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A letter to the editor is presented in response to the article on Tourette syndrome treatment through fluoxamine by Thomas A. Mellman, published in the previous issue.

This paper presents results from laboratory studies to measure the methane yield and rate of digestion of reject bananas. These parameters were determined in experiments that took into account the likely configuration of a full-scale plant in the banana growing region of north Queensland. The digestion was conducted in a 200-l reactor using fed-batch operation, relying entirely on the natural microbial consortia on the reject bananas to avoid reliance on external inocula such as sludge, an undesirable material around food packaging facilities. An enrichment culture was first established in a highly buffered 200-l batch digestion unit. The fed-batch digester was then started by exchanging leachate with the mature batch reactor. Under loading conditions of 0.6 kg VS m(-3)d(-1) over 70 days where the average working volume was 160 l, the digester produced 398+/-20 l CH4 kg VS(-1). Increasing the loading rate to 1.6 kg VS m(-3)d(-1) resulted in a reduced methane yield of 210 l CH4 kg VS(-1) over 23 days of operation, with a concomitant accumulation of banana waste in the digester. The leachate at the end of digestion contained over 4000 mg l(-1)K, 200 mg l(-1) N and 75 mg l(-1), levels that exceed acceptable limits for general agricultural irrigation.

Residence time distribution studies of gas through a rotating drum bioreactor for solid-state fermentation were performed using carbon monoxide as a tracer gas. The exit concentration as a function of time differed considerably from profiles expected for plug flow, plug flow with axial dispersion, and continuous stirred tank reactor (CSTR) models. The data were then fitted by least-squares analysis to mathematical models describing a central plug flow region surrounded by either one dead region (a three-parameter model) or two dead regions (a five-parameter model). Model parameters were the dispersion coefficient in the central plug flow region, the volumes of the dead regions, and the exchange rates between the different regions. The superficial velocity of the gas through the reactor has a large effect on parameter values. Increased superficial velocity tends to decrease dead region volumes, interregion transfer rates, and axial dispersion. The significant deviation from CSTR, plug flow, and plug flow with axial dispersion of the residence time distribution of gas within small-scale reactors can lead to underestimation of the calculation of mass and heat transfer coefficients and hence has implications for reactor design and scale-up., (Copyright 2001 John Wiley & Sons, Inc.)

The development of large-scale solid-state fermentation (SSF) processes is hampered by the lack of simple tools for the design of SSF bioreactors. The use of semifundamental mathematical models to design and operate SSF bioreactors can be complex. In this work, dimensionless design factors are used to predict the effects of scale and of operational variables on the performance of rotating drum bioreactors. The dimensionless design factor (DDF) is a ratio of the rate of heat generation to the rate of heat removal at the time of peak heat production. It can be used to predict maximum temperatures reached within the substrate bed for given operational variables. Alternatively, given the maximum temperature that can be tolerated during the fermentation, it can be used to explore the combinations of operating variables that prevent that temperature from being exceeded. Comparison of the predictions of the DDF approach with literature data for operation of rotating drums suggests that the DDF is a useful tool. The DDF approach was used to explore the consequences of three scale-up strategies on the required air flow rates and maximum temperatures achieved in the substrate bed as the bioreactor size was increased on the basis of geometric similarity. The first of these strategies was to maintain the superficial flow rate of the process air through the drum constant. The second was to maintain the ratio of volumes of air per volume of bioreactor constant. The third strategy was to adjust the air flow rate with increase in scale in such a manner as to maintain constant the maximum temperature attained in the substrate bed during the fermentation., (Copyright 2000 John Wiley & Sons, Inc.)

