Estimation of false discovery rates for wavelet-denoised statistical parametric maps.

Correction for multiple comparisons in neuroimaging data is an important area of research. Recently, wavelet-based methods have gained popularity and have been reported to achieve better sensitivity compared to spatial domain methods. However, these techniques produce smoothed statistical maps which are difficult to interpret. The generated maps have to be thresholded again in the spatial domain to delineate active from inactive regions. The selection of a proper threshold satisfying the required error rate control is not straightforward. In this paper, a framework is proposed for thresholding wavelet-denoised maps in which a rejection region is fixed, and the achieved false discovery rate (FDR) is estimated. This approach provides a meaningful strategy to choose thresholds for wavelet-denoised statistical parametric maps (SPMs). Two FDR estimation algorithms were used to assess the achieved error rate control when thresholding wavelet filtered SPMs at various rejection regions. Their performance was evaluated using both simulated and resting fMRI data. The proposed framework was also applied on in vivo data.

Quantitative trait loci on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18 control variation in levels of T and B lymphocyte subpopulations.

Lymphocyte subpopulation levels are used for prognosis and monitoring of a variety of human diseases, especially those with an infectious etiology. As a primary step to defining the major gene variation underlying these phenotypes, we conducted the first whole-genome screen for quantitative variation in lymphocyte count, CD4 T cell, CD8 T cell, B cell, and natural killer cell numbers, as well as CD4:CD8 ratio. The screen was performed in 15 of the CEPH families that form the main human genome genetic project mapping resource. Quantitative-trait loci (QTLs) that account for significant proportions of the phenotypic variance of lymphocyte subpopulations were detected on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18. The most significant QTL found was for CD4 levels on chromosome 8 (empirical P=.00005). Two regions of chromosome 4 showed significant linkage to CD4:CD8 ratio (empirical P=.00007 and P=.003). A QTL for the highly correlated measures of CD4 and CD19 levels colocalized at 18q21 (both P=.003). Similarly, a shared region of chromosome 1 was linked to CD8 and CD19 levels (P=.0001 and P=.002, respectively). Several of the identified chromosome regions are likely to harbor polymorphic candidate genes responsible for these important human phenotypes. Their discovery has important implications for understanding the generation of the immune repertoire and understanding immune-system homeostasis. More generally, these data show the power of an integrated human gene-mapping approach for heritable molecular phenotypes, using large pedigrees that have been extensively genotyped.

Impaired detection of variable duration embedded tones in ectopic NZB/BINJ mice.

Utilizing rodent models, prior research has demonstrated a significant association between focal neocortical malformations (i.e. induced microgyria, molecular layer ectopias), which are histologically similar to those observed in human dyslexic brains, and rate-specific auditory processing deficits as seen in language impaired populations. In the current study, we found that ectopic NZB/BINJ mice exhibit significant impairments in detecting a variable duration 5.6 kHz tone embedded in a 10.5 kHz continuous background, using both acoustic reflex modification and auditory event-related potentials (AERP). The current results add further support to the association between focal cortical malformations and impaired auditory processing, and the notion that these auditory effects may occur regardless of the cortical location of the anomaly.

A locus for febrile seizures (FEB3) maps to chromosome 2q23-24.

Febrile seizures are the most common form of childhood seizures, occurring in 2% to 5% of North American children. We report a large Utah family with 21 members affected by febrile seizures inherited as an autosomal dominant trait. All had generalized tonic-clonic seizures with onset associated with fever, consistent with the consensus febrile seizure phenotype, and none had febrile seizures beyond 6 years of age. Eighteen affected individuals had recurrent febrile seizures. Eight individuals developed afebrile seizures between ages 5 and 13 years. Afebrile seizures consisted of generalized tonic-clonic, generalized tonic, generalized atonic, simple partial, and partial complex seizure types and were associated with abnormal electroencephalographic findings in 5 individuals, all of whom were intellectually normal. We undertook linkage analysis in this family, defining the disease phenotype as febrile seizures alone. Linkage analysis in epilepsy candidate gene/loci regions failed to show evidence for linkage to febrile seizures. However, a genomewide scan and subsequent fine mapping revealed significant evidence for a new febrile seizure locus (FEB3) on chromosome 2q23-24 with linkage to the marker D2S2330 (LOD score 8.08 at theta = 0.001). Haplotype analysis defined a critical 10-cM region between markers D2S141 and D2S2345 that contains the FEB3 locus.

