Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands

The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early-onset obsessive-compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between-marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER(+). The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples.     

Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism

A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) is considered to be a plausible candidate gene for anxiety-related personality traits and for alcoholism. Empirical support for the association between 5-HTTLPR and psychological traits has been somewhat inconsistent; however, observations of the functional dominance of the low-activity s-allele over the l-allele have been more consistent. When studying the influence of particular genes on psychological traits, it seems useful also to assess more biological intermediate traits that may mediate the effects of those genes on the traits of interest. The present study examined relationships between 5-HTTLPR genotype, whole blood serotonin (5-HT) level, and platelet 5-HT binding in 150 Caucasian subjects from 50 biological families. Individuals with the s-allele had lower average platelet 5-HT binding availability than those with the l/l genotype (P<0.025). Whole blood 5-HT level was not associated with 5-HTTLPR genotype. In adult men, those with the s-allele had higher mean scores on the NEO-FFI personality trait of openness than did those with the l/l genotype (P=0.002). The effect was not statistically significant in women (P=0.42), although it was in the same direction. Our findings do not support an association of 5-HTTLPR genotype with alcoholism diagnosis, alcoholism subtype, or the personality trait of neuroticism. The results of this pilot study suggest that further work should examine the mediation of the genetic effects on personality traits by biochemical measures and their moderation by gender.     

Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau

Neurofibrillary pathology was produced in the brains of adult rats after localized gene transfer of human tau carrying the P301L mutation, which is associated with frontotemporal dementia with parkinsonism. Within 1 month of in situ transfection of the basal forebrain region of normal rats, tau-immunoreactive and argyrophilic neuronal lesions formed. The fibrillar lesions had features of neurofibrillary tangles and tau immunoreactivity at light and electron microscopic levels. In addition to neurofibrillary tangles, other tau pathology, including pretangles and neuropil threads, was abundant and widespread. Tau gene transfer to the hippocampal region of amyloid-depositing transgenic mice produced pretangles and threads, as well as intensely tau-immunoreactive neurites in amyloid plaques. The ability to produce neurofibrillary pathology in adult rodents makes this a useful method to study tau-related neurodegeneration.     

SKALP/elafin gene polymorphisms are not associated with pustular forms of psoriasis

Psoriasis is a multifactorial skin disease characterised by epidermal abnormalities and infiltration by lymphocytes and polymorphonuclear leukocytes (PMN). Skin-derived antileukoproteinase (SKALP), also known as elafin, is a potent inhibitor of human leukocyte elastase and proteinase 3, two PMN-derived proteinases implicated in tissue destruction and leukocyte migration. We have shown that, at least at the protein level, SKALP is significantly decreased in lesional skin of patients with pustular psoriasis compared with plaque-type psoriasis. This finding raised the possibility that SKALP could be one of the candidate genes for pustular forms of psoriasis. We therefore performed single strand conformation polymorphism (SSCP) analysis on the SKALP gene to screen for mutations/polymorphisms in the exons of 30 patients with plaque-type psoriasis, 15 patients with pustular psoriasis and 48 healthy controls. In exon 1 a polymorphism was detected at position + 43 relative to the translation start site, resulting in a substitution of threonine for alanine in the signal peptide. In the promoter region a dinucleotide repeat polymorphism was identified. Both polymorphisms were not associated with pustular psoriasis, or psoriasis in general. Our data indicate that the decrease in SKALP activity in pustular psoriasis is not caused by mutations in the coding region of the gene, and that there is no allelic association between pustular psoriasis and SKALP gene polymorphisms.     

High-conversion emulsion polymerization

The four important factors that determine the rate of emulsion polymerization are the propagation rate coefficient, the latex-particle concentration, the monomer concentration in the latex particles, and the free-radical concentration in the latex particles. Both theoretical considerations and experimental evidence suggest that the important factors that may reduce the rate of emulsion polymerization at high conversion are the propagation rate coefficient and the monomer concentration in the latex particles, and not the free-radical concentration in the latex particle, if the initiator is not depleted. Various approaches for increasing the rate of emulsion polymerization at high conversion are suggested.     

Behavioral analysis of the saccharin deprivation effect in rats

The deprivation effect (DE)--an increase in the level of free-choice consumption of alcohol after a period of forced abstinence--may reflect relapselike drinking and be relevant for modeling alcohol abuse. However, the behavioral mechanisms of the DE are unclear. In these experiments, rats had unlimited free-choice access to water and saccharin-containing solutions and underwent repeated episodes of saccharin deprivation. It was found that DE magnitude correlates positively with the deprivation phase duration, expression of the DE is highly context dependent, and the DE can be prevented by extinguishing response to the saccharin-associated stimuli. Thus, DE procedures may be useful for studying the effects of continued exposure to stimuli associated with various primary reinforcers such as drugs of abuse.     

