Very-low-birthweight children and speech and language development.

Very low birthweight (VLBW) is often considered to be a risk factor for speech and language disorders, yet data are equivocal. The present study compared speech and language comprehension and production between 249 very-low-birthweight (VLBW: less than 1.5 kg) and 363 normal-birthweight 8-year-olds, randomly sampled in a geographic area. Mean performance for the entire group of VLBW children and for the group when 24 VLBW children with major neurologic abnormalities were excluded, was significantly lower than for controls on the majority of speech and language measures. Further analyses addressed the clinical significance of these statistically significant differences. Test scores were converted to standard scores and grouped according to standard deviation intervals, thus portraying each child's performance in terms of the magnitude of discrepancy from each test's mean. When the 24 children with major neurological abnormalities were excluded, no significant differences between the VLBW and control children were observed. Using discrepancy between WISC-R performance IQ and language to define specific language impairment (SLI), a higher percentage of control than VLBW children were identified as having SLI. Neonatal risk factors did not differentiate between VLBW children with or without SLI. A higher proportion of VLBW than control children did present subnormal language associated with IQ less than 85, hearing deficits, and/or major neurological impairments. Thus, SLI is not more common among VLBW than control children. Language deficits accompanied by more general developmental problems, however, are more frequent.     

Syntactic findings in developmental verbal apraxia

Spontaneous language samples of eight children diagnosed as presenting developmental verbal apraxia were analyzed in terms of their mean length of utterance, Developmental Sentence Scores, use of 14 grammatical markers, and yes-no and wh-question forms. Although MLUs were greater than the range associated with stage V syntactic development, all children demonstrated difficulties with stage V and beyond grammatical markers and many omitted stage II markers. Developmental Sentence Scores were generally well below chronologic age expectations and revealed notable difficulties with personal pronoun and main verb selection. Omissions or noninversions of auxiliary and/or copulas in yes-no and wh-questions were apparent. Omissions of regular and irregular third-person singular markers, inconsistent use of regular and irregular past tense, and difficulty with question transformations provide evidence that at least some of the errors presented by this group of apraxic children cannot be attributed to motor speech and/or phonologic limitations but rather they evidence concomitant syntactic disorders.     

Acquired capsular/striatal aphasia in childhood

We studied a case of language loss caused by an acquired vascular lesion in the putamen, anterior limb of the internal capsule, and lateral aspect of the head of the caudate nucleus in a 7-year-old right-handed girl. Acute right-sided hemiplegia, mutism, oral apraxia, and disturbance in language comprehension but no dysarthria were present. During recovery, a nonfluent aphasia with anomia was evident. After six months, only mild hemiparesis and minor spelling difficulties persisted. We compared this patient with an 11-year-old right-handed girl with right-sided hemiparesis and dysarthria but no language loss following a lesion in the globus pallidus, a portion of the posterior limb of the internal capsule, and the body of the caudate. The presence of a language disturbance in the first but not the second patient was attributed to the difference in lesion location. The symptoms and lesions were similar to those in recent reports of adult patients. To our knowledge, this is the first report of these findings in a child with a left-hemisphere lesion.     

Increased CRF-like and NPY-like immunoreactivity in adult rats exposed to nicotine during adolescence: relation to anxiety-like and depressive-like behavior

OBJECTIVE: Recently, animal models have been developed that demonstrate that adolescent nicotine exposure produces neurobehavioral changes which persist into adulthood. This study further examined the impact of adolescent nicotine exposure on anxiety-like and depressive-like behavior, as well as on levels of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) in this model. METHODS: Male adolescent rats (35-40 days old) were administered nicotine using Nicoderm CQ patches (Smith-Kline Beecham). Behavior in the elevated plus maze (EPM) and forced swim test (FST) was assessed 2-3 weeks after exposure ended. Brain levels of CRF and NPY were then assessed 5-6 weeks after behavioral tests were completed. In addition, blood and brain levels of nicotine resulting from nicotine treatment were examined. RESULTS: After 5 days of exposure to 5 mg/kg/day nicotine, blood levels of nicotine averaged 66+/-5 ng/ml and brain nicotine levels averaged 52+/-4 ng/g. Rats exposed to nicotine displayed an anxiety-like profile in the EPM (i.e., decreased time spent in the open arms) and an antidepressant-like profile in the FST (i.e., less time spent immobile). Rats exposed to nicotine also had increased hypothalamic and frontal cortical CRF, increased hypothalamic and hippocampal NPY, and a decreased ratio of NPY to CRF in the amygdala. CONCLUSIONS: This study demonstrates that adolescent nicotine exposure produces lasting increases in anxiety-like behavior and may reduce depressive-like behavior. These behavioral changes also occurred in concert with alterations in CRF and NPY systems. Thus, lasting neurobehavioral changes associated with adolescent nicotine exposure may be related to allostatic changes in stress peptide systems.     

