A lateral-to-mesial organization of human ventral visual cortex at birth.

In human adults, ventral extra-striate visual cortex contains a mosaic of functionally specialized areas, some responding preferentially to natural visual categories such as faces (fusiform face area) or places (parahippocampal place area) and others to cultural inventions such as written words and numbers (visual word form and number form areas). It has been hypothesized that this mosaic arises from innate biases in cortico-cortical connectivity. We tested this hypothesis by examining functional resting-state correlation at birth using fMRI data from full-term human newborns. The results revealed that ventral visual regions are functionally connected with their contra-lateral homologous regions and also exhibit distinct patterns of long-distance functional correlation with anterior associative regions. A mesial-to-lateral organization was observed, with the signal of the more lateral regions, including the sites of visual word and number form areas, exhibiting higher correlations with voxels of the prefrontal, inferior parietal and temporal cortices, including language areas. Finally, we observed hemispheric asymmetries in the functional correlation of key areas of the language network that may influence later adult hemispheric lateralization. We suggest that long-distance circuits present at birth constrain the subsequent functional differentiation of the ventral visual cortex.

Parent coaching increases the parents' capacity for reflection and self-evaluation: results from a clinical trial in autism.

Family-centered parent coaching interventions in autism strive to encourage family engagement and support parent reflection and self-evaluation. This includes the parents' capacity to: (1) carefully observe the child's behavior; (2) reflect upon the child's thoughts, motives, and feelings; (3) consider links between the child's internal experiences and observable behavior; and (4) grapple with the complex interplay among the child's experiences and behaviors, contextual factors, parenting strategies, as well as parental goals and emotions. The current study reports data from a clinical trial of Focused Playtime Intervention (FPI), a parent coaching intervention targeting responsive parental behaviors and child communication. Seventy children with autism between 2 and 6 years and their parents were randomly assigned to participate in FPI for 12 weeks or an active control intervention. The Insightfulness Assessment was administered and used (a) to classify parents' baseline capacity for reflection and self-evaluation as either established (i.e., positively insightful) or emerging, and (b) to capture longitudinal change in the parents' capacity between baseline, exit (~5 months after baseline), and follow up (~14 months after exit) using a dimensional composite subscale score. Results revealed a significant treatment effect of FPI on growth in the parents' capacity for reflection and self-evaluation, conditional on the parents' classification at baseline. That is, parents whose capacity for reflection and self-evaluation was classified as emerging at baseline (n = 42) showed higher rates of growth when assigned to FPI, compared to the control condition. A similar treatment effect was not found for parents whose baseline capacity for reflection and self-evaluation was classified as established (i.e., positively insightful). This is the first study to show that a family-centered parent coaching intervention effectively increases the capacity for reflection and self-evaluation in parents of young children with autism. This capacity may enable parents to adapt and implement intervention strategies flexibly across contexts, daily routines, and interactions.

High-quality human and rat spermatozoal RNA isolation for functional genomic studies.

Sperm RNA is a sensitive monitoring endpoint for male reproductive toxicants, and a potential biomarker to assess male infertility and sperm quality. However, isolation of sperm RNA is a challenging procedure due to the heterogeneous population of cells present in the ejaculate, the low yield of RNA per spermatozoon, and the absence of 18S and 28S ribosomal RNA subunits. The unique biology of spermatozoa has created some uncertainty in the field about RNA isolation methods, indicating the need for rigorous quality control checks to ensure reproducibility of data generated from sperm RNA. Therefore, we developed a reliable and effective protocol for RNA isolation from rat and human spermatozoa that delivers highly purified and intact RNA, verified using RNA-specific electrophoretic chips and molecular biology approaches such as RT-PCR and Western blot analysis. The sperm RNA isolation technique was optimized using rat spermatozoa and then adapted to human spermatozoa. Three steps in the sperm isolation procedure, epididymal fluid collection, sperm purification, and spermatozoon RNA extraction, were evaluated and assessed. The sperm RNA extraction methodology consists of collection of rat epididymal fluid with repeated needle punctures of the epididymis, somatic cell elimination using detergent-based somatic cell lysis buffer (SCLB) and the use of RNA isolation Kit. Rat sperm heads are more resistant to disruption than human spermatozoa, necessitating the addition of mechanical lysis with microbeads and heat in the rat protocol, whereas the human sperm protocol only required lysis buffer. In conclusion, this methodology results in reliable and consistent isolation of high-quality sperm RNA. Using this technique will aid in translation of data collected from animal models, and reproducibility of clinical assessment of male factor fertility using RNA molecular biomarkers.

Intra- and inter-individual differences in human sperm DNA methylation.

