Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCR-based cDNA subtractive hybridization in a cell culture model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1alpha (SDF1alpha). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid beta-protein (Abeta) in pontine neurons containing nuclear inclusions. In addition, extracellular Abeta-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1beta, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.

Primary non-Hodgkin's lymphoma of the spinal cord.

STUDY DESIGN: Case report. OBJECTIVE: To report a rare case of primary lymphoma of the spinal cord and to discuss therapeutic options. SUMMARY OF BACKGROUND DATA: Only few cases of primary spinal cord lymphomas are reported. Prognosis is often poor, and therapy is not yet established. METHODS: A primary lymphoplasmacytoid lymphoma of the thoracic cord in a 75-year-old woman was treated with focal radiotherapy (30 Gy) and three cycles of chemotherapy consisting of procarbazine, lomustine, and vincristine. RESULTS: Complete tumor response and partial recovery of neurologic symptoms were achieved. The patient was in complete remission at last follow-up (11 months after diagnosis). CONCLUSIONS: Primary spinal cord lymphomas should be considered in the differential diagnosis of spinal cord tumors, especially in older patients. Combination therapy with radiotherapy and chemotherapy may be superior to radiotherapy alone in these tumors. Rapid initiation of treatment is essential to achieve recovery of neurologic function.

Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene.

BACKGROUND: Familial primary pulmonary hypertension (PPH) is an autosomal-dominant inherited disease with incomplete penetrance and poor prognosis. This study was performed to examine whether asymptomatic carriers of a mutated PPH gene can be identified at an early stage by their pulmonary artery systolic pressure (PASP) response to exercise. METHODS AND RESULTS: Stress Doppler echocardiography during supine bicycle exercise and genetic linkage analysis were performed on 52 members of 2 families with PPH. In 4 PPH patients, the mean PASP was increased at rest (73+/-16 mm Hg). Fourteen additional family members with normal PASP at rest revealed an abnormal PASP response to exercise (from 23+/-4 to 56+/-11 mm Hg) without secondary cause (abnormal response [AR] group). Twenty-seven other members (NR group) revealed a normal PASP response (maximal pressure <40 mm Hg) to exercise (from 24+/-4 to 37+/-3 mm Hg, P<0. 0001). All 14 AR but only 2 NR members shared the risk haplotype with the PPH patients. The molecular genetic analysis supported linkage to chromosome 2q31-32 with a logarithm of the odds score of 4.4 when the 4 patients and the 14 AR members were classified as affected. CONCLUSIONS: We conclude that the pathological rise of PASP in asymptomatic family members is linked to chromosome 2q31-32 and is probably an early sign of PPH. Therefore, stress Doppler echocardiography may be a useful tool to identify persons at risk for PPH even before pulmonary artery pressures at rest are elevated.

Investigation of the human serotonin 6 [5-HT6] receptor gene in bipolar affective disorder and schizophrenia.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5-HT(6) receptor gene to explore the contribution of this gene to the development of bipolar affective disorder and schizophrenia. Investigating 137 unrelated individuals (including 45 bipolar affective patients, 46 schizophrenic patients, and 46 unrelated controls), we identified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A/C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipolar patients (P=0. 023 not corrected for multiple testing). This finding was followed up in an independent sample of 105 bipolar family trios using a family-based association design. Fifty-one transmissions could be examined. In 30 cases allele 267C and in 21 cases allele 267T were transmitted to the affected offspring. Although this result was far from statistical significance (transmission disequilibrium test=1.59, P=0.208), the limited number of possible transmissions may have prevented detection of smaller effects. Our preliminary data suggest that bipolar affective disorder may be associated with variation in the 5-HT(6) gene. It will be important to extend the present analysis to larger samples. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:217-221, 2000.

Genetic linkage analysis with dyslexia: evidence for linkage of spelling disability to chromosome 15.