Neuropeptide y in euthymic lithium-treated women with bipolar disorder

Plasma neuropeptide Y-like immunoreactivity (NPY-LI) and platelet cyclic AMP (cAMP) activity were determined in 13 women with bipolar disorder stabilized on lithium (Li) and 12 matched healthy controls. No differences in plasma NPY-LI were found between the two groups. In euthymic Li-treated bipolar patients, there was an inverse correlation between plasma NPY-LI levels and intracellular cAMP in prostaglandin E1-stimulated platelets. A positive correlation was found between plasma NPY-LI levels and age in both the patient and the control group. Our findings support earlier findings that NPY is capable of inhibiting adenylyl cyclase and that aging is a physiological factor in regulating NPY-LI levels.     

Identification of a novel route of extraction of sirolimus in human small intestine: roles of metabolism and secretion

Using Caco-2 cell monolayers expressing CYP3A4, we investigated the interplay between metabolism and transport on the first-pass intestinal extraction of the immunosuppressant sirolimus, a CYP3A4/P-glycoprotein (P-gp) substrate. Modified Caco-2 cells metabolized [(14)C]sirolimus to the predicted amounts of CYP3A4-mediated products based on CYP3A4 content, which was approximately 20% of that measured in human small intestinal mucosal homogenate. [(14)C]Sirolimus also degraded to the known ring-opened product, seco-rapamycin. Unexpectedly, a ring-opened dihydro metabolite (M2) was the major product detected in cells at all sirolimus concentrations examined (2-100 microM). Greater M2 formation after apical versus basolateral dosing (1.6-fold) was explained by higher intracellular content of sirolimus after apical dosing. M2 was not detected in incubations with human liver and intestinal microsomes but was readily detected with corresponding homogenates. M2 formation was NADPH-dependent but unaffected by the CYP3A4 inhibitors ketoconazole and troleandomycin. Although M2 was formed from purified seco-rapamycin (20 microM) in the homogenates, it was not detected in cells when seco-rapamycin was added to the apical compartment, because seco-rapamycin was essentially impermeable to the apical membrane. Sirolimus, seco-rapamycin (basolaterally dosed), and M2 were all actively secreted across the apical membrane, and secretion of each was inhibited by the P-gp inhibitor LY335979 [(2R)-anti-5-[3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy]quinoline trihydrochloride]. Along with CYP3A4-mediated metabolism and P-gp-mediated secretion, we conclude that the following novel pathway, which occurs at least in the intestine, may contribute significantly to the first-pass extraction of sirolimus in humans: intracellular degradation of sirolimus to seco-rapamycin, metabolism of seco-rapamycin to M2 by an unidentified non-microsomal enzyme, and P-gp-mediated secretion of M2 and seco-rapamycin.     

Giant neuron pathway neurophysiological activity in per(0) mutants of Drosophila melanogaster

In Drosophila melanogaster, the clock gene period (per) has a clearly defined role in the molecular machinery involved in generating free-running circadian rhythms. per mutations also influence rhythms in the Drosophila love song and in the ultradian timescale. The relationship between these two phenomena has so far escaped satisfactory explanation. Here we analyzed the neurophysiological activity of the giant fiber neural pathway in per(0) flies. Under constant light, and at relatively low stimulation frequencies (1-2 Hz), per(01) flies habituate significantly earlier than they do under 12 h light-dark cycles. The results suggest an involvement of per in phenomena of short-term neural plasticity.