There is growing evidence that sperm DNA methylation is important in maintaining proper sperm health and function. Previous studies have associated sperm DNA methylation levels with sperm quality and function, however, little is known regarding the intra- and inter-individual variability in sperm methylation levels. This study characterizes this variation. Sperm epigenetic differences between successive semen samples from 12 patients were examined to identify the intra- and inter-individual differences globally across the genome, and in specifically defined genomic regions using the Illumina Infinium HumanMethylation450 BeadChips. Methylation analysis identified a bimodal distribution in the methylation levels that were non-uniformly distributed across the different genomic regions. The methylation levels were highly correlated in both the intra- and inter-individual comparisons. The intra-individual methylation levels were more highly correlated than the inter-individual comparison both globally and across the defined genomic regions, demonstrating that sperm DNA methylation levels are relatively stable between semen sample collections.

Iridium(iii)-bis(imidazolinyl)phenyl catalysts for enantioselective C-H functionalization with ethyl diazoacetate.

The intermolecular enantioselective C-H functionalization with acceptor-only metallocarbenes is reported using a new family of Ir(iii)-bis(imidazolinyl)phenyl catalysts, developed based on the interplay of experimental and computational insights. The reaction is tolerant of a variety of diazoacetate precursors and is found to be heavily influenced by the steric and electronic properties of the substrate. Phthalan and dihydrofuran derivatives are functionalized in good yields and excellent enantioselectivities.

Assessment of EndoPAT scores in men with vasculogenic and non-vasculogenic erectile dysfunction.

PURPOSE: The role of endothelial function testing using peripheral artery tonometry (PAT) in the evaluation of ED is not well established. Endothelial dysfunction is expected to be more common in men presenting with general or vasculogenic ED, compared with men who develop ED after prostatectomy. This study evaluated whether PAT could help identify men in whom endothelial cell dysfunction was the underlying cause of ED. MATERIALS AND METHODS: A chart review of 194 men with general ED and 98 men with postprostatectomy ED was performed to abstract data on demographics, medical comorbidities, SHIM-5 scores and EndoPAT scores. Patients with preoperative ED were excluded. Statistical analysis using Student's t-test and Chi-squared analysis was performed to compare the two groups of men with respect to these variables. RESULTS: EndoPAT scores were not significantly different between men with general vs. postprostatectomy ED (1.97 vs. 2.08, p = 0.074). There was no relationship between EndoPAT and SHIM-5 scores in the general ED cohort. The prevalence of hypertension, hyperlipidaemia and cardiovascular (CV) disease was similar between the two groups, but diabetes and hypogonadism were more prevalent in men with general ED (21% vs. 9%, and 28% vs. 7%, p < 0.015). Overall, EndoPAT scores in postprostatectomy men with at least one risk factor were not significantly different compared with men with general ED with the same comorbidity, or a combination of two or more comorbidities. CONCLUSIONS: The value of EndoPAT testing in the clinical evaluation of ED patients is questionable.

A quantitative philology of introspection.

The cultural evolution of introspective thought has been recognized to undergo a drastic change during the middle of the first millennium BC. This period, known as the "Axial Age," saw the birth of religions and philosophies still alive in modern culture, as well as the transition from orality to literacy-which led to the hypothesis of a link between introspection and literacy. Here we set out to examine the evolution of introspection in the Axial Age, studying the cultural record of the Greco-Roman and Judeo-Christian literary traditions. Using a statistical measure of semantic similarity, we identify a single "arrow of time" in the Old and New Testaments of the Bible, and a more complex non-monotonic dynamics in the Greco-Roman tradition reflecting the rise and fall of the respective societies. A comparable analysis of the twentieth century cultural record shows a steady increase in the incidence of introspective topics, punctuated by abrupt declines during and preceding the First and Second World Wars. Our results show that (a) it is possible to devise a consistent metric to quantify the history of a high-level concept such as introspection, cementing the path for a new quantitative philology and (b) to the extent that it is captured in the cultural record, the increased ability of human thought for self-reflection that the Axial Age brought about is still heavily determined by societal contingencies beyond the orality-literacy nexus.

Can family affectedness inform infant sibling outcomes of autism spectrum disorders?

