Feature uncertainty: a novel test to probe prefrontal dysfunction in unaffected siblings of schizophrenia patients

Previous studies indicated that neuropsychological impairments are potential endophenotypes of schizophrenia. However, the sensitivity of these procedures is not sufficient and their brain substrates are poorly defined. The aim of this study was to measure the behavioral performance of siblings of schizophrenia patients and controls on a novel feature uncertainty (FU) task that selectively activates dorsal anterior cingulate cortex relative to orientation (OR) and spatial frequency (SF) discrimination. During the FU task, two subsequent sinusoidal gratings are presented and participants are asked to remember both the OR and SF of the gratings. After the disappearance of the gratings, a color cue signifies the perceptual dimension (OR or SF) to discriminate. Results revealed that the siblings of schizophrenia patients (n = 25) showed a selective deficit on the FU task as compared with controls (n = 20). The FU deficit was more severe than that found on neuropsychological tests of executive functions, psychomotor speed, and verbal memory. These results suggest that anterior cingulate dysfunction is a potential endophenotype of schizophrenia.     

The order effect: reflections on the validity of multiple test presentations.

The effect of order has been previously addressed in test-retest studies but its effect on the presentation of more than one test, in the same time, is often underestimated. This study has shown that when two rating scales were given sequentially, each scored lower if received second in the pair, and that this particular form of order effect (occasion effect) was enough to affect markedly agreement on caseness when utilizing standard cut-off scores. It is therefore important that research workers not only adopt design strategies such as counterbalanced presentation, but also analyse their data for the effects of test order and position within such designs.     

From genotype to antibiotic susceptibility phenotype in the order Enterobacterales: a clinical perspective

ObjectivesPredicting the antibiotic susceptibility phenotype from genomic data is challenging, especially for some specific antibiotics in the order Enterobacterales. Here we aimed to assess the performance of whole genomic sequencing (WGS) for predicting the antibiotic susceptibility in various Enterobacterales species using the detection of antibiotic resistance genes (ARGs), specific mutations and a knowledge-based decision algorithm.MethodsWe sequenced (Illumina MiSeq, 2×250 bp) 187 clinical isolates from species possessing (n = 98) or not (n = 89) an intrinsic AmpC-type cephalosporinase. Phenotypic antibiotic susceptibility was performed by the disc diffusion method. Reads were assembled by A5-miseq and ARGs were identified from the ResFinder database using Diamond. Mutations on GyrA and ParC topoisomerases were studied. Piperacillin, piperacillin-tazobactam, ceftazidime, cefepime, meropenem, amikacin, gentamicin and ciprofloxacin were considered for prediction.ResultsA total of 1496 isolate/antibiotic combinations (187 isolates × 8 antibiotics) were considered. In 230 cases (15.4%), no attempt of prediction was made because it could not be supported by current knowledge. Among the 1266 attempts, 1220 (96.4%) were correct (963 for predicting susceptibility and 257 for predicting resistance), 24 (1.9%) were major errors (MEs) and 22 (1.7%) were very major errors (VMEs). Concordance were similar between non-AmpC and AmpC-producing Enterobacterales (754/784 (96.2%) vs 466/482 (96.7%), chi-square test p 0.15), but more VMEs were observed in non-AmpC producing strains than in those producing an AmpC (19/784 (2.4%) vs 3/466 (0.6%), chi-square test p 0.02). The majority of VMEs were putatively due to the overexpression of chromosomal genes.ConclusionsIn conclusion, the inference of antibiotic susceptibility from genomic data showed good performances for non-AmpC and AmpC-producing Enterobacterales species. However, more knowledge about the mechanisms underlying the derepression of AmpC are needed.     

Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dysplasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias.     

A goodness-of-fit test for the polygenic threshold model: Application to multiple sclerosis

Recently it has been suggested that multiple sclerosis may be a multifactorial disorder. We found in British Columbia 364 families (sibship size ? 2) in which at least one sibling was diagnosed as having “clinically definite” multiple sclerosis. The data were tested for goodness-of-fit to the multifactorial model using an analysis that considers various parameters including ascertainment probability, heritability, and sex-dependent prevalence rates. The results suggest that multiple sclerosis does not fit the multifactorial model. As an alternative genetic model we propose that a major gene could be responsible for at least a portion of the cases of multiple sclerosis.     

