Search

This study investigated conversational timing patterns among 22 children aged 3 years as each interacted with an adult. Most of the children were at high familial risk for dyslexia. When reading was tested in grade school, a group of 11 children was found to have dyslexia and the remaining 11 children read normally. At the age of 3 years, the 2 groups showed different patterns of timing in conversation. In comparison with children without dyslexia, those with dyslexia were significantly more likely to wait for adults to finish their speaking turn, and then offer a response that was semantically related to the adult's speech. The 2 groups did not differ in the percentage of no-responses defined as an absence of speech during the 2 seconds following the completion of an adult speaking turn. The results are discussed in terms of speech timing during child-adult interaction and spoken language deficits in dyslexia. [ABSTRACT FROM AUTHOR]

Scholars have addressed a range of questions about language development, but for some reason have neglected to ask why infants begin to talk. Biologists often prefer 'how 'to 'why' questions, but it is possible to ask about the immediate consequences of developing behaviours -- an acceptable strategy for attacking causation - and psycholinguists can study the immediate consequences to the infant of behaviours that lead to linguistic competence. This process is demonstrated with a series of illustrative proposals as to the short- and long-term consequences of vocal learning and utterance storage, two developmental phases that lead to talking, as well as the act of talking itself. The goal is to encourage investigation of behavioural dispositions that nudge the child, by degrees, towards proficiency in the use of spoken language. [ABSTRACT FROM AUTHOR]

Early childhood stress is a risk factor for the development of substance-abuse disorders. A nonhuman primate model of early life stress, social impoverishment through nursery-rearing rather than mother-rearing, has been shown to produce increased impulsive and anxiety-like behaviors, cognitive and motor deficits, and increased alcohol consumption. These behavioral changes have been linked to changes in cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin (5-HT) metabolite. The effects of different rearing conditions on ethanol drinking and three measures of 5-HT function in the central nervous system were evaluated, including CSF 5-HIAA levels and tissue levels of 5-HT and 5-HIAA in brain samples. Brain samples were taken from the dorsal caudate, putamen, substantia nigra (SN) pars reticulata, SN pars compacta and hippocampus. There was a clear effect of rearing condition on the 5-HT system. Overall 5-HIAA and 5-HIAA/5-HT ratio measures of 5-HT turnover were significantly lower in nursery reared compared to mother-reared animals. In addition, there was a strong within-subject correlation between CSF and brain tissue 5-HIAA levels. Ethanol drinking was greater in nursery reared monkeys, consistent with previous results. These findings show that CSF 5-HIAA measurements can be used to predict brain 5-HT activity that may be involved in behavioral outcomes such as anxiety and alcohol consumption. Thus, CSF sampling may provide a minimally invasive test for neurochemical risk factors related to alcohol abuse. [ABSTRACT FROM AUTHOR]

The Relative Age Effect (RAE) suggests older athletes within an annual cohort have advantages over their younger peers. We hypothesized that younger athletes could overcome these disadvantages through favorable α-actinin-3 ( ACTN3 ) and angiotensin converting enzyme ( ACE ) polymorphisms. This study aimed to: 1) examine RAE prevalence among Brazilian football players; 2) investigate the distribution of the ACTN3 and ACE polymorphisms; and 3) explore the association between polymorphisms and RAE across competitive levels and positions. The sample included 627 male players from first-division Brazilian teams in four age categories: U15 ( n  = 172), U17 ( n  = 166), U20 ( n  = 161), and Professionals ( n  = 128). A control group was established using data from the general Brazilian population documented in previous studies Results showed RAE presence across all competitive levels and positions. Players with the ACTN3 R allele, especially the RR genotype, had the strongest associations with football players, particularly among defenders. On the other hand, the distribution of ACE polymorphism was not significantly different between controls and players, except in the U17 category, where the I/I genotype was more common. Relatively older players had higher total genotype scores than younger counterparts in the overall sample and defender subgroups. In conclusion, RAE is prevalent among Brazilian football players, with older athletes benefiting from favorable ACTN3 and ACE polymorphisms, contrary to our initial hypothesis.

Synaptogyrin-3, a functionally obscure synaptic vesicle protein, interacts with vesicular monoamine and dopamine transporters, bringing together dopamine release and reuptake sites. Synaptogyrin-3 was reduced by chronic cocaine exposure in both humans and rats, and synaptogyrin-3 levels inversely correlated with motivation to take cocaine in rats. Synaptogyrin-3 overexpression in dopamine neurons reduced cocaine self-administration, decreased anxiety-like behavior, and enhanced cognitive flexibility. Overexpression also enhanced nucleus accumbens dopamine signaling and prevented cocaine-induced deficits, suggesting a putative therapeutic role for synaptogyrin-3 in cocaine use disorder.

