Drooling is no early sign of dysphagia in Parkinson's disease.

BACKGROUND: Dysphagia is frequent and clinically highly relevant in Parkinson's disease (PD). For a rational dysphagia screening predictors are required. Previous investigations suggested that drooling correlates with dysphagia and may serve as its early sign. The aim of this study was to clarify the interrelationship of drooling and dysphagia. METHODS: In a controlled, cross-sectional, observational study, a total of 119 Parkinson outpatients and 32 controls were examined clinically and by flexible-endoscopic evaluation of swallowing (FEES). Drooling, dysphagia including retained pharyngeal secretions, and cognitive function were assessed by established evaluation scales. KEY RESULTS: Fifty percent of all PD patients but only 9% of controls had drooling (P < .001). Drooling and dysphagia were related in PD (P = .027) but the data do not support to view drooling as a hallmark symptom for critical dysphagia. Thirty-nine percent of the patients with critical aspiration had no drooling. In contrast, 41% of the patients with severe drooling had no clinically relevant dysphagia in FEES. The oral, but not the pharyngeal secretion management was impaired in PD patients and there was no clear association between drooling and pharyngeal secretion accumulation. Cognitive impaired patients had significantly more drooling (P = .005). CONCLUSIONS & INFERENCES: Although frequent in PD, drooling and dysphagia are only weakly related and drooling cannot be viewed as an early sign of dysphagia. Our data further suggest that the underlying cause of drooling is located in the voluntary oral phase, which is negatively influenced by cognitive deficits.

The Positively Aging teaching materials improve middle school students' images of older people.

PURPOSE: The Positively Aging program is an innovative set of interdisciplinary teaching materials that uses examples from geriatrics and gerontology to teach sixth through eighth grade curricular elements. The purpose of this study was to determine if use of the Positively Aging teaching materials by regular classroom teachers could change middle school students' images of elders. DESIGN AND METHODS: At the beginning of the 1998-1999 school year, students at two San Antonio, Texas, middle schools were asked to draw a typical older person. These drawings were coded as positive, neutral, or negative portrayals of elders. One school then used the Positively Aging materials as part of the curriculum; the other school served as the control. Second drawings were obtained from the students at the end of the school year and compared to those from baseline. RESULTS: Both drawings were completed by 60% of students at the intervention school and 55% of students at the control school. Of the 782 paired drawings from the intervention school, 34% were more positive at Time 2 compared to 25% of 591 paired drawings from the control school (chi2 = 13.9, p < .001). In addition, only 20% of the second drawings from the intervention school were more negative than the first drawing compared to 27% from the control school (chi2 = 11.3, p < .001). Using a generalized logit model, we adjusted for each student's baseline drawing (positive-neutral-negative), grade level, gender, ethnic group, and socioeconomic status. After adjustment, students in the intervention school were more likely to draw positive (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.13, 1.94) or positive and neutral images (OR 1.58, 95% CI 1.21, 2.19) at follow-up compared to the control school. IMPLICATIONS: This controlled study demonstrated that use of the Positively Aging teaching materials and activities moved middle school students toward a more positive view of elders. Interdisciplinary teaching materials based on geriatrics and gerontology can be successfully developed and tested in public school systems to affect attitudes about aging.

Characterization of a family with dominant hypophosphatasia.

A kindred with dominant hypophosphatasia resulting from an alanine to threonine substitution at position 99 of the alkaline phosphatase protein is described. The clinical findings of individual members of the kindred were assessed by oral and physical examinations, or from the descriptions of multiple family members. The proband displayed enamel hypoplasia and premature loss of fully rooted primary anterior teeth, which were shown by histological examination to lack cementum. Serum alkaline phosphatase (ALP) and a vitamin B6 panel, and urine phosphoethanolamine (PEA) were measured on 21 family members. Based upon the clinical and laboratory tests, affected and unaffected status was assigned. Parametric linkage analysis of the kindred using different dominant models and frequency distributions for the disease allele and the mutation gave lodscores > 4.2 and confirmed the strong linkage between the disease and the mutation. Assuming the defined mutation causes the disease, the reliability of clinical and laboratory tests is assessed.