Dyslexia (reading and spelling disability) is one of the most frequently diagnosed disorders in childhood. Twin studies of dyslexia have indicated that deficits in spelling are substantially heritable and that the heritability of spelling deficits is higher than the heritability of reading deficits. We conducted a linkage study for spelling disability in seven multiplex families from Germany. Following previously reported linkage findings of components of dyslexia to chromosome 6p21-p22 and 15q21, we genotyped 26 microsatellite markers covering all of chromosome 6, and 13 microsatellite markers covering all of chromosome 15. While the chromosome 6 data were negative, results from chromosome 15 markers supported a locus on 15q21. The highest two-point LOD score was 1.26 with marker D15S143 at theta = 0. A multipoint LOD score of 1.78 (p = 0.0042) was achieved with a maximum at D15S132. Thus, our results provide independent support for a dyslexia gene on the long arm of chromosome 15.

Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia.

Complete or partial congenital absence of hair (congenital alopecia) may occur isolated or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal recessive mode of inheritance (MIM 203655). We have previously mapped the gene for autosomal recessive congenital alopecia in a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia) to a 15 cM region on chromosome 8p21-22. Here we report the cloning and characterization of the human homologue of the mouse hairless gene and show that it is located in the critical region on chromosome 8p21-22. Determining the exon-intron structure allowed detailed mutational analysis of DNA samples of patients with universal congenital alopecia. We detected a homozygous missense mutation in the Pakistani family and a homozygous splice donor mutation in a family from Oman. In addition, we show that the human hairless gene undergoes alternative splicing and that at least two isoforms generated by alternative usage of exon 17 are found in human tissues. Interestingly, the isoform containing exon 17 is the predominantly expressed isoform in all tissues but skin, where exclusive expression of the shorter isoform was observed. We speculate that this tissue-specific difference in the proportion of hairless transcripts lacking exon 17 sequences could contribute to the tissue-specific disease phenotype observed in individuals with isolated congenital alopecia.

Male gonadal environment paradoxically promotes dacryoadenitis in nonobese diabetic mice.

Similar to pancreatic islets, submandibular glands are more rapidly infiltrated in female NOD mice than in males. The present comparative analysis of cellular infiltrations in lacrimal glands, however, revealed the opposite finding. At 12 wk of age, approximately 25% of male lacrimal tissue area is infiltrated, whereas age-matched female NOD mice still lack major signs of inflammation. T cells predominate in early stages of invasion, but B cells accumulate promptly in more advanced stages, and ultimately dominate over T cells. Dacryoadenitis is promoted by sex hormones, as suggested by the reduced infiltrations seen in orchidectomized NOD males (P < 0.01). It is also controlled by the local environment provided by the lacrimal tissue. Splenocytes from 4- and 20-wk-old female NOD mice cause massive lesions upon adoptive transfer into NOD male recipients while, conversely, female recipients develop barely any histological sign of infiltration, even after transfer of splenocytes from 20-wk-old donor males. These observations provide strong evidence for a dacryoadenitis-promoting role of male gonadal hormones in NOD mice, a finding that contrasts the known androgen-mediated protective effects on insulitis and submandibulitis in the same strain and on dacryoadenitis in other animal models of Sjögren's syndrome.

A gene for universal congenital alopecia maps to chromosome 8p21-22.

Complete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.

Human 5-HT5A receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 7q34-q36 using a polymorphism in the 5' untranslated region.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of sensory, motor, and cortical functions by activating multiple 5-HT receptor subtypes. In the present study we performed a systematic mutation scan of the complete coding region of the 5-HT5A receptor to explore its variability in the general population. Investigating 46 unrelated healthy subjects by single-strand conformation analysis no sequence changes of likely functional relevance were observed. The detection of a frequent G-->C substitution at position -19 was used for fine scale linkage mapping of the 5-HT5A gene. Employing a polymerase-chain-reaction based assay we genotyped 7 CEPH families (Centre d'Etude du Polymorphisme Humaine) and mapped the receptor to genetic markers on chromosome 7q34-q36.