In early 2020, one of the most prevalent symptoms of SARS-CoV-2 infection was the loss of smell (anosmia), found in 60-70% of all cases. Anosmia used to occur early, concomitantly with other symptoms, and often persisted after recovery for an extended period, sometimes for months. In addition to smell disturbance, COVID-19 has also been associated with loss of taste (ageusia). The latest research suggests that SARS-CoV-2 could spread from the respiratory system to the brain through receptors in sustentacular cells localized to the olfactory epithelium. The virus invades human cells via the obligatory receptor, angiotensin-converting enzyme II (ACE2), and a priming protease, TMPRSS2, facilitating viral penetration. There is an abundant expression of both ACE2 and TMPRSS2 in sustentacular cells. In this study, we evaluated 102 COVID-19 hospitalized patients, of which 17.60% presented anosmia and 9.80% ageusia. ACE1 , ACE2 , and TMPRSS2 gene expression levels in nasopharyngeal tissue were obtained by RT-qPCR and measured using ΔCT analysis. ACE1 Alu 287bp association was also evaluated. Logistic regression models were generated to estimate the effects of variables on ageusia and anosmia Association of ACE2 expression levels with ageusia. was observed (OR: 1.35; 95% CI: 1.098-1.775); however, no association was observed between TMPRSS2 and ACE1 expression levels and ageusia. No association was observed among the three genes and anosmia, and the Alu 287bp polymorphism was not associated with any of the outcomes. Lastly, we discuss whetherthere is a bridge linking these initial symptoms, including molecular factors, to long-term COVID-19 health consequences such as cognitive dysfunctions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Braga-Paz, Ferreira de Araújo, Alves, de Ávila, Resende, Teixeira, de Aguiar, de Souza and Bahia.)

Biomarker identification may provide strategic opportunities to understand disease pathophysiology, predict outcomes, improve human health, and reduce healthcare costs. The highly heterogeneous Covid-19 clinical manifestation suggests a complex interaction of several different human, viral and environmental factors. Here, we systematically reviewed genetic association studies evaluating Covid-19 severity or susceptibility to SARS-CoV-2 infection following PRISMA recommendations. Our research comprised papers published until December 31 st , 2020, in PubMed and BioRXiv databases focusing on genetic association studies with Covid-19 prognosis or susceptibility. We found 20 eligible genetic association studies, of which 11 assessed Covid-19 outcome and 14 evaluated infection susceptibility (five analyzed both effects). Q-genie assessment indicated moderate quality. Five large-scale association studies (GWAS, whole-genome, or exome sequencing) were reported with no consistent replication to date. Promising hits were found on the 3p21.31 region and ABO locus. Candidate gene studies examined ACE1, ACE2, TMPRSS2, IFITM3, APOE, Furin, IFNL3, IFNL4, HLA, TNF-ɑ genes, and ABO system. The most evaluated single locus was the ABO, and the most sampled region was the HLA with three and five candidate gene studies, respectively. Meta-analysis could not be performed. Available data showed the need for further reports to replicate claimed associations., (© 2021 John Wiley & Sons Ltd.)

Introduction: Coronavirus disease 2019 (COVID-19) has forced health care systems to rethink the optimal delivery of health care services and has dramatically increased demand for general medicine providers (internal medicine, family medicine, emergency medicine), while simultaneously reducing demand for many subspecialty services. At Kaiser Permanente, we implemented a program wherein health care providers drawn from multiple disciplines perform daily telemedicine check-ins on COVID-19 patients, allowing us to both maintain social distancing and make use of providers in specialties who otherwise may have had lower in-clinic volumes. Methods: Kaiser Permanente patients testing positive for COVID-19 between March and October 2020 were referred to our program. Physicians and nurses (RNs) were invited to participate in our program and were trained using Microsoft Teams™ meetings. Patients receive daily phone calls by a physician or RN. Select patients receive portable pulse oximeter devices based on standardized criteria incorporating age and comorbidities. When patients are determined to be clinically stable, they are discharged back to their primary care physician for ongoing management. Results: Descriptive results for the virtual home care program (VHCP) are reported through October 2020, though these results do not represent a planned statistical analysis. Forty-two percent of the patients were male, 43% were black, and 30% were Hispanic. The most common comorbidities of patients in our program were obesity (body mass index >30 kg/m 2 ; 35%), followed by hypertension (32%) and diabetes mellitus (19%). Then, 8.2% of patients ultimately required hospital admission. Mortality rate for patients in our program was 1.33%. Discussion: Our program was able to provide virtual care for thousands of COVID-19 positive Kaiser members in the Washington, DC, and Baltimore Metro regions. We did so by utilizing physicians and RNs from specialties experiencing a decrease in clinic volume attributable to the COVID-19 pandemic. The experiences of our program may be valuable to clinicians wishing to establish similar programs of their own.

Many studies of primate vocalization have been undertaken to improve our understanding of the evolution of language. Perhaps, for this reason, investigators have focused on calls that were thought to carry symbolic information about the environment. Here I suggest that even if these calls were in fact symbolic, there were independent reasons to question this approach in the first place. I begin by asking what kind of communication system would satisfy a species' biological needs. For example, where animals benefit from living in large groups, I ask how members would need to communicate to keep their groups from fragmenting. In this context, I discuss the role of social grooming and "close calls," including lip-smacking and grunting. Parallels exist in human societies, where information is exchanged about all kinds of things, often less about the nominal topic than the communicants themselves. This sort of indexical (or personal) information is vital to group living, which presupposes the ability to tolerate, relate to, and interact constructively with other individuals. Making indexical communication the focus of comparative research encourages consideration of somatic and behavioral cues that facilitate relationships and social benefits, including cooperation and collaboration. There is ample room here for a different and potentially more fruitful approach to communication in humans and other primates, one that focuses on personal appraisals, based on cues originating with individuals, rather than signals excited by environmental events., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Locke.)