To evaluate the efficacy of fluoxetine in the treatment of tics and obsessive-compulsive symptoms in patients with Tourette's syndrome (TS), 14 subjects (8-33 years old) with TS participated in a 20-week, fixed-dose (20 mg daily), double-blind, placebo-controlled crossover trial of fluoxetine monotherapy. Five subjects met criteria for obsessive-compulsive disorder (OCD), 6 additional subjects had obsessive-compulsive features, and 3 subjects had TS without obsessive-compulsive symptoms. There was no improvement in tics after 8 weeks of treatment with fluoxetine (p = 0.58). In contrast, fluoxetine treatment was associated with a significant reduction in obsessive-compulsive symptoms for the group of 6 subjects initially randomized to fluoxetine (p = 0.04). Crossover analysis showed that fluoxetine had no marked effect on tics (n = 10, p = 0.30, but produced a modest decrease in obsessive-compulsive symptoms (n = 8, p = 0.06). Order effects and carry-over effects were not significant. Withdrawal to placebo was associated with a 55% increase in obsessive-compulsive symptoms (p = 0.05), but there was no effect on tics. The most common side effect was transient behavioral activation, which occurred in about half of the subjects and was more common in children. Fluoxetine may be useful for the treatment of obsessive-compulsive symptoms in some patients with TS, but does not appear to be effective for tics.

To examine the role of noradrenergic, dopaminergic, and serotonergic mechanisms in the pathobiology of obsessive compulsive disorder (OCD) and Tourette's syndrome (TS), concentrations of tyrosine (TYR), norepinephrine (NE), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA), tryptophan (TRP), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the lumbar cerebrospinal fluid (CSF) of 39 medication-free OCD patients, 33 medication-free TS patients, and 44 healthy volunteers. CSF TYR concentrations were reduced (p < .05) in the OCD patients compared to the healthy subjects. CSF NE in TS patients was 55% higher than in healthy controls (p < .001) and 35% higher than in OCD patients (p < .001). After covarying for height, CSF HVA levels were reduced (p < .05) in the OCD group compared to TS patients but not compared to the normal volunteers. No mean differences in CSF MHPG, TRP, and 5-HIAA were observed in this study across the three groups. The CSF NE data support the hypothesis that noradrenergic mechanisms are involved in the pathobiology of TS. Alterations in the balance of noradrenergic, dopaminergic, and serotonergic systems are likely involved in the pathobiology of OCD.

We measured the midline cross-sectional area and other morphologic features of the corpus callosum (CC) from magnetic resonance (MR) images in 14 unmedicated patients with Tourette's syndrome (TS) and 14 normal control subjects matched for age, sex, handedness, and socioeconomic status. Each CC was manually circumscribed on midline images from a T1-weighted sagittal series, and the area of the entire CC and five anatomic subdivisions were measured. CC circumference, regional width, and mean callosal curvature were also measured. CC cross-sectional area correlated positively with brain size and basal ganglia volumes. The magnitude of reduction (17.7%) in total CC area in TS patients compared with control subjects was similar to the reductions seen in all CC subdivision areas. Analyses of covariance with total midsagittal cross-sectional head area as a covariate revealed the reductions to be statistically significant for the overall CC area and all subregion areas. CC width tended to be nonsignificantly thinner in all subdivisions (from 5% to 11%), and the overall length of the center line measured from rostrum to splenium was significantly reduced in the TS group (by 5.3%). Measures of mean callosal curvature suggested that CCs in TS patients are less rounded than those of normal control subjects. Worst-ever motor tic symptoms showed the strongest significant correlation with the length of the CC center line in TS patients (r = 0.88). These findings suggest that structural interhemispheric connectivity may be aberrant in the central nervous systems of TS patients, and they provide indirect supportive evidence for the presence of altered cerebral lateralization in the disorder.

We report here the first use in Tourette's syndrome of the nonsteroidal androgen receptor blocking agent flutamide. One man and one woman underwent open trials of the medication, and a second man participated in a placebo-controlled, double-blind crossover trial. Improvement in tic symptoms ranged from 45 to 60%. The improvement was sustained in the woman during daily flutamide use and in one man during its intermittent use. One man's symptoms became refractory to treatment after 5 weeks of flutamide use, whereas the woman became depressed and had protracted diarrhea during her treatment.