Carpenter syndrome: Marked variability of expression to include the summitt and Goodman syndromes

Here we report on two sibs with Carpenter syndrome showing marked intrafamilial variability. One patient had craniosynostosis of the sagittal suture, normal intelligence, and no abnormalities of hands and feet. The second patient had polysyndactyly of hands and feet, normal intelligence, and no craniosynostosis. The diagnosis of Carpenter syndrome was made after the second affected child in the family was born. This report emphasizes previous suggestions that acrocephalopolysyndactyly, type II, has variable clinical expression. It is suggested that polysyndactyly of feet is not an absolute requisite for the diagnosis of Carpenter syndrome. This allows the inclusion of Summitt and Goodman syndromes within the clinical spectrum of this disorder.     

Regional variation in the incidence of schizophrenia in Finland: a study of birth cohorts born from 1950 to 1969

BACKGROUND: We investigated whether there is regional variation in the incidence of schizophrenia and if so. whether it is caused by urban-rural differences, larger spatial clustering, or both. To control for the effect of migration, we examined regional variation in the incidence according to place of birth. METHODS: Finnish birth cohorts born from 1950 to 1969 were followed in the National Hospital Discharge Register from 1969 until 1991, and all cases of schizophrenia (ICD-8 or ICD-9 295) were identified (N = 14828). Forty-eight of the 559 municipalities were classified as urban and 25% of the Finnish population lived in these municipalities in 1960. For the analysis of spatial clustering, municipalities were grouped into 57 functional small-areas. We used Poisson regression model with the number of births of individuals who later developed schizophrenia as a response variable, and place of birth (urban/rural), birth cohort (1950-54, 1955-9, 1960-64, and 1965-9), functional small-area units, and sex as response variables. RESULTS: The incidence was slightly higher among the rural-born in the oldest birth cohort. In the other cohorts, it was higher among the urban-born, and the difference between urban and rural born increased in the youngest cohorts. Significant spatial clustering of schizophrenia was observed in eastern Finland. CONCLUSIONS: Urban birth is a risk factor for schizophrenia in Finland in cohorts born since 1955. However, genuine spatial clustering of schizophrenia in eastern Finland was also observed, possibly caused by genetic isolation.     

Assessing sleepiness in the rat: a multiple sleep latencies test compared to polysomnographic measures of sleepiness

Sleepiness following 6 h of sleep deprivation (SD) was evaluated with a rat multiple sleep latencies test (rMSLT), and the findings were compared to conventional polysomnographic measures of sleepiness. The 6 h of SD was produced by automated activity wheels, and was terminated at either the end of the light period or at the beginning of the dark period. The rMSLT consisted of 5 min wakefulness induced by sensory stimulation followed by 25 min of freedom to sleep. This procedure was repeated every 30 min for 3 h and was designed to minimize the amount of sleep lost due to the testing procedure. In separate rats, 6 h SD was followed by undisturbed recovery, allowing evaluation of conventional polysomnographic measures of sleepiness. Sleep onset latencies were reduced following SD, with recovery in the light (baseline = 8 min, 3 s versus post-SD = 1 min, 17 s) and dark period (baseline = 14 min, 17 s versus 7 min, 7 s). Sleep onset latencies were not altered by varying the duration criterion for the first sleep bout (i.e., sleep bout length criteria of 10, 20, 30, or 60 s were compared). Polysomnographic variables (non-rapid eye movement sleep episode duration, delta power, and number of awakenings) also provided reliable indirect measures of sleepiness, regardless of whether the recovery sleep occurred in the light or dark period. Evaluation of effect size indicated that the rMSLT was a strong measure of sleepiness, and was influenced by homeostatic, circadian, and illumination factors. The rMSLT provided a simple, objective, robust and direct measure of sleepiness that was as effective as conventional polysomnographic measures of sleepiness.     

Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study.

Evidence for an involvement of aberrant homocysteine metabolism in the aetiology of schizophrenia is limited and controversial. A case-control study was performed to quantify the risk of schizophrenia in the presence of elevated homocysteine concentrations or homozygosity for the 677C --> T polymorphism (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene in subjects of Dutch ancestry. We determined the 677C --> T MTHFR genotype distribution in 254 well-defined patients and 414 healthy controls. Plasma homocysteine concentrations were measured in 62 patients with schizophrenia and 432 control subjects. When homocysteine concentrations were stratified into quartiles of the control distribution, we calculated an increased risk for schizophrenia in the fourth and third quartile versus the lowest quartile [odds ratio (OR) = 3.3; 95% confidence interval (CI): 1.2-9.2, and OR = 3.1; 95% CI: 1.2-8.0, respectively]. A significant dose-response relation of increasing homocysteine levels and increasing risk for schizophrenia was observed (P = 0.036). The 677TT genotype was associated with an OR of 1.6 [95% CI: 0.96-2.8] of having schizophrenia. Heterozygosity for the T allele compared to 677CC subjects accounted for an OR of 1.3 [95% CI: 0.91-1.8]. Elevated homocysteine levels and the MTHFR 677TT genotype are associated with an increased risk for schizophrenia. These observations support a causal relation between disturbed homocysteine metabolism and schizophrenia.     