Introduction: We assessed the impact of a diabetic foot ulcer prevention program incorporating once-daily foot temperature monitoring on hospitalizations, emergency department and outpatient visits, and rates of diabetic foot ulcer recurrence and lower extremity amputations for patients with recently healed foot ulcers., Research Design and Methods: In this retrospective analysis of real-world data, we enrolled 80 participants with a healed diabetic foot ulcer in a year-long foot ulcer recurrence prevention program. Four outpatient centers within a large integrated healthcare system in the USA contributed to enrollment. We evaluated diabetic foot-related outcomes and associated resource utilization for participants during three periods: the 2 years before the program, the year during the program, and after the program ended. We reported unadjusted resource utilization rates during the program and the periods before and after it. We then adjusted rates of outcomes in each phase using an interrupted time series approach, explicitly controlling for overall trends in resource utilization and recurrence during the three periods., Results: Our unadjusted data showed high initial rates of resource utilization and recurrence before enrollment in the program, followed by lower rates during the program, and higher rates of resource utilization and similar rates of recurrence in the period following the end of the program. The adjusted data showed lower rates of hospitalizations (relative risk reduction (RRR)=0.52; number needed to treat (NNT)=3.4), lower extremity amputations (RRR=0.71; NNT=6.4), and outpatient visits (RRR=0.26; absolute risk reduction (ARR)=3.5) during the program. We also found lower rates of foot ulcer recurrence during the program in the adjusted data, particularly for wounds with infection or greater than superficial depth (RRR=0.91; NNT=4.4)., Conclusions: We observed lower rates of healthcare resource utilization for high-risk participants during enrollment in a diabetic foot prevention program incorporating once-daily foot temperature monitoring., Trial Registration Number: NCT04345016., Competing Interests: Competing interests: JDB, BJP, DRL, SJS, and NJN are employees and shareholders of Podimetrics Inc, which manufactures the study device. All other authors report no real or potential conflicts of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that acute stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with optogenetics-assisted fast-scan cyclic voltammetry (FSCV). We demonstrate that while corticosterone habituates to chronic restraint stress, cFos activation of medullary norepinephrine neurons shows equivalent activation under both acute and chronic stress conditions. Mice exposed to a single restraint session show an identical optically stimulated norepinephrine release profile compared to that of unexposed mice. Mice experiencing 5 days of restraint stress, however, show elevated norepinephrine release across multiple stimulation parameters, and reduced sensitivity to the α 2 -adrenergic receptor (AR) antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.

A randomized control trial compared the effects of two kinds of vocabulary instruction on component reading skills of adult struggling readers. Participants seeking alternative high school diplomas received 8 h of scripted tutoring to learn forty academic vocabulary words embedded within a civics curriculum. They were matched for language background and reading levels, then randomly assigned to either morpho-phonemic analysis teaching word origins, morpheme and syllable structures, or traditional whole word study teaching multiple sentence contexts, meaningful connections, and spellings. Both groups made comparable gains in learning the target words, but the morpho-phonemic group showed greater gains in reading unfamiliar words on standardized tests of word reading, including word attack and word recognition. Findings support theories of word learning and literacy that promote explicit instruction in word analysis to increase poor readers' linguistic awareness by revealing connections between morphological, phonological, and orthographic structures within words.

The hypocretin/orexin (HCRT) system is implicated in reward and reinforcement processes through actions on the mesolimbic dopamine (DA) system. Here we provide evidence for the relationship between HCRT and DA in vivo in anesthetized and freely moving mice. The ability of cocaine to elicit reward-related behaviors in mice lacking the HCRT prepro-peptide (HCRT knock-out; KO) and wild-type controls was determined using conditioned place preference. Using a combination of microdialysis and in vivo fast scan cyclic voltammetry in anesthetized and freely moving mice, we investigated the underlying role of HCRT in the regulation of DA release and uptake. We show that, unlike wild-type mice, HCRT KO mice fail to develop characteristic conditioned place preference for cocaine. These mice also demonstrated reduced DA release and uptake under baseline conditions in both anesthetized and freely moving experiments. Further, diminished DA signaling in HCRT KO mice persists following administration of cocaine. These findings indicate that HCRT is essential for the expression of behaviors associated with the rewarding effects of cocaine, and suggest that HCRT regulation of reward and reinforcement may be related to disruptions to DA neurotransmission., (© 2016 Society for the Study of Addiction.)