Viscoelastic response of intervertebral disks at audiofrequencies

The viscoelastic responses of intervertebral disks taken from the cervical regions of the spinal columns of several adult, male, mongrel dogs have been determined. The results are presented in terms of a mean complex shear compliance,J _d*=J′ _d ?iJ″ _d , for the disk structures when these are subjected to small-amplitude audiofrequency vibrations (25–5000 Hz) while surrounded by normal salt solution, both at room temperatures and at 98·6°F (37.0°C) (in vitro). Values of the general compliance levels decrease with time after sacrifice, and an abrupt transition in the 100-Hz compliance-time curves at 5·5 hours after death is attributed to the completion of rigor mortis (at room temperature). Comparisons of the broad compliance-frequency disk spectra with those of five synthetic polymeric materials, including a silicone rubber, are presented and suggestions for materials suitable to be used in disk prosthesis are made. Such materials must have values of both elastic compliance (J′) and viscous compliance (J″) which are close to the corresponding living disk compliances. A brief discussion of the characteristic sharp resonance dispersions or fine structure observed in the disk spectra is also presented along with suggestions for future measurements. Finally, the idea is advanced that a composite synthetic structure with a stiff, outer ring of low compliance and a very compliant inner core might most satisfactorily mimic the viscoelastic behaviour of a normal intervertebral diskin vivo.     

Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: Is there a need for routine screening?

Mutations in the methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome, a severe neurodevelopmental disorder occurring predominantly in females. Male patients with Rett syndrome are extremely rare, as the Rett-causing mutations in the MECP2 gene are usually lethal in hemizygous males. However, different mutations in the same gene were reported to cause mental retardation, both in sporadic non-syndromic males as well as in syndromic families with disease manifestation in carrier females. The majority of the reported MECP2 mutations in mentally retarded patients cause amino acid substitutions and, especially in isolated cases, discrimination between a disease-causing mutation and a rare polymorphism is not obvious and the significance of each individual variation should be verified. We mapped a new non-syndromic X-linked family (MRX79) to the chromosomal region Xq27.3-Xq28 and identified an A140V mutation in the MEPC2 gene in all patients with the disease haplotype. In addition to data published by others, this suggests that A140V is a recurrent mutation (and not a polymorphism) found in patients with X-linked mental retardation.     

Fischer 344 rats display age-related memory deficits in trace fear conditioning

A functional hippocampus is required for trace fear conditioning, which involves learning the association of a tone and shock that are separated over time. Young and aged rats received 10 trace conditioning trials. Twenty-four hours later, rats were tested for fear to the tone in a novel chamber by measuring freezing. The results showed significantly lower levels of freezing in aged rats as compared with young rats, which provides evidence of age-related memory impairments. Pseudorandom conditioning groups showed low levels of freezing, indicative of no associative memory. Age-related memory deficits were not found with delay conditioning, which suggests no age-related sensory-motor deficits. These data suggest that aging hinders the ability of the hippocampus to process information separated over time.     

Tumor nuclear grade,estrogen receptor,and progesterone receptor: Their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer

Summary Previous reports by us have shown that the outcome of breast cancer patients who have received systemic adjuvant therapy is influenced by tumor estrogen or progesterone receptor (ER or PR) content or by nuclear grade. This publication provides information regarding the relative merit of those three markers. Findings from patients receiving L-PAM plus 5-FU (PF) or PF plus tamoxifen (PFT) indicate that the disease-free survival and survival within each regimen was almost identical when related to either ER, PR, or nuclear grade. Those having tumors with either of the receptors 10 fmol or a good nuclear grade had a better outcome through five postoperative years than did those with ER or PR 0–9 fmol or poor nuclear grade. The magnitude of the difference was similar for each of the three discriminants. Since they were found to be of equal predictive value, one marker might well serve as a substitute for another. Cox regression analyses, however, clearly indicate that ER, PR, and nuclear grade have an independent influence on outcome and that a more accurate assessment of outcome is obtained when more than one marker is employed. Thus, information should be obtained on as many markers as possible. This conclusion is supported by observations presented which indicate that nuclear grade in combination with either or both of the receptors is a better predictor than either marker alone and that, as indicated by life table probability values and relative odds ratios, an increasing number of favorable tumor prognostic indicators results in a better patient outcome particularly in PFT-treated patients. A possible explanation is considered for why the separation of receptor/nuclear grade categories is more orderly and pronounced in PF-treated patients receiving tamoxifen than in those given PF alone. See Appendix I