Risk perceptions among patients and their relatives regarding prostate cancer and its heredity.

We performed a qualitative study to examine how prostate cancer (PC) patients and their spouses and relatives take into account family history when considering susceptibility to PC. Semi-structured interviews were conducted with 20 participants. All interviews were tape-recorded, transcribed and content analyzed. Patients' and spouses' views concerning the seriousness of PC were different. Wives viewed PC as a serious disease because it has affected their marital relationships; patients found PC to be less serious because it can be treated. All participants viewed PC as a male disease that can be passed on from fathers to sons. Furthermore, participants were aware of PC clustering in their families. However, this awareness did not encourage (healthy) male relatives to seek early detection. Additionally, participants perceived age, high-fat diet, and less exercise as important risk factors, while socioeconomic status, ethnic origin and a family history of PC were viewed as less important. We recommend that health educators pay special attention to these findings when planning to teach patients, spouses and their relatives about PC, its heredity and risks. Prostate Cancer and Prostatic Diseases (2000) 3, 176-185

Magnetic resonance imaging demonstrates incomplete myelination in 18q- syndrome: evidence for myelin basic protein haploinsufficiency.

Magnetic resonance imaging (MRI) and MRI relaxometry were used to investigate disturbed brain myelination in 18q- syndrome, a disorder characterized by mental retardation, dysmorphic features, and growth failure. T1-weighted and dual spin-echo T2-weighted MR images were obtained, and T1 and T2 parametric image maps were created for 20 patients and 12 controls. MRI demonstrated abnormal brain white matter in all patients. White matter T1 and T2 relaxation times were significantly prolonged in patients compared to controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the myelin basic protein (MBP) gene. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q- is associated with haploinsufficiency of the gene for MBP.

Preferential loss of the paternal alleles in the 18q- syndrome.

Individuals with the 18q- syndrome have variable deletions from the long arm of chromosome 18. They also exhibit a highly variable phenotype. To correlate genotype with phenotype accurately, extensive molecular and phenotypic analyses are needed on each affected individual. As a part of this analysis, we have determined the parental origin of the deleted chromosome in 34 individuals with the 18q- syndrome. We have found that 85% of the de novo deletions are paternal in origin. The percentage of fathers of individuals with paternally derived deletions who were > 30 years old was (not significantly) greater than that of the general population. The mothers of individuals with maternally derived deletions were near an average age for childbearing compared to the general population. Individuals with maternally derived terminal deletions had breakpoints as varied as those with paternally derived deletions. These results are consistent with the hypothesis that the reduced incidence of maternally derived deletions is not due to reduced viability, since individuals with large maternally derived deletions of chromosome 18q were found. We hypothesize that the prevalence of paternally derived deletions is due to an increased frequency of chromosome breakage in male germ cells. These results are consistent with results observed in other segmental aneusomies in which there is a high incidence of paternally derived deletions.

Reassignment of the 92-kDa type IV collagenase gene (CLG4B) to human chromosome 20.

The collagenase type IV B gene (CLG4B) was previously mapped to human chromosome 16 by hybridization of a cDNA probe to DNAs from a somatic cell hybrid panel. We have relocalized CLG4B to chromosome 20 based on three different lines of evidence: screening a somatic cell hybrid mapping panel, fluorescence in situ hybridization (FISH), and linkage analysis using a newly identified polymorphism.

Two statistical tests for meiotic breakpoint analysis.

Meiotic breakpoint analysis (BPA), a statistical method for ordering genetic markers, is increasing in importance as a method for building genetic maps of human chromosomes. Although BPA does not provide estimates of genetic distances between markers, it efficiently locates new markers on already defined dense maps, when likelihood analysis becomes cumbersome or the sample size is small. However, until now no assessments of statistical significance have been available for evaluating the possibility that the results of a BPA were produced by chance. In this paper, we propose two statistical tests to determine whether the size of a sample and its genetic information content are sufficient to distinguish between "no linkage" and "linkage" of a marker mapped by BPA to a certain region. Both tests are exact and should be conducted after a BPA has assigned the marker to an interval on the map. Applications of the new tests are demonstrated by three examples: (1) a synthetic data set, (2) a data set of five markers on human chromosome 8p, and (3) a data set of four markers on human chromosome 17q.