Although language is generally spoken, most evolutionary proposals say little about any changes that may have induced vocal control. Here I suggest that the interaction of two changes in our species-one in sociality, the other in life history-liberated the voice from its affective moorings, enabling it to serve as a fitness cue or signal. The modification of life history increased the helplessness of infants, thus their competition for care, pressuring them to emit, and parents (and others) to evaluate, new vocal cues in bids for attention. This change elaborated and formalized the care communication system that was used in infancy and, because of parental adoption of social criteria, extended it into childhood, supporting the extrafamilial relationships that intensify in those stages. The remodeling of life history, in conjunction with intensified sociality, also enhanced vocal signaling in adolescence-a second stage that is unique to humans-and adulthood. Building on the new vocal skills and fitness criteria that emerged earlier, I claim that males with ornamented speech enjoyed advantages in their pursuit of dominance and reproductive opportunities in evolutionary history, as they do today. There are implications of this scenario for the mechanistic level of vocal diversification. Today, intentionality plays a role both in the instrumental crying of infants and the modulated vocalizations of adults. In evolutionary history, I claim that in both cases, spontaneously emitted behavioral cues elicited perceptible responses, giving rise to strategic signals that were sent, and processed, under a new and fundamentally different neural regime.

Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aimed at elucidating the neurobiological mechanisms underlying maladaptive alcohol drinking in an effort to design rational treatment strategies. In preclinical literature, the use of inbred mouse lines has allowed for the examination of ethanol effects across vulnerable and resistant phenotypes. C57BL/6J mice consistently show higher rates of ethanol drinking compared to most mouse strains. Conversely, DBA/2J mice display low rates of ethanol consumption. Given that the reinforcing and rewarding effects of ethanol are thought to be in part mediated by its actions on dopamine neurotransmission, we hypothesized that alcohol-preferring C57BL/6J and alcohol-avoiding DBA/2J mice would display basal differences in dopamine system function. By administering an L-aromatic acid decarboxylase inhibitor and measuring L-Dopa accumulation via high-performance liquid chromatography as a measure of tyrosine hydroxylase activity, we found no difference in dopamine synthesis between mouse strains in the midbrain, dorsal striatum, or ventral striatum. However, we did find that quinpirole-induced inhibition of dopamine synthesis was greater in the ventral striatum of C57BL/6J mice, suggesting increased presynaptic D2-type dopamine autoreceptor sensitivity. To determine whether dopamine synthesis or autoreceptor sensitivity was altered by a history of ethanol, we exposed C57BL/6J mice to one or two weekly cycles of chronic intermittent ethanol (CIE) exposure and withdrawal. We found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of CIE. Finally, we examined tissue content of dopamine and dopamine metabolites across recombinant inbred mice bred from a C57BL/6J × DBA/2J cross (BXD). We found that low dopaminergic activity, as indicated by high dopamine/metabolite ratios, was positively correlated with drinking. Together, these findings show differential autoreceptor effects on dopamine synthesis between C57BL/6J and DBA/2J mice, and suggest that decreased dopaminergic activity is associated with excessive drinking., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as βarrestin2. We evaluated a newly developed G protein signaling-biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. We found that triazole 1.1 retained the antinociceptive and antipruritic efficacies of a conventional KOR agonist, yet it did not induce sedation or reductions in dopamine release in mice, nor did it produce dysphoria as determined by intracranial self-stimulation in rats. These data demonstrated that biased agonists may be used to segregate physiological responses downstream of the receptor. Moreover, the findings suggest that biased KOR agonists may present a means to treat pain and intractable itch without the side effects of dysphoria and sedation and with reduced abuse potential., (Copyright © 2016, American Association for the Advancement of Science.)

High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3 d/week) or extended (24 h 7 d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed mice coincided with elevated DAT function and increased AMPH potency; however, the enhanced behavioral response to AMPH after HF exposure was unique in that it coincided with reduced DAT function and diet pattern-specific adaptations., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Early-life stress is associated with increased vulnerability to alcohol addiction. However, the neural substrates linking chronic childhood/adolescent stress and increased risk of alcohol addiction are not well understood. In the nucleus accumbens (NAc), dopamine (DA) and norepinephrine (NE) signaling can be profoundly influenced by stress, anxiety, and drugs of abuse, including ethanol (EtOH). Here, we employed a rodent model of early-life stress that results in enduring increases in behavioral risk factors of alcoholism to gain a better understanding of how chronic adolescent stress may impact the EtOH sensitivity of DA and NE release in the NAc., Methods: Male Long-Evans rats were either group housed (GH; 4 rats/cage) or socially isolated (SI; 1 rat/cage) for 6 weeks beginning on postnatal day 28. SI and GH rats were tested in adulthood for anxiety-like behaviors (elevated plus maze), and the effects of EtOH (1 and 2 g/kg; intraperitoneally.) on NAc DA and NE were assessed by microdialysis., Results: SI animals showed increased anxiety-like behavior compared to GH animals. Although SI had no effect on baseline levels of DA or NE, baseline DA levels were positively correlated with anxiety measures. In addition, while no significant differences were observed with 1 g/kg EtOH, the 2 g/kg dose induced significantly greater DA release in SI animals. Moreover, EtOH (2 g/kg) only elevated NAc NE levels in SI rats., Conclusions: These results suggest that chronic early-life stress sensitizes accumbal DA and NE release in response to an acute EtOH challenge. A greater EtOH sensitivity of DA and NE release dynamics in the NAc may contribute to increases in behavioral risk factors of alcoholism, like greater EtOH self-administration, that are observed in SI rats., (Copyright © 2014 by the Research Society on Alcoholism.)