Objective: We examined the short- and long-term temporal stability of tic counts to estimate the minimum length of videotape needed for a reliable index of overall tic activity and determined the interrater reliability and validity of tic counts based on prolonged videotape segments (> 10 minutes)., Method: Motor and phonic tic counts and clinician ratings were performed on 43 patients with Tourette's syndrome (TS), aged 7 to 50 years. Short-term stability was estimated by determining the mean interval-to-interval correlation of sequential equal-length segments from 30-minute videotape recordings of 20 subjects. Long-term stability was determined by correlating tic counts at 1-week (N = 14) and 2-week intervals (N = 11). In addition, tic counts were correlated with the most widely used clinical ratings of TS., Results: The short-term stability data indicated that estimates of motor and phonic tic frequencies should be based on videotape counts of at least 5 minutes' duration. Tic counts also were highly reliable and were significantly correlated with clinical ratings with the Yale Global Tic Severity Scale and the Clinical Global Impression Scale for Tourette Syndrome., Conclusions: Standardized videotape tic counts can provide highly reliable, stable measures of tic frequencies that are moderately correlated with selected global ratings of tic severity.

Clinical assessment of a child with Tourette's syndrome (TS) includes a careful review of motor and phonic tics. In addition, commonly associated problems of such as obsessive-compulsive symptoms, or symptoms of attention deficit hyperactivity disorder (inattention, impulsiveness, and overactivity) should also be evaluated. Treatment almost always includes education of the child, family, and school personnel concerning the natural history and behavioral boundaries of the disorder. Other treatment interventions depend to a great extent on the primary source of impairment. This article, the second of two parts, presents three illustrative cases and reviews current treatment interventions for children and adolescents with TS.

Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by a changing repertoire of motor and phonic tics that typically begin in childhood and exhibit a fluctuating course. Obsessive-compulsive symptoms and problems of inattention, overactivity, and impulsiveness are present in some cases. Historically, TS has been viewed as a severe disorder. However, data from epidemiologic and family-genetic studies indicate that it shows a wide range of severity. This article, the first of two parts, examines the current notions concerning the origin, pathophysiology, and diagnosis of TS. The second article will present three cases and describe contemporary approaches to treatment.

Rigorously designed clinical trials have demonstrated the efficacy and safety of fluoxetine in adults with major depressive disorder and obsessive-compulsive disorder (OCD) but not in patients below 18 years old. This report describes a randomized, double-blind, placebo-controlled, fixed-dose (20 mg qd) trial of fluoxetine in 14 children and adolescents with OCD, ages 8 to 15 years old; the study was 20 weeks long with crossover at 8 weeks. Obsessive-compulsive symptom severity was measured on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinician's Global Impression-Obsessive Compulsive Disorder scale (CGI-OCD). The CY-BOCS total score decreased 44% (N = 7, p = .003) after the initial 8 weeks of fluoxetine treatment, compared with a 27% decrease (N = 6, p = .13) after placebo. During the initial 8 weeks, the magnitude of improvement for the fluoxetine group significantly exceeded that for the placebo group as measured by the CGI-OCD (p = .01) but not by the CY-BOCS (p = .17). The most common drug side effects were generally well tolerated. The results suggest that fluoxetine is a generally safe and effective short-term treatment for children with OCD.

The safety and effectiveness of clonidine hydrochloride (3 to 5 micrograms/kg per day) were evaluated in 47 subjects with Gilles de la Tourette's syndrome, aged 7 to 48 years. Twenty-four subjects were randomly assigned to clonidine treatment and 23 to placebo. Forty subjects (21 given clonidine and 19 placebo) successfully completed the 12-week, double-blind clinical trial. Clinical ratings of tic severity improved for both groups. The magnitude of response was greater in the group receiving clonidine. Clinician-rated measures of motor tic severity, the degree to which the tics are "noticeable to others," motor tic counts from videotaped interviews, and parent-rated measures of impulsivity and hyperactivity were the most responsive to clonidine treatment. These results indicate that clonidine is more effective than placebo in reducing some of the tic and other behavioral symptoms associated with Gilles de la Tourette's syndrome.