BACKGROUND: Difficulties in communication and reciprocal social behavior are core features of autism spectrum disorders (ASD) and are often present, to varying degrees, in other family members. This prospective longitudinal infant sibling study examines whether social-communicative features of family members may inform which infants are at increased risk for ASD and other developmental concerns. METHOD: Two hundred and seventeen families participated in this study. Infant siblings were recruited from families with at least one older child diagnosed with an ASD (n = 135) or at least one typically developing older child (n = 82). Families completed the Social Responsiveness Scale to assess social and communication features of the broader autism phenotype (BAP), sometimes called quantitative autistic traits (QAT). Family affectedness was assessed in two ways: categorically, based on number of affected older siblings (i.e., typical, simplex, multiplex risk groups) and dimensionally, by assessing varying degrees of QAT in all family members. Infant siblings were assessed at 36 months of age and completed the Autism Diagnostic Observation Schedule and the Mullen Scales of Early Learning. RESULTS: In structural equation models, comparisons between multiplex, simplex and typical groups revealed the highest rates of QAT in the multiplex group followed by the simplex and typical groups. Infant sibling outcomes were predicted by gender, family risk group, proband QAT, and additional sibling QAT. CONCLUSIONS: Replicating previous cross-sectional and family history findings, the present study found elevated social and communication features of the BAP in siblings and fathers of ASD families, but not in mothers. While social and communication features of the BAP in mothers, fathers, and undiagnosed siblings did not predict infant sibling outcomes, having more than one affected older sibling did. Infant siblings from multiplex families were at significantly higher risk for ASD than infant siblings from simplex families in this sample.

Computational models for detection of endocrinopathy in subfertile males.

The observation that men with sperm density greater than 10 million/ml had low probability of endocrinopathy led to a refinement in the evaluation of subfertility. Using statistical methods, we sought to provide a more accurate prediction of which patients have an endocrinopathy, and to report the outcome as the odds of having disease. In addition, by examining the parameters that influenced the model significantly, the underlying pathophysiology might be better understood. Records of 1035 men containing variables including testis volume, sperm density, motility as well as the presence of endocrinopathy were randomized into 'training' and 'test' data sets. We modeled the data set using linear and quadratic discriminant function analysis, logistic regression (LR) and a neural network. Wilk's regression analysis was performed to determine which variables influenced the model significantly. Of the four models investigated, LR and a neural network performed the best with receiver operating characteristic areas under the curve of 0.93 and 0.95, respectively, correlating to a sensitivity of 28% and a specificity of 99% for the LR model, and a sensitivity and specificity of 56 and 97% for the neural network model. Reverse regression yielded P-values for the testis volume and sperm density of <0.0001. The neural network and LR models accurately predicted the probability of an endocrinopathy from testis volume, sperm density and motility without serum assays. These models may be accessed via the Internet, allowing urologists to select patients for endocrinologic evaluation at http://www.urocomp.org.

Parsing a sequence of brain activations at psychological times using fMRI.

Identifying the sequence of computations which constitute a cognitive task is a fundamental problem in neuroscience. Here we show, using functional magnetic resonance imaging (fMRI), that we can parse, at the time scale of about 100 ms, the different stages of brain activations which compose a complex sequential task. To identify timing information from the slow blood oxygen level-dependent (BOLD) signal response, we use a simple analytic method, based on periodic stimulation and an analysis of covariation of the spectral parameters (phase and power spectrum at the stimulation frequency) with the different experimental conditions. We implement this strategy in a sequential task, where the onset and duration of different stages are under experimental control. We are able to detect changes in onset latency and in the duration of the response, in an invariant fashion across different brain regions, and reconstruct the stream of activations consistent with five distinct stages of processing of the task. Sensory and motor clusters activate in the expected order and for the expected duration. The timing of sensory activations is more precise than the timing of motor activation. We also parse in time the reading-verbal network: visual extrastriate and phonological access regions (supramarginal gyrus) activate at the time of word presentation, while the inferior frontal gyrus, the anterior cingulate and the supplementary motor area are activated during the rehearsal period.

Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanism for partial hexasomy.

Rearrangements of chromosome 15q, including isodicentric 15 chromosomes and interstitial duplications and triplications, have been previously reported in association with autism spectrum disorders. We have identified two boys with exceptionally large der(15) chromosomes that are tricentric and contain four copies of the proximal long arm, including the Prader Willi/Angelman critical region, and leading to hexasomy of the involved segment. Biallelic inheritance of maternal alleles and methylation analysis indicate that the markers are maternally derived. Clinical assessment of the boys indicated severe cognitive impairment associated with marked delays in gross and fine motor skills. Social and language deficits were present in both, although the severity of the mental retardation precluded diagnosis of autism (both were considered to have pervasive developmental disorder-not otherwise specified). Neurologic manifestations included infantile spasms evolving into intractable early-onset myoclonic seizures, psychomotor regression, and profound diffuse hypotonia. These patients represent the most severe end of the spectrum of phenotypes associated with segmental aneuploidy for chromosome 15q11-q13.

The neural basis of perceptual learning.