The majority of neurotransmitter systems shows variations in state-dependent cell firing rates that are mechanistically linked to variations in extracellular levels, or tone, of their respective neurotransmitter. Diurnal variation in dopamine tone has also been demonstrated within the striatum, but this neurotransmitter is unique, in that variation in dopamine tone is likely not related to dopamine cell firing; this is largely because of the observation that midbrain dopamine neurons do not display diurnal fluctuations in firing rates. Therefore, we conducted a systematic investigation of possible mechanisms for the variation in extracellular dopamine tone. Using microdialysis and fast-scan cyclic voltammetry in rats, as well as wild-type and dopamine transporter (DAT) knock-out mice, we demonstrate that dopamine uptake through the DAT and the magnitude of subsecond dopamine release is inversely related to the magnitude of extracellular dopamine tone. We investigated dopamine metabolism, uptake, release, D2 autoreceptor sensitivity, and tyrosine hydroxylase expression and activity as mechanisms for this variation. Using this approach, we have pinpointed the DAT as a critical governor of diurnal variation in extracellular dopamine tone and, as a consequence, influencing the magnitude of electrically stimulated dopamine release. Understanding diurnal variation in dopamine tone is critical for understanding and treating the multitude of psychiatric disorders that originate from perturbations of the dopamine system.

Fetal ethanol (EtOH) exposure leads to a range of neurobehavioral alterations, including deficits in emotional processing. The basolateral amygdala (BLA) plays a critical role in modulating emotional processing, in part, via dopamine (DA) regulation of GABA transmission. This BLA modulatory system is acquired during the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) and we hypothesized that it could be altered by EtOH exposure during this period. We found that exposure of rats to moderate levels of EtOH vapor during the third trimester-equivalent [postnatal days (P) 2-12] alters DA modulation of GABAergic transmission in BLA pyramidal neurons during periadolescence. Specifically, D1R-mediated potentiation of spontaneous inhibitory postsynaptic currents (IPSCs) was significantly attenuated in EtOH-exposed animals. However, this was associated with a compensatory decrease in D3R-mediated suppression of miniature IPSCs. Western blot analysis revealed that these effects were not a result of altered D1R or D3R levels. BLA samples from EtOH-exposed animals also had significantly lower levels of the DA precursor (L-3,4-dihydroxyphenylalanine) but DA levels were not affected. This is likely a consequence of reduced catabolism of DA, as indicated by reduced levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the BLA samples. Anxiety-like behavior was not altered in EtOH-exposed animals. This is the first study to demonstrate that the modulatory actions of DA in the BLA are altered by developmental EtOH exposure. Although compensatory adaptations were engaged in our moderate EtOH exposure paradigm, it is possible that these are not able to restore homeostasis and correct anxiety-like behaviors under conditions of heavier EtOH exposure. Therefore, future studies should investigate the potential role of alterations in the modulatory actions of DA in the pathophysiology of fetal alcohol spectrum disorders.

Van de Vliert embraces a "supply side" model of human needs, underplaying a "demand" model whereby individuals, motivated by psychological needs, develop coping strategies that help them meet their personal goals and collectively exert an influence on social and economic systems. Undesirable climates may inflate the value of financial capital, but they also boost the value of social capital.

Babbling between the ages of 8 and 19 months was examined in 19 children, 13 of whom were at high risk for reading disorder (RD) and 6 normally reading children at low familial risk for RD. Development of syllable complexity was examined at five periods across this 11-month window. Results indicated that children who later evidenced RD produced a lower proportion of canonical utterances and less complex syllable structures than children without RD. As syllable complexity is an early indicator of phonological sophistication, differences at this level may offer a window into how the phonological system of children with RD is structured. Future directions for this line of research are discussed.

Recent evidence suggests that the hypocretin-orexin system participates in the regulation of reinforcement processes. The current studies examined the extent to which hypocretin neurotransmission regulates behavioral and neurochemical responses to cocaine, and behavioral responses to food reinforcement. These studies used a combination of fixed ratio, discrete trials, progressive ratio and threshold self-administration procedures to assess whether the hypocretin 1 receptor antagonist, SB-334867, reduces cocaine self-administration in rats. Progressive ratio sucrose self-administration procedures were also used to assess the extent to which SB-334867 reduces responding to a natural reinforcer in food-restricted and food-sated rats. Additionally, these studies used microdialysis and in vivo voltammetry in rats to examine whether SB-334867 attenuates the effects of cocaine on dopamine signaling within the nucleus accumbens core. Furthermore, in vitro voltammetry was used to examine whether hypocretin knockout mice display attenuated dopamine responses to cocaine. Results indicate that when SB-334867 was administered peripherally or within the ventral tegmental area, it reduced the motivation to self-administer cocaine and attenuated cocaine-induced enhancement of dopamine signaling. SB-334867 also reduced the motivation to self-administer sucrose in food-sated but not food-restricted rats. Finally, hypocretin knockout mice displayed altered baseline dopamine signaling and reduced dopamine responses to cocaine. Combined, these studies suggest that hypocretin neurotransmission participates in reinforcement processes, likely through modulation of the mesolimbic dopamine system. Additionally, the current observations suggest that the hypocretin system may provide a target for pharmacotherapies to treat cocaine addiction.