Self-injurious ideation or behavior appeared de novo or intensified during fluoxetine treatment of obsessive-compulsive disorder in six patients, age 10 to 17 years old, who were among 42 young patients receiving fluoxetine for obsessive-compulsive disorder at a university clinical research center. These symptoms required the hospitalization of four patients. Before receiving fluoxetine, four patients had major risk factors for self-destructive behavior including depression or prior suicidal ideation or self-injury. Three hypotheses concerning the apparent association between fluoxetine and these self-injurious phenomena are discussed: (1) coincidence; (2) disorganization of vulnerable individuals secondary to drug-induced activation; and (3) a specific serotonergic-mediated effect on the regulation of aggression.

Phenomenology and family history in 21 clinically referred children and adolescents with obsessive compulsive disorder are described. Each child and family participated in a standard clinical psychiatric assessment. The most frequently reported symptoms were repeating rituals, washing, ordering and arranging, checking, and contamination concerns. Controlling behaviors involving other family members were seen in 57% of the patients. Associated psychopathology was common: 38% received an anxiety disorder diagnosis; 29% received a mood disorder diagnosis; tics were observed in 24%. Fifteen (71%) of the children had a parent with either obsessive compulsive disorder (N = 4) or obsessive-compulsive symptoms (N = 11). The clinical and research implications of these findings are discussed.

The search for nongenetic factors that mediate the expression of a genetic vulnerability to Tourette's syndrome (TS) is an important undertaking that may provide valuable clues concerning the pathophysiology of this disorder as well as potential treatment approaches. In a direct interview study, the perinatal experiences of 31 TS patients were compiled in an effort to identify risk factors associated with tic severity. Severity of maternal life stress during pregnancy, gender of the child, and severe nausea and/or vomiting during the first trimester were found to be significantly associated with current tic severity. Future longitudinal studies of "at-risk" children are needed to confirm these findings. Set in the context of a known chromosomal site for the TS diathesis, such studies will permit the identification and quantification of risk and protective factors in the expression of TS and further develop TS as a model neuropsychiatric disorder for the study of gene-environment interactions.

Fluoxetine hydrochloride is the first selective serotonin uptake inhibitor introduced commercially in the United States. This report describes preliminary clinical experience with fluoxetine in 10 children and adolescents, aged 8 to 15 years, with primary obsessive compulsive disorder (OCD) or Tourette's syndrome (TS) plus OCD. In general, fluoxetine, which was administered from 4 to 20 weeks at a dosage of 10 or 40 mg per day, was well tolerated. Adverse effects included behavioral agitation/activation in four patients and mild gastrointestinal symptoms in two patients. No abnormalities were noted in the seven children who had follow-up EKGs. Five of the 10 patients (50%) were considered responders; their obsessive-compulsive symptoms decreased substantially during treatment with fluoxetine. Responder rates were similar in the primary OCD (two of four, 50%) and TS + OCD (three of six, 50%) groups. In conclusion, short-term fluoxetine administration appears to be safe in children and adolescents. Placebo-controlled trials are needed to further assess the efficacy of fluoxetine.

Plasma concentrations of unconjugated homovanillic acid (pHVA) reflect both central nervous system (CNS) and peripheral dopamine metabolism. Debrisoquin sulfate (DBQ) blocks peripheral, but not CNS, production of HVA from dopamine. Administration of DBQ has been used to decrease the proportion of peripherally produced HVA in pHVA measurements, making such measurements more reflective of CNS turnover of dopamine. We studied the relationships between DBQ dose, plasma DBQ (pDBQ) levels, and changes in pHVA in a group of 21 subjects (9 normal controls and 12 with Tourette's syndrome). DBQ dose was moderately correlated with pDBQ levels (r = 0.63, p = 0.002). Subjects (n = 8) with mean pDBQ levels above 60 ng/ml had a 48% to 66% decrease in mean pHVA levels; this may reflect nearly complete inhibition of peripheral HVA production. Subjects (n = 13) with mean pDBQ levels below 55 ng/ml had decreases in pHVA levels from 10% to 58%. No debrisoquin was detected in cerebrospinal fluid samples. These data suggest that pDBQ levels above 60 ng/ml are sufficient to assure substantial inhibition of peripheral HVA production and that monitoring pDBQ levels may be useful when employing this method for studying CNS metabolism.