Perceptual learning is a lifelong process. We begin by encoding information about the basic structure of the natural world and continue to assimilate information about specific patterns with which we become familiar. The specificity of the learning suggests that all areas of the cerebral cortex are plastic and can represent various aspects of learned information. The neural substrate of perceptual learning relates to the nature of the neural code itself, including changes in cortical maps, in the temporal characteristics of neuronal responses, and in modulation of contextual influences. Top-down control of these representations suggests that learning involves an interaction between multiple cortical areas.

Links between social understanding and social behavior in verbally able children with autism.

This study investigated the relations between various measures of social understanding and social interaction competence in verbally able children with autism. Measures of social understanding included measures of verbalizable knowledge (false belief understanding, affective perspective taking), as well as measures of more intuitive forms of social responsiveness (empathy, concern to distress, and initiating joint attention). Two measures of social interaction competence were employed: level of engagement with peers on the playground, and prosocial behavior in a structured laboratory task. For children with autism, initiating joint attention and empathy were strongly related to both measures of social interaction competence. No understanding-behavior links were identified for a language-age matched comparison sample of developmentally delayed children. Several accounts of these understanding-behavior links are considered, including the possibility that for children with autism, more impaired forms of understanding are more closely linked to behavior because they serve as limits on competence.

Performance evaluation of an in-injection port thermal desorption/gas chromatographic/negative ion chemical ionization mass spectrometric method for trace explosive vapor analysis.

A gas chromatographic method utilizing thermal desorption of Tenax TA and sol-gel sorbent traps has been developed and validated for the analysis of trace explosive vapor with negative ion chemical ionization mass spectrometric detection. Sorbent tubes were packed with Tenax TA and sorbent particles prepared in-house by the sol-gel process. Thermal desorption was performed within a split/splitless injection port with minimal instrument modification. Performance was characterized by relative thermal desorption recovery, precision (reproducibility), linearity of the calibration, and method detection limits. Method validation was performed with a series of dinitrotoluenes, dinitrobenzene, trinitrotoluene, trinitrobenzene, two aminodinitrotoluenes, three nitroesters, and two nitramines. The performance of Tenax TA and the sol-gel sorbents is evaluated based on the method validation data. The method was applied to the analysis of trace explosive vapor collected and concentrated with sol-gel solid sorbent traps from the headspace of a smokeless gunpowder sample.

Detection limits for GC/MS analysis of organic explosives.

Method detection limits are determined and compared for analysis of liquid injections of organic explosives and related compounds by gas chromatography-mass spectroscopy utilizing electron impact (EI), negative ion chemical ionization (NICI), and positive ion chemical ionization (PICI) detection methods. Detection limits were rigorously determined for a series of dinitrotoluenes, trinitrotoluene, two nitroester explosives, and one nitramine explosive. The detection limits are lower by NICI than by EI or PICI for all explosives examined, with the exception of RDX. The lowest detection limit for RDX was achieved in the PICI ionization mode. Judicious choice of the appropriate ionization mode can enhance selectivity and significantly lower detection limits. Major ions are reported for each analyte in EI, PICI, and NICI detection modes.

On a common circle: natural scenes and Gestalt rules.

To understand how the human visual system analyzes images, it is essential to know the structure of the visual environment. In particular, natural images display consistent statistical properties that distinguish them from random luminance distributions. We have studied the geometric regularities of oriented elements (edges or line segments) present in an ensemble of visual scenes, asking how much information the presence of a segment in a particular location of the visual scene carries about the presence of a second segment at different relative positions and orientations. We observed strong long-range correlations in the distribution of oriented segments that extend over the whole visual field. We further show that a very simple geometric rule, cocircularity, predicts the arrangement of segments in natural scenes, and that different geometrical arrangements show relevant differences in their scaling properties. Our results show similarities to geometric features of previous physiological and psychophysical studies. We discuss the implications of these findings for theories of early vision.

Helping mothers discuss sexuality and AIDS with adolescents.

The current study was designed to alter experimentally mothers' style when discussing sexuality and AIDS with their adolescent children. Mothers of 11- to 15-year-olds (N = 50) were assigned to an intervention or control group, resulting in 20 dyads in each group. All dyads were assessed twice, on self-reported and observed communication, AIDS knowledge, and perceived vulnerability to AIDS. Intervention group mothers received two training sessions. Observational data revealed that intervention group mothers reduced their amount of speaking, asked more open-ended questions, acted less judgmental, and discussed dating and sexuality more than did control group mothers. Intervention group adolescents reported increased discussions of birth control and increased daily comfort talking to their mothers. There was some evidence that intervention group girls increased in AIDS knowledge. There was no change in AIDS-related beliefs.