TGF-beta 1 and skin carcinogenesis: antiproliferative effect in vitro and TGF-beta 1 mRNA expression during epidermal hyperproliferation and multistage tumorigenesis.

The role of transforming growth factor-beta 1 (TGF-beta 1) in multisage carcinogenesis in mouse skin was assessed by studying its growth inhibitory effects on nontumorigenic and tumorigenic keratinocytes and by examining its mRNA expression in vitro and during epidermal hyperproliferation and multistage carcinogenesis. While growth of primary basal keratinocytes was inhibited by TGF-beta 1 in doses as low as 0.1 ng/mL, the immortal keratinocyte line MCA/3D ("putatively initiated" cells) responded to TGF-beta 1 with slightly reduced sensitivity, and the papilloma-producing keratinocyte line 308 was considerably less sensitive. In contrast, the squamous carcinoma cell line Carc B was completely nonresponsive, and two other tumorigenic cell lines (PDV and PDVC57) were sensitive to growth inhibition by TGF-beta 1. Steady-state levels of TGF-beta 1 mRNA were high in all the malignant cell lines and in line 308 papilloma cells, but low in primary basal cells and in the nontumorigenic keratinocyte lines V2, Reb1, and MCA/3D. Our in vivo studies showed that tumor promoters, but not mitogenic or weak hyperplasiogenic agents, were able to induce transient expression of TGF-beta 1 mRNA in mouse epidermis. A constitutive overexpression of TGF-beta 1 mRNA was observed in malignant carcinomas but not in the benign premalignant lesions, indicating that overexpression may be associated with malignant progression.

Isolation, characterization and in vitro cultivation of subfractions of neonatal mouse keratinocytes: effects of phorbol esters.

Using discontinuous Percoll density gradient centrifugation, keratinocytes from neonatal mouse skin were separated into four fractions. The fractions were characterized by light microscopy, by indirect immunofluorescence using lectins (Bandeira simplicifolia and Ulex europaeus) or an antibody against bullous pemphigoid antigen, and by electrophoretic analysis of the keratin polypeptide patterns. Two fractions, F1 and F2, were identified as being derived from suprabasal layers and two fractions, F3 and F4, as originating from the basal cell layer. F3 and F4 cells could be cultivated on plastic substratum in the presence of 4 X minimum essential medium, 10% fetal calf serum at 34 degrees C with plating efficiencies of 80-85%. DNA labeling of cultures of F3 and F4 cells indicated that basal cells in fractions F3 and F4 exhibited different growth behaviour in culture. Confluent cultures of F3 and F4 cells responded to phorbol esters by increased DNA synthesis. This result contradicts the in vivo situation where neonatal mouse skin is resistant to the irritant and mitogenic effects of phorbol esters. The mitogenic effect of 12-O-tetradecanoylphorbol-13-acetate on F3 cells is not mediated by endogenous prostaglandin formation.

Defining alcohol problems as a repressive mechanism: its formative phase in imperial Germany and its strength today.

In Germany, in the takeoff years of industrialization, judgments about drinking, drunkenness, and drunken comportment changed drastically. While for centuries drunkenness had been seen as the transitory effect of too much drinking, it now was perceived as a sign of moral weakness which afflicted most strongly the working class. Naming someone a drunkard, then, was as much a label for denouncement as for a sickness, which since then has been called alcoholism. It can be shown that structurally similar processes are in use in today's debate over the changing drinking habits of women in West Germany.

[Receptors for complement on rat mast cells and release of histamine]. / Komplementrezeptoren auf Rattenmastzellen und Histaminfreisetzung.

Using rat complement-treated zymosan particles a rosetting of purified rat peritoneal mast cells could be demonstrated. The question was investigated whether the binding of activated complement could be a trigger of histamine release. Varying the degree of complement label on the zymosan particles, the time and temperature of incubation and the dependence on Ca2+ ions, we could not induce a release of histamine in any case. The addition of labeled zymosan increased slightly the mediator release induced by ATP. The immunologic significance of the complement receptors on mast cells is still unclear.