Purpose: This study examined the development of timing characteristics in early spontaneous speech of children who were later identified as having reading disability (RD)., Method: Child-adult play sessions were recorded longitudinally at 2 and 3 years of age in 27 children, most of whom were at high familial risk for RD. For each speaking turn, the number of syllables was determined and an acoustic analysis measured the time allocated to articulation, pausing before speaking, and pausing during speaking., Results: In grade school, a reading battery identified 9 children with RD and 18 children without RD (9 at high risk, 9 at low risk). Early speaking rate was significantly slower in the group with RD, with significantly different patterns of pausing compared with children without RD. Group differences became more distinct by age 3, as longer speaking turns were attempted., Conclusions: The results are discussed in terms of speech and language formulation. Phonetic plans may be shorter and/or less specified in children with RD, surfacing as slow, short speaking turns with increased pausing relative to articulation. This explanation is consistent with several accounts of RD and provides a perspective on how speech and language deficits may manifest during spontaneous verbal interactions between young children and adults.

The handicap principle has been applied to a number of different traits in the last three decades, but it is difficult to characterize its record, or even its perceived relevance, when it comes to an important human attribute-spoken language. In some cases, assumptions regarding the energetic cost of speech, and the veracity of linguistically encoded messages, have failed to recognize critical aspects of human development, cognition, and social ecology. In other cases, the fact that speech contains honest (physiological) information, and tends to be used honestly with family and friends, has been overlooked. Speech and language are functionally related but they involve different resources. Individuals can increase the attractiveness of their speech, and of more stylized vocal and verbal performances, without enhancing linguistic structure or content; and they can modify their use of language without significant changes in the physical form of speech. That its production costs are normally low enables speech to be produced extravagantly in bids for status and mating relationships, and in evolution, may have allowed its content--linguistic knowledge and structure--to become complex.

Purpose: This study evaluated whether developmental reading disability could be predicted in children at the age of 30 months, according to 3 measures of speech production: speaking rate, articulation rate, and the proportion of speaking time allocated to pausing., Method: Speech samples of 18 children at high risk and 10 children at low risk for reading disability were recorded at 30 months of age. High risk was determined by history of reading disability in at least 1 of the child's parents. In grade school, a reading evaluation identified 9 children within the high-risk group as having reading disability and 9 children as not having reading disability. The 10 children at low risk for reading disability tested negative for reading disability., Results: Children with reading disability showed a significantly slower speaking rate than children at high risk without reading disability. Children with reading disability allocated significantly more time to pausing, as compared with the other groups. Articulation rate did not differ significantly across groups., Conclusions: Speaking rate and the proportion of pausing time to speaking time may provide an early indication of reading outcome in children at high risk for reading disability.

It has long been claimed that Homo sapiens is the only species that has language, but only recently has it been recognized that humans also have an unusual pattern of growth and development. Social mammals have two stages of pre-adult development: infancy and juvenility. Humans have two additional prolonged and pronounced life history stages: childhood, an interval of four years extending between infancy and the juvenile period that follows, and adolescence, a stage of about eight years that stretches from juvenility to adulthood. We begin by reviewing the primary biological and linguistic changes occurring in each of the four pre-adult ontogenetic stages in human life history. Then we attempt to trace the evolution of childhood and juvenility in our hominin ancestors. We propose that several different forms of selection applied in infancy and childhood; and that, in adolescence, elaborated vocal behaviors played a role in courtship and intrasexual competition, enhancing fitness and ultimately integrating performative and pragmatic skills with linguistic knowledge in a broad faculty of language. A theoretical consequence of our proposal is that fossil evidence of the uniquely human stages may be used, with other findings, to date the emergence of language. If important aspects of language cannot appear until sexual maturity, as we propose, then a second consequence is that the development of language requires the whole of modern human ontogeny. Our life history model thus offers new ways of investigating, and thinking about, the evolution, development, and ultimately the nature of human language.

Although all natural languages are spoken, there is no accepted account of the evolution of a skill prerequisite to language-control of the movements of speech. If selection applied at sexual maturity, individuals achieving some command of articulate vocal behavior in previous stages would have enjoyed unusual advantages in adulthood. I offer a parental selection hypothesis, according to which hominin parents apportioned care, in part, on the basis of their infants' vocal behavior. Specifically, it is suggested that persistent or noxious crying reduced care to individuals who would have had difficulty learning complex behaviors, and that cooing and babbling increased social interaction and care as well as control over complex oralmotor activity of the sort required by spoken language. Several different tests of the hypothesis are suggested.

