A PET study of the neural systems of stuttering

The cause of stuttering is unknown. Failure to develop left-hemispheric dominance for speech is a long-standing theory although others implicated the motor system more broadly, often postulating hyperactivity of the right (language nondominant) cerebral hemisphere. As knowledge of motor circuitry has advanced, theories of stuttering have become more anatomically specific, postulating hyperactivity of premotor cortex, either directly or through connectivity with the thalamus and basal ganglia. Alternative theories target the auditory and speech production systems. By contrasting stuttering with fluent speech using positron emission tomography combined with chorus reading to induce fluency, we found support for each of these hypotheses. Stuttering induced widespread overactivations of the motor system in both cerebrum and cerebellum, with right cerebral dominance. Stuttered reading lacked left-lateralized activations of the auditory system, which are thought to support the self-monitoring of speech, and selectively deactivated a frontal-temporal system implicated in speech production. Induced fluency decreased or eliminated the overactivity in most motor areas, and largely reversed the auditory-system underactivations and the deactivation of the speech production system. Thus stuttering is a disorder affecting the multiple neural systems used for speaking.     

Site and parameters of microstimulation: evidence for independent effects on the properties of saccades evoked from the primate superior colliculus

1. Microstimulation is used to investigate how activity in the superior colliculus (SC) contributes to determining the properties of primate saccadic eye movements. The site of collicular stimulation, the duration of the stimulation train, and the frequency of the stimulation train are each varied to examine the relative contributions of the locus, duration, and level of collicular activity to determining saccade amplitude, direction, duration, and velocity. 2. For any given site of stimulation, a relationship between movement amplitude and train duration can be demonstrated. Movement amplitude is a monotonically increasing, but saturating, function of increasing train duration. The size of the largest movement is dictated by the site of stimulation. Within the range over which amplitude can be modulated, movement offset is linked to the offset of the stimulation train. As a result, each decrement or increment in train duration produces a corresponding decrement or increment in movement duration. 3. The peak velocity of an evoked movement is influenced by the frequency of stimulation; a higher frequency of stimulation produces a movement of higher velocity. 4. The effects of train duration and frequency can be traded to produce movements that have comparable amplitudes but different dynamic characteristics; high-velocity movements of short duration and low-velocity movements of long duration can be produced by stimulating with high-frequency, short-duration, and low-frequency, long-duration trains, respectively. Across stimulation frequencies, the amplitude of an evoked movement is best related to the total number of pulses in the stimulation train. 5. Because it is possible to compensate for reduced velocity by increasing the duration of the stimulation train, the same site-specific maximum amplitude can be attained with different frequencies of stimulation. 6. Small, but significant, changes in movement direction occur as a result of varying train duration or train frequency. 7. The latency to movement onset (i.e., interval from stimulation onset to movement onset) depends upon the frequency of stimulation. A higher frequency of stimulation produces a movement of shorter latency. 8. These data demonstrate that both the site of stimulation and the parameters of stimulation contribute to determining the properties of a movement evoked from the primate SC. In doing so, they contradict the results of early microstimulation studies that suggest that the properties of eye movements evoked from the primate SC are determined solely by the site of stimulation. The findings conflict with the traditional view of collicular function that suggests that the collicular motor representation is purely anatomic. Rather, these data support a revised view whereby the locus, duration, and level of collicular activity contribute to determining the properties of a primate saccadic eye movement. According to this view, independent information relating to desired displacement and saccade velocity are extracted from the spatiotemporal profile of collicular activity.     

Antihypertensive agent moxonidine enhances muscle glucose transport in insulin-resistant rats

The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia--on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.     

Nonsulfhydryl-reactive phenoxyacetic acids increase aqueous humor outflow facility

PURPOSE: The phenoxyacetic acid, ethacrynic acid (ECA), has potential use in glaucoma therapy because it acts to increase aqueous outflow in vivo and in vitro. In human trabecular meshwork (HTM) cell culture, ECA acts to change cell shape and attachment, effects that have been correlated with microtubule (MT) alterations and chemical sulfhydryl (SH) reactivity. To further explore these actions, we evaluated two non-SH reactive phenoxyacetic acids, inadcrinone and ticrynafen, and the MT-disrupting drug vinblastine. METHODS: Excised bovine and porcine eyes were perfused and outflow facility measured. Calf pulmonary artery endothelial and HTM cells were grown in culture and cytoskeletal effects evaluated after drug treatment. RESULTS: Indacrinone, ticrynafen, and vinblastine all caused an increase in outflow facility. In contrast with ECA, the outflow effects of indacrinone and ticrynafen were not blocked by excess cysteine. Although indacrinone and ticrynafen produced changes in cell shape in vitro, the beta-tubulin staining pattern of treated cells was not altered. Vinblastine caused cell shape change and the expected MT disruption. CONCLUSIONS: Phenoxyacetic acids can increase aqueous outflow facility and alter HTM cell shape and attachment in vitro by a non-SH, non-MT mechanism (which is probably shared also by ECA). These findings suggest the possibility of a broader class of glaucoma drugs that may be directed at the HTM. An understanding of the cellular target for these drugs has implications both for potential glaucoma therapy and for the cytoskeletal mechanisms involved in normal outflow function.     