Microcephaly with simplified gyral pattern in six related children.

We describe clinical and neurophysiological findings in six related children with congenital microcephaly, seizures that began within the first 2-4 months of life, and severe mental retardation (MR). These affected children (five girls and one boy), born to two women who are half-sisters, inherited the disease as an autosomal recessive trait. Physical examination of these children did not show any of the anomalies in the known cortical malformation syndromes such as lissencephaly types I and II. Neuroradiological studies in these children documented microcephaly and a simplified gyral pattern with no pachygyria. Chromosomal analysis showed neither karyotypic abnormalities nor a microdeletion at 17p13.3, site of the lissencephaly type I gene locus (LIS1). Genetic studies failed to show linkage of this family to LIS1, LIS2 (a region on chromosome 2p homologous to LIS1), or MCPH1 (a locus for primary autosomal recessive microcephaly). The unique clinical and genetic findings in this family suggest that these children may be affected by an as-of-yet unmapped neuronal proliferation disorder.

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of severe central visual impairment among the elderly and is associated both with environmental factors such as smoking and with genetic factors. Here, 167 unrelated AMD patients were screened for alterations in ABCR, a gene that encodes a retinal rod photoreceptor protein and is defective in Stargardt disease, a common hereditary form of macular dystrophy. Thirteen different AMD-associated alterations, both deletions and amino acid substitutions, were found in one allele of ABCR in 26 patients (16%). Identification of ABCR alterations will permit presymptomatic testing of high-risk individuals and may lead to earlier diagnosis of AMD and to new strategies for prevention and therapy.

A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy.

Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbour the STGD gene. This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization. Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage. These data indicate that ABCR is the causal gene of STGD/FFM.

[The diagnosis of facial asymmetry]. / Le diagnostic des asymétries faciales.

Diagnosis of aetiology of facial asymmetry is dependent on results of clinical and complementary examinations. Its most frequent causes are illustrated by several case reports.

Hormonal regulation of type II glucocorticoid receptor messenger ribonucleic acid in rat brain.

Differences in the regulation of type II glucocorticoid receptor (GR) mRNA levels in female rat brain regions involved in the control of the hypothalamic-pituitary-adrenal axis were studied by Northern blot analysis after chronic administration of corticosterone or dexamethasone to adrenalectomized (ADX), ovariectomized (OVX), and ADX/OVX animals. The effect of chronic estradiol or progesterone treatment of intact animals was also studied. Our results show that type II GR mRNA levels of ADX animals were significantly increased above control values in amygdala (140%) and hippocampus (196%), but not in hypothalamus. These increased transcript levels were down-regulated by corticosterone or dexamethasone, with the exception of those in the amygdala, where corticosterone had no effect. Ovariectomy significantly increased hypothalamic GR mRNA content (174%) over control values, and this increase was sensitive to dexamethasone. The combined effect of adrenalectomy/ovariectomy on GR mRNA levels was greater than that of adrenalectomy only in amygdala. Corticosterone increased amygdala transcript levels in OVX and ADX/OVX animals. Estradiol administration to intact animals raised the GR mRNA content of amygdala, while progesterone treatment had no effect on any of the brain regions studied. We conclude that there exists heterogeneity with respect to type II GR mRNA regulation by corticosterone and dexamethasone in brain regions of ADX female rats, and that certain limbic structures show greater sensitivity to these hormonal manipulations, suggesting a more prominent role in the regulation of the hypothalamic-pituitary-adrenal axis. Our results also suggest that circulating estrogens can influence the sensitivity of brain structures (i.e. hypothalamus and amygdala) to glucocorticoids by altering GR mRNA levels. These regions may represent integration sites at which gonadal steroids are able to alter stress hormone secretion.

Age-related changes in glucocorticoid receptor binding and mRNA levels in the rat brain and pituitary.