Oculoectodermal syndrome with coarctation of the aorta and moyamoya disease: expanding the phenotype to include vascular anomalies

Oculoectodermal syndrome (OES, OMIM 600268) is characterized by discrete areas of alopecia of the scalp and epibulbar dermoids which are present from birth, with additional variable anomalies. We describe two patients, one of whom has been reported [Lees et al. (2000); Am J Med Genet 91:391–395], who both had coarctation of the descending aorta and moyamoya disease, and developed epilepsy, recurrent transient ischemic attacks, and cerebrovascular accidents during early childhood. We suspect that the vascular findings are an integral part of the syndrome. © 2011 Wiley‐Liss, Inc.     

First trimester fetal reduction: its role in the management of twin and higher order multiple pregnancies

Multiple pregnancy may be the result of stimulated or non-stimulated,and of assisted or natural conception. As observed in the pastdecade, assisted conception technologies have significantlyincreased the prevalence of multiple pregnancy. The increasehas been much more marked for triplets and higher order births.Rates of perinatal mortality and fetal and maternal complicationsare higher in twins than in singletons, and the adverse outcomerises with increasing number of multiples. Unplanned multiplepregnancy may be felt to be emotionally and physically so stressfulan experience as to drive patients to refusal of pregnancy itself,or to want to reduce the number of fetuses to an acceptablestandard. Fetal reduction techniques have emerged as a veryeffective medical approach to improve pregnancy outcome anda key option of patients trying to carry a pregnancy to term.Multiple fetuses are most frequently heterozygotes; thereforethe risk of each of them being affected by a Mendelian diseaseor sporadic chromosomal aberration is an independent probability.Thus, the incidence of genetic defects in at least one fetusis increased and directly related to the order of multiples,and this makes it worthwhile to offer karyotyping of the fetus(es)to be spared, before the reduction procedure takes place. Whena multiple pregnancy is established, one may conclude selectivereduction is the most effective therapeutic approach for reducingrisks.     

Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype

Tetrahydrobiopterin (BH4) responsiveness in patients with mutations in the phenylalanine hydroxylase (PAH) gene is a recently recognized subtype of hyperphenylalaninemia characterized by a positive BH4 loading test. According to recent estimates, this phenotype may be quite common, suggesting that a large group of individuals may benefit from BH4 substitution, eliminating the need of life-long dietary restrictions. This underscores the importance of identifying BH4-responsive patients in each population, establishing the association with specific PAH mutations. In this work, we describe the results of a pilot study performed with 31 Spanish PAH-deficient patients subjected to a BH4 loading test. Overall, 11/31 (37%) showed a positive response with a 30% decrease in blood Phe levels 8 h after the BH4 challenge, and three additional patients, considered slow responders, showed this decrease only after 12-16 h. We report for the first time a patient homozygous for a splicing mutation with a slow response, suggesting an effect of BH4 supplementation on PAH gene expression. Most of the responsive patients belong to the mild hyperphenylalaninemia (MHP) or mild phenylketonuria phenotypic groups. In MHP patients we report for the first time the results of parallel single Phe doses confirming the utility of these analyses for a better evaluation of the response. Genotype analysis confirms the involvement in the response of specific mutations (D415N, S87R, R176L, E390G, and A309V) present in hemizygous patients, and provide relevant information for the discussion of the potential mechanisms underlying BH4 responsiveness.     

Discordant phenylketonuria phenotypes in one family: the relationship between genotype and clinical outcome is a function of multiple effects.

