The role of candidate-gene CNTNAP2 in childhood apraxia of speech and specific language impairment.

Childhood apraxia of speech (CAS) is a debilitating pediatric speech disorder characterized by varying symptom profiles, comorbid deficits, and limited response to intervention. Specific Language Impairment (SLI) is an inherited pediatric language disorder characterized by delayed and/or disordered oral language skills including impaired semantics, syntax, and discourse. To date, the genes associated with CAS and SLI are not fully characterized. In the current study, we evaluated behavioral and genetic profiles of seven children with CAS and eight children with SLI, while ensuring all children were free of comorbid impairments. Deletions within CNTNAP2 were found in two children with CAS but not in any of the children with SLI. These children exhibited average to high performance on language and word reading assessments in spite of poor articulation scores. These findings suggest that genetic variation within CNTNAP2 may be related to speech production deficits.

Use of local anesthesia for inguinal hernia repair has decreased over time in the VA system.

PURPOSE: In 2003, randomized trials demonstrated potentially improved outcomes when local instead of general anesthesia is used for inguinal hernia repair. Our study aimed to evaluate how the use of local anesthesia for this procedure changed over time following the publication of the trials' level 1 evidence. METHODS: We used the 1998-2018 Veterans Affairs Surgical Quality Improvement Program database to identify adults who underwent open, unilateral inguinal hernia repair under local or general anesthesia. Our primary outcome was the percentage of cases performed under local anesthesia. We used a time-series design to examine the trend and rate of change of the use of local anesthesia. RESULTS: We included 97,437 veterans, of which 22,333 (22.9%) had hernia surgery under local anesthesia. The median age of veterans receiving local anesthesia remained stable at 64-67 years over time. The use of local anesthesia decreased steadily, from 38.2% at the beginning year to 15.1% in the final year (P < 0.0001). The publication of results from randomized trials (in 2003) did not appear to increase the overall use or change the rate of decline in the use of local anesthesia. Overall, we found that the use of local anesthesia decreased by about 1.5% per year. CONCLUSION: The utilization of local anesthesia for inguinal hernia repair in the VA has steadily declined over the last 20 + years, despite data showing equivalence or superiority to general anesthesia. Future studies should explore barriers to the use of local anesthesia for hernia repair.

Increased variability of stimulus-driven cortical responses is associated with genetic variability in children with and without dyslexia.

Individuals with dyslexia exhibit increased brainstem variability in response to sound. It is unknown as to whether increased variability extends to neocortical regions associated with audition and reading, extends to visual stimuli, and whether increased variability characterizes all children with dyslexia or, instead, a specific subset of children. We evaluated the consistency of stimulus-evoked neural responses in children with (N = 20) or without dyslexia (N = 12) as measured by magnetoencephalography (MEG). Approximately half of the children with dyslexia had significantly higher levels of variability in cortical responses to both auditory and visual stimuli in multiple nodes of the reading network. There was a significant and positive relationship between the number of risk alleles at rs6935076 in the dyslexia-susceptibility gene KIAA0319 and the degree of neural variability in primary auditory cortex across all participants. This gene has been linked with neural variability in rodents and in typical readers. These findings indicate that unstable representations of auditory and visual stimuli in auditory and other reading-related neocortical regions are present in a subset of children with dyslexia and support the link between the gene KIAA0319 and the auditory neural variability across children with or without dyslexia.

Measurement of therapeutic response in schizophrenia. A critical survey.

A recurrent criticism of measurement in schizophrenia research is that symptom suppression is overemphasized as the sole criterion measure of treatment effectiveness, to the neglect of other endpoints, such as the quality of life and subjective experience of the patient. This paper addresses the current status of response measures used in schizophrenia therapeutics. A computer literature search of all clinical trials (drug, psychosocial, or rehabilitative) in schizophrenia for the years 1986 through 1989 yielded 175 papers, 79 of which were trials of therapy. Almost all the trials focused on productive symptoms, with 19% considering negative symptoms scales as well. Approximately one-quarter of the studies incorporated some measure of patient functioning, but only 13% considered the patient's self-report or ratings of significant others. The findings suggest that the measurement of treatment response in schizophrenia research continues to be unidimensional and symptom-based. It is proposed that treatment effectiveness may be obscured when measures of patient functioning, subjective experience and assessments of significant others are not included with those of symptomatology.

Biochemical and anatomical analysis of cholinergic, noradrenergic and serotonergic innervation of fetal neocortical transplants placed in excitotoxin-induced neocortical lesions of adult rats.