Hypothalamic-pituitary-adrenal (HPA) activity under both basal and poststress conditions is often increased in the aged rat. This change has been associated with the loss of corticosteroid receptors in specific regions that mediate glucocorticoid negative feedback. In order to study the cellular basis for the loss of receptors, we measured glucocorticoid (type II corticosteroid) receptor binding and mRNA levels in pituitary and selected brain regions in rats at 6, 12, and 24 months of age. Receptor binding, measured using [3H]RU 28362, was stable in all regions (pituitary, hypothalamus, amygdala, and frontal cortex) except the hippocampus, where there was about a 40% decrease in binding capacity, with no change in the affinity of the receptor for RU 28362. The loss of receptors in the hippocampus was apparent in animals at 12 months of age, and binding was further decreased at 24 months. Glucocorticoid receptor mRNA levels were significantly higher in all regions at 12 months of age than at 6 months. By 24 months, however, receptor mRNA levels in most regions had returned to levels that were similar to those at 6 months of age. In contrast, glucocorticoid receptor mRNA levels in the hippocampus were significantly decreased at 24 months of age compared to levels at both 6 and 12 months of age. Thus, in general, variations in receptor mRNA levels parallel those in receptor binding in animals 6 and 24 months of age, with the hippocampus as the only region showing a significant loss of receptors and a decrease in mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain.

The effect of imipramine, desipramine, ketanserin and lithium on Type II glucocorticoid receptor (GR) mRNA levels was studied in rat brain regions involved in the control of the hypothalamo-pituitary-adrenal (HPA) axis, the dysregulation of which has been implicated in the pathophysiology of major depression. Northern blot analysis of Type II GR mRNA showed that treatment of male rats with either desipramine or imipramine increased hypothalamic and hippocampal GR mRNA levels. Upregulation of GR mRNA following administration of imipramine was found in brain regions of female rats, while desipramine had no effect. Ketanserin increased levels of GR mRNA in hippocampus of male, but not female, rats. Lithium also was able to induce important increases rat brain GR mRNA; this effect was particularly marked in females. We conclude that desipramine, imipramine, ketanserin and lithium can modulate GR mRNA in regions of rat brain involved in the control of the HPA axis and may have a common mechanism of action at the level of the GR gene. Sexual dimorphism for drug regulation of brain GR mRNA content was shown and may be related to sex differences in the prevalence of certain affective disorders.

[Mandibular reconstruction using a pedicled osteomyocutaneous flap of the latissimus dorsi]. / Reconstruction mandibulaire par lambeau ostéomyocutané pédiculé de grand dorsal.

The authors report their experience with reconstruction of loss of mandibular substance due to wide or complicated resections for cancer. A series of 8 reconstructions using a latissimus dorsi osteo-myocutaneous pediculated flap and the 10th rib helped to define the advantages and disadvantages of this form of complex flap. Since a latissimus dorsi pediculated flap has classically been used in maxillo-facial reconstruction, an osteo-myocutaneous flap, including a portion of the 10th rib, is naturally appropriate for the reconstruction of a major loss of substance involving the mandible and related structures. The separation technique and trans-cervical transposition are described. The advantages of this form of flap are the ease with which it may be detached and the reliability of the vascular pedicle. The principal disadvantages are the relatively large volume, the difficulty in dissociating the cutaneous layer from the bony layer and the difficulties involved in the fixation of the bone graft to a prosthetic plate. Problems with rehabilitation are also discussed.

Estrogen-induced decrease of glucocorticoid receptor messenger ribonucleic acid concentration in rat anterior pituitary gland.

Using Northern blots and hybridization techniques, we have identified an approximately 6.5 kilobase glucocorticoid receptor mRNA species in rat anterior pituitary gland. Ovariectomy resulted in an approximately 2-fold increase in glucocorticoid receptor mRNA concentrations. This effect was maximal 8 days after surgery and glucocorticoid receptor mRNA levels remained elevated for at least up to 4 weeks. Administration of 17-beta-estradiol completely reversed the ovariectomy-induced increase in glucocorticoid receptor mRNA content of pituitary gland. Treatment of rats with corticosterone did not influence the ovariectomy-induced increase in glucocorticoid receptor mRNA content, indicating that this increase is not mediated via effects on circulating glucocorticoid levels or availability. In situ hybridization experiments confirmed the ovariectomy-induced increase in glucocorticoid receptor mRNA content and indicated that this action is widely distributed throughout the anterior pituitary gland.

Phosphorylation of zymogen granule membrane proteins in intact rat pancreatic acinar cells.

Phosphorylated substrates of molecular weights 130,000, 70,000, and 29,000, were identified by SDS-gel electrophoresis in zymogen granule membranes of rat pancreatic acinar cells incubated in vitro with protein kinase catalytic subunit. However, when intact cells were incubated with [32P]-orthophosphate, only the 29,000 molecular weight protein was phosphorylated.