Four members spanning three generations of one family have phenylketonuria of varying degrees of severity. Two first cousins were screened in the neonatal period and have had dietary phenylalanine restriction since diagnosis, the older patient having been classified as having more severe PKU and the younger one as having mild PKU. Their mutual grandfather and his older brother also have a significant hyperphenylalaninaemia and are of normal intelligence despite never having had restricted phenylalanine intake. Mutation analysis of the phenylalanine hydroxylase (PAH) gene has established that there are four different mutations, two in exon 2 (F39L and L48S) and two in exon 3 (R111X and S67P), which give rise to PKU in this family. In order to establish their relative severity, we screened the PKU populations of western Scotland and the south west of England for these mutations. The exon 3 mutations are rare; however, F39L is relatively common in Scotland and L48S in England. A comparison of diagnostic blood phenylalanine concentrations in subjects carrying L48S/null or F39L/null mutations with those carrying two null mutations suggest that these exon 2 mutations are less deleterious. Thus, in this family, the different biochemical phenotypes can be explained, in part, by different genotypes at the PAH locus but our results show that the relationship between genotype and clinical outcome is more complex and is a function of multiple effects.     

Auditory hallucinations and the P3a: Attention-switching to speech in schizophrenia

Background

In line with emerging research strategies focusing on specific symptoms rather than global syndromes in psychiatric disorders, we examined the functional neural correlates of auditory verbal hallucinations (AHs) in schizophrenia. Recent neuroimaging and behavioural evidence suggest altered early cognitive processes may be seen in patients with AH as a result of limited processing resources.

Methods

The P3a subcomponent of the P300, an event-related potential (ERP) index of early attention switching, was assessed in 12 hallucinating patients (HP), 12 non-hallucinating patients (NP) and 12 healthy controls (HC) within a passive two-tone auditory oddball paradigm using vowel phonemes. P3a amplitudes and latencies were measured in response to across-phoneme changes. Following P3a acquisition, patients indicated the duration, intensity and clarity of their auditory hallucinations during recording.

Results

Hallucinating patients exhibited smaller P3a amplitudes than non-hallucinating patients and healthy controls. In HPs, P3a amplitude was negatively correlated with AH trait scores.

Significance

These findings suggest that AHs are associated with impaired processing of speech as evidenced by altered P3a amplitudes to vowel phonemes. This finding may be due to limited cognitive resources available for incoming external stimuli due to a usurping of finite resources by AHs. The P3a may be a useful non-invasive tool for probing relationships between hallucinatory and neural states within schizophrenia and the manner in which auditory processing is altered in these afflicted patients.     

Auditory hallucinations and the P3a: Attention-switching to speech in schizophrenia

BackgroundIn line with emerging research strategies focusing on specific symptoms rather than global syndromes in psychiatric disorders, we examined the functional neural correlates of auditory verbal hallucinations (AHs) in schizophrenia. Recent neuroimaging and behavioural evidence suggest altered early cognitive processes may be seen in patients with AH as a result of limited processing resources.MethodsThe P3a subcomponent of the P300, an event-related potential (ERP) index of early attention switching, was assessed in 12 hallucinating patients (HP), 12 non-hallucinating patients (NP) and 12 healthy controls (HC) within a passive two-tone auditory oddball paradigm using vowel phonemes. P3a amplitudes and latencies were measured in response to across-phoneme changes. Following P3a acquisition, patients indicated the duration, intensity and clarity of their auditory hallucinations during recording.ResultsHallucinating patients exhibited smaller P3a amplitudes than non-hallucinating patients and healthy controls. In HPs, P3a amplitude was negatively correlated with AH trait scores.SignificanceThese findings suggest that AHs are associated with impaired processing of speech as evidenced by altered P3a amplitudes to vowel phonemes. This finding may be due to limited cognitive resources available for incoming external stimuli due to a usurping of finite resources by AHs. The P3a may be a useful non-invasive tool for probing relationships between hallucinatory and neural states within schizophrenia and the manner in which auditory processing is altered in these afflicted patients.     

Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test

Linkage and association studies in complex diseases are used to identify and fine map disease loci. The process of identifying the aetiological polymorphism, the molecular variant responsible for the linkage and association of the chromosome region with disease, is complicated by the low penetrance of the disease variant, the linkage disequilibrium between physically-linked polymorphic markers flanking the disease variant, and the possibility that more than one polymorphism in the most associated region is aetiological. It is important to be able to detect additional disease determinants in a region containing a cluster of genes, such as the major histocompatibility complex (MHC) region on chromosome 6p21. Some methods have been developed for detection of additional variants, such as the Haplotype Method, Marker Association Segregation Chi-squares (MASC) Method, and the Homozygous Parent Test. Here, the Extended Transmission/Disequilibrium Test is adapted to test for association conditional on a previously associated locus. This test is referred to as the Conditional Extended TDT (CETDT). We discuss the advantages of the CETDT compared to existing methods and, using simulated data, investigate the effect of polymorphism, inheritance, and linkage disequilibrium on the CETDT.