Genetic mapping of the BRCA1 region on chromosome 17q21.

Chromosome 17q21 harbors a gene (BRCA1) associated with a hereditary form of breast cancer. As a step toward identification of this gene itself we developed a number of simple-sequence-repeat (SSR) markers for chromosome 17 and constructed a high-resolution genetic map of a 40-cM region around 17q21. As part of this effort we captured genotypes from five of the markers by using an ABI sequencing instrument and stored them in a locally developed database, as a step toward automated genotyping. In addition, YACs that physically link some of the SSR markers were identified. The results provided by this study should facilitate physical mapping of the BRCA1 region and isolation of the BRCA1 gene.

Use of a neurophysiological trait in linkage analysis of schizophrenia.

Traditional diagnostic techniques may not provide all the information necessary to reveal the genetic causes of schizophrenia through linkage analysis. Use of neurophysiological indicator variables that are associated with the disease may increase the probability of detecting linkage. Such variables not only produce simpler phenotypes for analysis, but they also may be more proximal to the gene products involved in neurological dysfunctions underlying schizophrenia. We have used a previously characterized neurophysiological variable, the P50 evoked-auditory response, to search for chromosomal regions that may be of interest in the study of schizophrenia. Although our scan of over 300 markers did not show strong evidence for linkage to P50 in nine families, this exploratory analysis has revealed several chromosomal regions that may deserve further study.

A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance.

Manic-depressive illness (MDI), also known as "bipolar affective disorder," is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, we ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping 5 cM from the disease gene, the pedigree sample has > 97% power to detect a dominant allele under genetic homogeneity and has > 73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores < -2.0 at recombination fraction (theta) = .0, 174 DNA loci produced lod scores < -2.0 at theta = .05, and 4 DNA marker loci yielded lod scores > 1 (chromosome 5--D5S39, D5S43, and D5S62; chromosome 11--D11S85). Of the markers giving lod scores > 1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, our linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk.

A genetic linkage map with 29 loci spanning human chromosome 13q.

A genetic linkage map for the long arm of human chromosome 13 contains 29 loci derived from 38 probe and enzyme combinations and two protein polymorphisms. Thirteen loci form a continuous linkage map of 106 cM in males and 230 cM in females; each was placed on the map with support of at least 1000:1 against alternative orders. On a sex-combined basis, the mean distance between markers is less than 13 cM. The order of loci on the genetic map agrees with physical localization data that show that together these 13 loci cover 13q13 to 13q34. This map was used to regionally localize the 16 remaining loci. The linkage maps reported here should prove to be useful to investigators mapping disease genes and other genetic markers on human chromosome 13.

An extended genetic linkage map and an "index" map for human chromosome 17.

Our previous genetic map for chromosome 17 has been expanded to include 72 loci defined by 90 RFLP markers and four microsatellite markers assayed by the polymerase chain reaction. Forty-one of these loci were ordered with odds greater than 1000:1 against local inversion, and the other 31 were ordered within 95% confidence limits. From the set of 41 unambiguously mapped loci, 14 well-spaced "index markers" can be extracted for efficient genetic studies. The complete map spans 173 cM (136 cM in males and 214 cM in females); average spacing between markers is 4.2 cM.

The human endothelin-1 gene (EDN1) encoding a peptide with potent vasoactive properties maps distal to HLA on chromosome arm 6p in close linkage to D6S89.

We determined the precise genetic location of the human endothelin-1 gene (EDN1), which encodes a peptide with extremely potent vasoactive properties and is apparently involved in a spectrum of diseases ranging from hypertension to asthma. Analyzing the segregation of a four-allele EDN1 polymorphism in 40 CEPH families including 480 individuals, we detected significant linkage of EDN1 to DNA markers spanning the telomeric half of chromosome arm 6p. EDN1 was closest to the highly polymorphic nucleotide-repeat marker D6S89 at a theta = 0.06 with the highest pairwise LOD score Zmax = 31.2. Subsequent multipoint analysis placed EDN1 at 8 cM distal to D6S89; EDN1 was flanked at its telomeric site at a 13-cM distance by the gene encoding the A subunit of blood clotting factor XIII (F13A1). Furthermore, EDN1 was located at approximately 34-36 cM distal to the HLA region defined by HLA-A, -B, and -DRB1, and 31 cM proximal to the most telomeric marker D6S7. This location of EDN1 on the primary genetic map is strongly supported with odds of 2.7 x 10(12):1 against the next best alternative.