Despite the overt nature of most motor and phonic tic phenomena, the development of valid and reliable scales to rate tic severity has been an elusive goal. The Yale Global Tic Severity Scale (YGTSS) is a new clinical rating instrument that was designed for use in studies of Tourette's syndrome and other tic disorders. The YGTSS provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. Data from 105 subjects, aged 5 to 51 years, support the construct, convergent, and discriminant validity of the instrument. These results indicate that the YGTSS is a promising instrument for the assessment of tic severity in children, adolescents and adults.

Within- and across-day stability of plasma-free homovanillic acid (pHVA) was assessed in children and adults with Tourette's syndrome. A diurnal fall in pHVA was observed in 13 of 15 subjects. There was a small but significant (p less than .0001) decrease (8%) in mean morning pHVA levels obtained just 20 minutes apart (8:30 A.M. and 8:50 A.M.). A substantial and significant (p less than .001) mean decrease in pHVA (25%) was observed when samples obtained between 8:00 and 8:30 A.M. were compared with samples obtained at 12:00 noon. Changes in pHVA levels observed during the afternoon (between 12:00 noon and 4:00 P.M.) were small, nondirectional, and nonsignificant. Repeated measurement of morning pHVA in the same individual after 24 or more hours revealed marked increases or decreases in many individuals, suggesting that morning pHVA is not a stable measure. The results of this and previous studies suggest that pHVA obtained at 12:00 noon or later in the day may be a more reliable measure of centrally produced HVA. Further studies are needed regarding the stability of pHVA over time.

Within- and across-day stability of unconjugated plasma 3-methoxy-4-hydroxyphenethyleneglycol (pMHPG, the major metabolite of norepinephrine) levels were assessed in several subgroups of 47 primarily child and adolescent subjects with Tourette's syndrome (TS). Mean morning pMHPG levels remained stable over a 20-min period from 8:30 to 8:50 AM at 3.5 +/- 0.8 ng/ml. However, the mean intraindividual fluctuation in pMHPG levels over 20 min was +/- 12%. Mean pMHPG levels remained stable in the morning from 8:00-8:30 AM to noon. However, an 11% decrease (p less than 0.01) in mean pMHPG levels was observed in the afternoon between noon and 3:00-4:00 PM. Monitored on consecutive days, mean morning pMHPG levels fell 12% (p less than 0.002). The afternoon and across-day falls in pMHPG levels observed in this study of primarily children and adolescents with TS have not been observed in studies of adult control subjects. The results suggest that the design of research protocols involving children and adolescents that use pMHPG should take into consideration the effects of time, both within- and across-day, in pMHPG levels.

Central dopaminergic (DA) function in children was assessed by monitoring plasma-free homovanillic acid (pHVA) levels after brief (18 hour) administration with debrisoquin sulfate, a peripherally active antihypertensive agent that blocks peripheral, but not central, HVA production. Brief debrisoquin administration resulted in marked reductions in pHVA in each of six patients studied. In five of the six patients, post-debrisoquin pHVA levels remained relatively stable over the six-hour period of observation. No significant cardiovascular or behavioral side effects of debrisoquin were observed. The brief debrisoquin administration method appears to be a safe, simple, and potentially valid peripheral technique for evaluating aspects of central dopaminergic function in children with neuropsychiatric disorders. Additional work is needed to further establish this method's validity and reliability.