Determination of total non-sulphonated aromatic amines in soft drinks and hard candies by reduction and derivatization followed by high-performance liquid chromatography.

Utilizing elements of methodology developed previously for food colours, total free and bound non-sulphonated aromatic amines (NSAA) were determined in commercial samples of soft drink beverages and hard candies. Bound amines in the samples were reduced using sodium dithionite, then total NSAA were extracted into chlorofom, transferred to aqueous acid solution and diazotized with sodium nitrite before coupling with 2-naphthol-3,6-disulphonic acid, disodium salt (R-salt). The coloured derivatives were analysed using reversed-phase ion pair high-performance liquid chromatography (HPLC) and an absorbance detector set at 512 nm. Solid phase extraction cartridges were utilized for extraction and clean-up of the food colours present in the sample, and the concentration of each dye was determined quantitatively using HPLC and absorbance detector wavelengths of 426, 516 or 625 nm. Levels of total NSAA were compatible with those observed previously in food colours. Commercial soft drinks were found to contain (expressed in terms of total free plus bound NSAA in the beverage) 0.19-12.6 ng/ml of aniline, 0.83-8.25 ng/ml 1-naphthylamine and 0.62-1.12 ng/ml 2-naphthylamine. Levels of 0.66-9.15 ng/g of aniline and 2.48-10.6 ng/g 1-naphthylamine were found in commercial samples of hard candies. Bound NSAA in hard candies appeared to survive the manufacturing process. Recoveries averaged 96.9% for tartrazine and 89.6-97.2% for the bound amines when hard candies were prepared in the laboratory.     

DSM-III-R personality disorders in a mood and anxiety disorders clinic: prevalence, comorbidity, and clinical correlates

This study examined the prevalence, comorbidity, and clinical correlates of personality disorders in an outpatient sample (N = 352) with anxiety and depression. Subjects were diagnosed using the Structured Clinical Interview for DSM-III-R (SCID) on Axes I and II, and they also completed interview and self-report measures of symptoms. Subjects with a personality disorder were less likely to be married, more likely to be single or divorced, had lower family incomes, had more severe symptoms of both anxiety and depression, and had a greater number of lifetime Axis I diagnoses. Subjects with dysthymic and bipolar disorders were more likely, and subjects with panic disorder uncomplicated by agoraphobia were less likely to have a personality disorder compared to the rest of the sample. The most prevalent personality disorders were Avoidant, Obsessive-Compulsive, Paranoid, and Borderline. Paranoid co-occurred with Narcissistic, and Borderline co-occurred with Histrionic personality disorder significantly more often than chance and base rates would predict.     

Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes

OBJECTIVE: To determine the relative influences of induction of withdrawal bleedings secretory transformation, and reduction of mitosis in glands on prevention of endometrial hyperplasia during long-term hormonal replacement therapy. DESIGN: Observational expanded clinical case report. SETTING: Reproductive Endocrine Department of Hospital Necker, Paris, France, and Pathology Department of Women's Hospital, Los Angeles County and University of Southern California Medical Center, Los Angeles, California. PATIENTS: Postmenopausal women seeking treatment for symptomatic menopause. INTERVENTIONS: Endometrial biopsy and/or ambulatory hysteroscopy. MAIN OUTCOME MEASURE: Endometrial histology including progestational maturation patterns and glandular epithelial mitosis rates. Macroscopic endometrial appearance. RESULTS: The use of larger doses of E2 and P induced more marked secretory changes and more frequent withdrawal bleeding than the lower doses. There was no evidence of endometrial hyperplasia after 5 years of E2/P replacement therapy independently of bleeding pattern or progestational maturation. Consistent reduction of mitosis rates in glandular epithelium was found after 9 or more days of P administration in each cycle. CONCLUSIONS: Control of endometrial growth is mainly related to control of mitosis in glands by a relatively low doses of P. Induction of withdrawal bleeding and endometrial secretory transformation, which require larger doses of Progesterone, do not provide additional benefit for prevention of hyperplasia. Induction of amenorrhea with a relatively low dose of P may be offered to women seeking hormone replacement therapy with similar levels of safety.     

Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin

Thrombopoietin (TPO) has recently been cloned and shown to regulate megakaryocyte and platelet production by activating the cytokine receptor c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were generated by gene targeting. TPO-/- mice have a >80% decrease in their platelets and megakaryocytes but have normal levels of all the other hematopoietic cell types. A gene dosage effect observed in heterozygous mice suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bone marrow from TPO-/- mice have decreased numbers of megakaryocyte-committed progenitors as well as lower ploidy in the megakaryocytes that are present. These results demonstrate that TPO alone is the major physiological regulator of both proliferation and differentiation of hematopoietic progenitor cells into mature megakaryocytes but that TPO is not critical to the final step of platelet production.