Linkage analysis of schizophrenia: the D1 dopamine receptor gene and several flanking DNA markers.

Alterations in dopaminergic activity may play an important role in the pathogenesis of schizophrenia. The central effects of dopamine are mediated by at least five G protein-coupled receptors, D1, D2, D3, D4 and D5. The D1 receptor maps to 5q35.1 and it identifies an Eco RI as well as a Taq I RFLP. In the present study we undertook a linkage analysis between the D1 receptor RFLPs and schizophrenia in 9 multigenerational families in which segregation of disease was consistent with autosomal dominant inheritance and reduced penetrance. Several flanking DNA markers were also analyzed as the D1 receptor RFLPs were relatively uninformative in our families. Pairwise analyses of schizophrenia and several flanking markers indicate that inheritability of this region is unlikely to be involved in the pathogenesis of schizophrenia in the 9 families studied.

Genetic linkage of the human gene for phenylethanolamine N-methyltransferase (PNMT), the adrenaline-synthesizing enzyme, to DNA markers on chromosome 17q21-q22.

We have determined the genetic location of the human gene encoding phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholamine pathway catalyzing the synthesis of epinephrine (adrenaline) from norepinephrine. This gene is linked to DNA markers on the long arm of chromosome 17, q21-q22, most closely to the DNA markers MFD15 (D17S250) (Zmax = 15.0, theta = 0.065) and fLB17.1 (Zmax = 14.6, theta = 0.045). Multipoint linkage analysis placed the PNMT locus in the interval fLB17.1-CMM86 (D17S74), at 4 centiMorgans (cM) distal to fLB17.1, and at 17 cM proximal to CMM86. Mapping of the PNMT gene will provide the basis for genetic linkage studies in families with disease which might pathogenetically involve this enzyme. The human chromosomal region 17q21-22 identified here to harbour the PNMT gene may be syntenic to the chromosomal region in the stroke-prone spontaneously hypertensive rat (SHR-SP) recently linked to blood-pressure regulation. As an increase of PNMT activity has been associated with the development of hypertension in SHR-SP, it will be of interest to perform comparative mapping of the PNMT gene.

Linkage analysis of the D1 dopamine receptor gene and manic depression in six families.

Disturbances in dopaminergic activity may play an important role in the pathogenesis of manic depression. The effects of dopamine are mediated by at least five G protein coupled receptors, D1, D2, D3, D4 and D5. Recently, three separate research groups have cloned and characterized the D1 dopamine receptor, which localizes to 5q35.1. We undertook a linkage analysis between the D1 receptor polymorphisms and manic depression in six families in which segregation of the disease was consistent with autosomal dominant inheritance. A highly polymorphic flanking DNA marker, CRI-L1200, was also analyzed as the D1 gene RFLPs were relatively uninformative in our families. Multipoint analyses of manic depression and these DNA markers resulted in lod scores of less than -3.0 at the D1 locus, indicating that the D1 dopamine receptor gene does not confer an inherited susceptibility to manic-depressive illness in the families studied.

Tyrosine hydroxylase gene not linked to manic-depression in seven of eight pedigrees.

We ascertained 8 multigenerational pedigrees afflicted with multiple cases of bipolar and recurrent major depressive disorder. Alterations in dopaminergic and noradrenergic neurotransmission have been implicated in the pathogenesis of this disease, and tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of these two catecholamines. As TH mutations could underlie susceptibility to manic-depression, we carried out a linkage analysis between this disease in 8 families and two RFLP probes that map to the TH gene region on the short arm of chromosome 11. Evidence of linkage was not found in 7 of 8 kindreds.