This article offers a developmental theory of language and the neural systems that lead to and subserve linguistic capabilities. Early perceptual experience and discontinuities in linguistic development suggest that language develops in four phases that occur in a fixed, interdependent sequence. In each phase of language, a unique ontogenetic function is accomplished. These functions have proprietary neural systems that vary in their degree of specialization. Of particular interest is an analytical mechanism that is responsible for linguistic grammar. This mechanism is time-locked and can only be turned on in the third phase. Confirming evidence is provided by children who are delayed in the second phase of the language learning process. These children store insufficient lexical material to activate their analytic mechanism. Inactivation behaves like damage, shifting language functions to homologous mechanisms in the nondominant hemisphere, thereby increasing functional and anatomical symmetry across the hemispheres. This atypical assembly of neurolinguistic resources produces functional but imperfect command of spoken language and may complicate learning of written language. The theory thus offers a different role for genetics and early experience, and a different interpretation of neuroanatomic findings, from those entertained in most other proposals on developmental language disorders.

Alprazolam is one of the most widely prescribed benzodiazepines in the United States. It is generally considered a safe and effective drug for the treatment of anxiety disorders and panic attacks. Few overdoses that are due to the sole ingestion of alprazolam have been reported. This paper documents a fatality due to alprazolam intoxication and describes the distribution of alprazolam and an active metabolite, alpha-hydroxyalprazolam, in tissues obtained at autopsy. Qualitative identification of the drugs was achieved by full-scan gas chromatography-mass spectrometry, and quantitative analysis was performed by high-performance liquid chromatography. High concentrations of alprazolam were found in all specimens analyzed, but the metabolite was detected only in subclavian blood, urine, bile, and liver. A postmortem heart blood alprazolam concentration of 2.1 mg/L is the highest reported in the literature to date.

Babbling typically precedes, resembles, and conceivably facilitates development of speech, and yet there is no accepted neurobiological characterization of babbling. Here we report a study of infants' developing control of vocal behavior in relation to manual activity performed under differing conditions of audibility. We hypothesized that babbling is associated with the onset of left-lateralized motor control, as expressed in repetitive right-handed activity, and that audibility facilitates such activity. Sixty-one normally developing infants were seen before (N = 21) or at various intervals following (N = 40) the onset of babbling. In experimental trials, audible or inaudible rattles were placed in left or right hands equally often. Analysis of manual activity revealed little shaking movement in the youngest and vocally least differentiated infants, and a sharp increase in shaking in slightly older infants who had recently begun to babble. Surprisingly, audibility only marginally enhanced shaking activity. A dextral bias was evident in the shaking of infants who had recently begun to babble, but not in younger or older infants. These and other findings suggest that the left cerebral hemisphere may be disproportionately involved in the production of repetitive vocal-motor activity as occurs in babbling.

This article presents a theory of normal and delayed development of language. According to the theory, linguistic capacity develops in critically timed phases that occur gradually and sequentially. Normally, the rapid accumulation of stored utterances activates analytical mechanisms that are needed for the development of linguistic grammar. Children with slowly developing brains have delays in the socially cognitive systems that store utterances, and a critical period for activation of experience-dependent grammatical mechanisms declines without optimal result. Continuing efforts to speak induct species-atypical allocations of neural resources into linguistic service. It is speculated that this compensatory activity leads to compensatory growth, which may ultimately be revealed as volumetric symmetry of perisylvian areas. Because rate of brain maturation is under genetic as well as environmental control, the stage is thus set for an impairment that will seem to be specific and a brain that will appear to be abnormal.

A body of medically important work has accumulated in the field of developmental neurolinguistics in the 30 years since Lenneberg set forth a research agenda for that field, consisting of the following: (1) the physiologic specialization or endowment for speech; (2) the genetic origin or natural history of vocalization and speech; (3) the nature of prelinguistic behavior, making possible the detection of any environmental (social) influences; (4) the development of motor-speech organization from birth; and (5) the limiting effects of deficient intelligence, hearing, and environmental stimulation. Subsequent study of these questions has established a genetic, neuroanatomic, and functional basis for such outwardly disparate disorders as dyslexia, stuttering, autism, and delayed language. Studies of emergent motor behavior suggest that babbling may index a state of neural maturation favoring expression of spoken languages. Based on studies of the congenitally deaf, mentally retarded, and other clinical populations it is now considered possible to detect early warning signs of developmental language disorders during the first year of life based on analyses of vocal turn-taking, gesturing, and utterance complexity.

Linguistic innateness is a fundamentally physical notion, which ultimately requires independent physical evidence. For spoken language, it is relevant to consider babbling, components of which are unaffected by ambient stimulation and are predicted by models of vocal tract function. Links between babbling and speech point to innate factors in the ontogeny of spoken language and invite attention to central control mechanisms. These neural capabilities enable oral language learning by providing children with control over an initial stock of speech-like movements and by directing their attention to salient linguistic patterns. Dispositions to attend to some cues are so strong that little stimulation is required. In other cases, predispositions are weak, and acquisition requires correspondingly more experience. To understand the ontogeny of language, we need to learn which cases are which and to know how these interactions occur and change over the course of acquisition.