Fetal neocortical block transplants were implanted into the excitotoxically ablated sensorimotor cortex of adult rats in order to examine the density of innervation and distribution of presumptive host derived afferent fibers within these transplants. Cholinergic fiber innervation was examined at 3 months post grafting by measuring acetylcholinesterase (AChE) and choline acetyl-transferase (ChAT) enzyme activities within the grafts and within the corresponding host cortex by radiochemical enzyme assays as well as by AChE histochemistry for the visualization of AChE positive fibers. Noradrenergic and serotonergic inputs were examined by high performance liquid chromatography (HPLC) measurements of noradrenaline (NA) and serotonin (5-hydroxytryp-tamine, 5-HT) concentrations as well as by tyrosine hydroxylase (TH) and 5-HT immunocytochemistry for the visualization of monoaminergic fiber distribution. Our results demonstrated that the grafts contained significantly lower levels of neurotransmitter markers when compared to normal unablated cortex. The anatomical analysis showed an unequal fiber distribution within the transplants. Areas adjacent to the host tissue revealed a relatively dense fiber innervation when compared to the density observed within the more central parts of the transplants, and the anatomical data therefore supported the biochemical data in suggesting an overall lower cholinergic and monoaminergic innervation of fetal neocortical transplants placed into the lesioned adult cortex when compared to normal cortex.

Fetal neocortical transplants grafted into neocortical lesion cavities made in newborn rats: an analysis of transplant integration with the host brain.

Fetal neocortical transplants placed into frontal cortex aspiration lesion cavities in newborn rats have been shown to survive and exchange connections with the host brain. To further study the afferent innervation of such transplants, enzyme- and immunohistochemical techniques were employed to examine the distribution of cholinergic, catecholaminergic and serotonergic fibers within the transplants, and radiochemical enzyme assays and high performance liquid chromatography were used to determine the content of neurotransmitter markers for these same fiber systems. To examine functional integration of the transplanted neurons in terms of activation of molecular signaling systems, the graft recipient animals were exposed to a novel open field environment. This behavioral testing paradigm is known to induce c-fos mRNA and Fos protein within several areas of the normal brain, including the sensorimotor cortex. Subsequent detection of the induction of this particular immediate early gene (transcription as well as translation) in the grafts would gene (transcription as well as translation) in the grafts would accordingly indicate genomic activation and therefore functional integration at the level of molecular signaling systems. Our results showed that these global fiber systems are distributed evenly throughout the extent of three mo old neocortical grafts and that the content of transmitter-related markers for these systems do not differ significantly from control cortex. Open field exposure of the grafted animals resulted in c-fos mRNA and Fos protein expression of cells distributed throughout the transplants. We conclude that the "global" fiber system innervation of neocortical transplants placed into newborn rats is similar to the innervation of normal cortex and that grafted neurons respond to host brain activation at the level of molecular signaling systems.

Heterotopic neocortical transplants. An anatomical and electrophysiological analysis of host projections to occipital cortical grafts placed into sensorimotor cortical lesions made in newborn rats.

Plates of presumptive occipital neocortex obtained from fetal rats at 14-16 days gestation were grafted into the cerebral hemisphere of newborn rats. The transplants were placed heterotopically into sensorimotor cortical lesion cavities made immediately prior to grafting. At maturity, some of the transplants were injected with the retrograde fluorescent tracers Fast Blue and Diamidino yellow. In other animals, single-unit activity in the transplants or in normal cortex was recorded using standard electrophysiological techniques. Histologically, host projections to the transplants were demonstrated by the presence of retrogradely labeled neurons in the host primary and secondary somatosensory cortices as well as several thalamic areas including the anteroventral, anteromedial, ventrobasal, mediodorsal and central medial nuclei. Additional labeling was found in the claustrum, lateral hypothalamus, zona incerta and basal forebrain. Electrophysiologically, transplant single-unit activity was evoked in 43/69 (62%) neurons by thalamic stimulation, but only 1/69 transplant neurons responded to electrical stimulation of the contralateral forepaw. In further work, volumetric measurements showed that the transplants did not ameliorate the thalamic atrophy found after neocortical lesions. These results are compared to previous studies involving the homotopic placement of sensorimotor cortical grafts.

Analysis of neocortical grafts placed into focal ischemic lesions in adult rats.

This study investigated the viability of fetal neocortical block grafts transplanted into adult ischemic cortical lesions. Recipient rats sustained focal ischemic lesions by permanent occlusion of the middle cerebral artery 4-7 days prior to transplantation. Twenty days later, the animals were sacrificed and the brains examined using triphenyltetrazolium chloride, routine Nissl or acetylcholinesterase histochemistry. Ischemic infarctions were localized to the ipsilateral sensorimotor cortex and transplants were integrated with the host cerebral cortex or striatum. Cholinergic fibers were found crossing the host-transplant interface, presumably innervating the graft. This study demonstrates that fetal neocortical block grafts placed into adult focal ischemic lesions following permanent arterial occlusion can survive and establish connections with the host brain.

