PD + D. The study cohort of 43 PD + D and 51 PD-D subjects was analyzed examining environmental, sociodemographic and clinical variables along with 3 candidate gene markers: poor debrisoquine metabolizer allele (CYP 2D6 29B+), monoamine oxidase B allele 1, and apolipoprotein E epsilon 4 allele. Variables were initially entered into a multivariate model singly. Again lower education, age at onset and motor impairment appeared as predictors of PD + D while other variables (including allele status) failed to emerge as significant individual risk factors for dementia. We then examined environmental and genetic variables analyzed in tandem to look for potential variable interactions. Subjects who had pesticide exposure and at least 1 copy of the CYP 2D6 29B+ allele had 83% predicted probability of PD + D (stepwise logistic regression model: p = 0.0491). This case-control study provides preliminary evidence that a gene-toxin interaction may play an etiological role in PD + D. Further assessment of the role of these putative risk factors in incident dementia in PD is indicated.

Rapid reorganization of resistance gene homologues in cereal genomes.

We used conserved domains in the major class (nucleotide binding site plus leucine-rich repeat) of dicot resistance (R) genes to isolate related gene fragments via PCR from the monocot species rice and barley. Peptide sequence comparison of dicot R genes and monocot R-like genes revealed shared motifs but provided no evidence for a monocot-specific signature. Mapping of these genes in rice and barley showed linkage to genetically characterized R genes and revealed the existence of mixed clusters, each harboring at least two highly dissimilar R-like genes. Diversity was detected intraspecifically with wide variation in copy number between varieties of a particular species. Interspecific analyses of R-like genes frequently revealed nonsyntenic map locations between the cereal species rice, barley, and foxtail millet although tight collinear gene order is a hallmark of monocot genomes. Our data suggest a dramatic rearrangement of R gene loci between related species and implies a different mechanism for nucleotide binding site plus leucine-rich repeat gene evolution compared with the rest of the monocot genome.