The role of babbling in language development is not well understood. One source of evidence is the utterances of infants who were tracheostomized during the period in which they would normally have produced syllabic vocalization. We describe here the phonetic patterns and linguistic development of a girl called Jenny. She was tracheostomized and generally aphonic from 0.5-1.8 but cognitively and socially normal, with near-normal comprehension of language. Acoustic analyses of Jenny's utterances following decannulation revealed a tenth of the canonical syllables which might be expected in normally developing infants, an extremely small inventory of consonant-like segments, and a marked preference for labial obstruents. In these ways, she resembled a group of infants of the same age who also cannot hear their oral-motor movements, the congenitally deaf, suggesting that the audibility of babbling contributes to its onset. Two months following decannulation, when Jenny was 1.10, she produced only a handful of different words. We think this is because aphonia prevented her from discovering the referential value of vocal expression and discouraged the formation of a phonetic repertoire that could be appropriated for lexical service. This unusual case suggests that babbling normally facilitates the development of language and speech.

Several procedures used to assess speech perception of children with disorders at the phonological level of language are described. In most cases of segmental substitution, children discriminated target and substitution phonemes regardless of whether both were spoken by an adult, or one form was produced by an adult and the other was the child's internal representation of the target phoneme. However, in about a third of the cases there was consistent failure to discriminate the target phoneme from the substituted phoneme. Perceptual approaches to the treatment of sound production problems are questioned when perception is inferably differential. Certain phonetic effects, and their implications for theories of phonological acquisition and disorder, are discussed.

In the course of routine chest examination, 80 asymptomatic patients were observed to have localized hyperostosis of the posterior ribs and articulating transverse processes. The authors studied the distributions of lesions in these 80 patients, and records were reviewed in the 50 cases in which they were available. The occupational histories, male-to-female ratio (5:1), and ratio of right-to-left rib involvement (9:1)--in addition to results of electromyographic and histologic studies and the principles of bone remodeling--suggest that this hyperostosis occurs at sites most stressed with bending and rotation of the thorax. The authors hypothesize that this stress-related change occurs due to the pull of the iliocostalis thoracis muscle and is of no clinical significance.

This paper considers the rationale and presents some criteria for assessing the speech perception of children with disorders at the phonological level of language. An examination of conventional test procedures suggests that none is useful in identifying clinically relevant perceptual disorders. However, readers are encouraged to inspect Part II (Locke, 1980), which describes procedures with more clinical promise.

Eighty-six adults serially recalled lists of visually presented consonant letters similar in auditory or visual features or dissimilar in both feature sets. There were significantly more errors at every auditory list position than at the corresponding visual and neutral list positions, which did not themselves differ. There was a positive correlation between the tendency toward phonetic coding and overall performance, with 75 subjects making more errors on the auditory list than either of the other lists. The eight subjects who made more errors on the visual list showed poor performance in the recall of all lists. Factors governing the perceivability of stimuli apparently do not continue to operate significantly in controlling their recallability, at least in the case of veridical visual input.

Angiosarcoma is a malignant tumor of vascular origin. Malignant primary vein tumors are rare. The case of a 64-year-old patient who underwent a left forequarter amputation for angiosarcoma arising from the left axillary vein, a site not previously described, is presented. Also, the literature is reviewed.

Recent controversy about the innateness of language has awakened interest in the genetic basis of linguistic development. In this study, we analysed more extensively data from Mather & Black (1984) in order to test the hypothesis that the speech articulation of monozygotic (MZ) twins would be qualitatively more similar than that of age- and sex-matched dizygotic (DZ) twins. Analyses revealed that 4-year-old MZ twin pairs were significantly more likely to misproduce the same sounds on an articulation test than were DZ twin pairs, and that DZ twins were no more likely to share errors than were children who were both genetically and environmentally unrelated. There was no evidence that MZ twins made more similar errors than DZ twins, and indeed it was difficult to make this determination since only broad categories of error (substitution, distortion, omission) were available for analysis. The greater amount of genetic material shared by MZ twins, and the presumably more similar morphology of their speech mechanisms, may have caused certain sound patterns to be of more nearly equal difficulty for both members of a MZ pair. However, these findings need to be confirmed with phonetically more detailed analyses.

Eight aphasic and eight brain-damaged nonaphasic patients silently "read" a short passage while performing an internal search for specified consonant letters of varying phonological and syntactic salience. The nonaphasic patients showed the phonological and syntactic effects customarily achieved by normal readers. For example, they were more likely to find a letter if it were pronounced than if it were silent, and they were more likely to find a letter if it were in a content word than in a function word. The aphasics had reliable phonological effects but no observable syntactic effects. Those aphasics with relatively large phonological effects performed better on a separate task requiring the oral reading of isolated words. For reading theory, the primary message from this study is that phonological recoding may occur between word recognition and the completion of semantic analysis, and that recoding may not by itself be sufficient to reading for meaning. For aphasia theory, the main implication of this study is that aphasics read by applying the appropriate phonological strategies, but that such strategies are limited in the face of ineffective syntactic and semantic processing, as occurs in aphasia.