Early treatment events and prediction of response to neuroleptics in schizophrenia.

Events that occur early in the course of neuroleptic drug therapy in schizophrenia and which may be useful in predicting clinical outcome were investigated. Early subjective response and symptom change at twenty-four and forty-eight hours following initiation of drug therapy with either CPZ or haloperidol were the only variables that significantly related to therapeutic outcome. These preliminary results replicate and confirm previous results and provide a tool which can be included with other available approaches in developing a battery for prediction of drug response.

Patients' subjective experiences on antipsychotic medications: implications for outcome and quality of life.

The phenomenon of subjective response to antipsychotic medications in schizophrenia was reviewed, focusing on validity, measurement, implications for clinical outcome and quality of life. Recommendations were made on improvements in research approaches to important factors that may contribute to the genesis of this phenomenon. Clinicians should pay attention to the subjective complaints of their patients about medications and not ignore them as unreliable. Researchers should not dismiss research into subjective experiences as non-scientific, because it provides valuable information on recognizing psychopathology and for improving the management of patients.

Assessment of the patient's subjective experience in acute neuroleptic treatment: implications for compliance and outcome.

The concept of subjective response to neuroleptics in schizophrenia was reviewed with particular focus on scales for its measurement. The significance of recognizing such a phenomenon early on in the course of treatment has been illustrated by research data linking it to compliance, clinical improvement, quality of life, suicidal behaviour and comorbid drug abuse. Negative subjective response to neuroleptics has been identified as a strong predictor of compliance and outcome. Awareness of this subjective response in the management of the acute phase of the illness would require the physician to develop specific or additional approaches to the management of such dysphoric patients on neuroleptics at the time of discharge.

Subjective response to neuroleptics and the quality of life: implications for treatment outcome.

The concept of subjective response to neuroleptics in schizophrenic patients is reviewed in terms of its measurement and validity. Evidence is presented to link negative subjective response to neuroleptics to noncompliance and less favourable therapeutic outcome. The relevance of the construct of subjective responses to neuroleptics is examined in terms of its impact on the functional status and quality of life of patients. There is a great need for improved methods in researching subjective responses as well as better understanding of the factors that contribute to its genesis. The advent of new neuroleptics with superior risk-benefit ratios should encourage such research developments.

Subjective response to neuroleptics and outcome in schizophrenia: a re-examination comparing two measures.

The schizophrenic patient's early psychological response to neuroleptic treatment has been demonstrated to be a significant predictor of treatment response. The validity of the construct of subjective response is evaluated by comparison of two measures. Fifty-five recently admitted and unmedicated schizophrenic patients were randomly allocated to chlorpromazine or haloperidol. Subjective responses at 24 and 48 hours as assessed by two different scales, the Van Putten & May scale and the self-administered Drug Attitude Inventory, were strongly correlated with outcome at three weeks. Early emergence of extrapyramidal symptoms was not related to subjective response, but dysphoric patients had a greater incidence of EPS by the end of treatment than did non-dysphoric patients. The two measures showed high concordance in identification of early drug dysphoria.

Pharmacotherapy and suicide risk in schizophrenia.

The authors examined drug prescribing patterns and incidence of side effects in schizophrenic patients who committed suicide as compared with a matched control group. The groups did not differ in type of drug prescribed, though patients in the suicide group received significantly higher doses of fluphenazine enanthate. Extrapyramidal reactions occurred more frequently among the patients in the suicide group in the thirty days preceding suicide, and autonomic side effects less frequently, than in control patients for a corresponding period prior to discharge. The authors conclude that the probability of suicide is not related to the type of drug prescribed.

A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity.

Schizophrenic patients' self-reports of their experience of neuroleptic treatment were used as the basis for the construction of a scale predictive of drug compliance. Reliability analysis of the responses of 150 patients indicated high internal consistency in the 30-item scale, and preliminary validation in the form of discriminant classification accurately assigned 89% of the sample to complaint and non-compliant groupings. Both discriminant and factor analyses suggest that maximum variability in responding is accounted for by items reflecting how the patient feels on medication, rather than what he knows or believes about medication.

Early subjective response and prediction of outcome to neuroleptic drug therapy in schizophrenia.

Events that occur early in the course of neuroleptic treatment, and which may have utility in predicting short-term clinical outcome, were investigated. Such events include the patient's subjective response to drug, early clinical response, and the emergence of side effects. From all the variables examined, early subjective response and symptom change at 24 and 48 hours following initiation of neuroleptic drug therapy were found to be significantly related to short-term outcome. These findings are assessed with respect to their predictive utility and relative contribution to the development of a strategy for individualized drug treatment approaches in schizophrenia.