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BACKGROUND AND PURPOSE: Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS). This could decrease multiple sclerosis (MS) activity, but may compromise CNS immune surveillance. We aimed to quantitate the effect of firategrast treatment on cerebrospinal fluid (CSF) lymphocyte count and the extent/speed of recovery after its discontinuation. METHODS: Forty-six subjects with relapsing forms of MS were treated for up to 24 weeks with open-label firategrast, 900 (females) or 1200 (males) mg twice daily. CSF and blood cell counts, and lymphocyte composition were determined using flow cytometry. RESULTS: Median (n, range) CSF lymphocyte counts (cells/µl) at weeks 0, 24, 28 and 36 were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5 (29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a similar pattern. Minimal changes were observed for CD3-CD16+CD56+ natural killer cells. Median CD4 : CD8 ratios were: 2.9 (41, 1.1-10.9), 2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood lymphocyte counts were elevated at weeks 4 and 24, consistent with the mechanism of firategrast, and returned to baseline when firategrast was discontinued. There were minimal changes in CD4 : CD8 ratios. CONCLUSIONS: Firategrast treatment was associated with modest decreases in median CSF total, CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of decreases suggests that sufficient numbers of lymphocytes can access the subarachnoid space, preserving CNS immune surveillance.

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Study design factors are partly to blame for the high failure rate in trials with antidepressant drugs. Clinical trial simulation (CTS) allows the investigation of the influence of design characteristics on important aspects of clinical trials such as power and type I error. Using CTS scenarios, we evaluated the impact of population size, randomization ratio, frequency of assessments, dropout mechanisms, clinical end point, and statistical method on the outcome of clinical trials with antidepressant drugs. The results reveal that (i) an increase in the frequency of visits does not increase statistical power, (ii) a skewed randomization for a placebo or comparator arm may decrease statistical power, and (iii) analysis of the percentage of responders should be avoided. CTS should become best practice in the optimization of study design. To date, no other statistical approach has enabled such comprehensive evaluation of the factors contributing to study failure in depression.

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BACKGROUND AND OBJECTIVES: Two different leucocyte-inactivation technologies--gamma irradiation and INACTINE PEN110--were evaluated for their effects on cell-associated human cytomegalovirus (CMV). MATERIALS AND METHODS: In vitro CMV-infected cells were spiked into leucoreduced red blood cell concentrates (RCC) or medium at a final concentration of 0.5 - 1 x 10(7) cells/ml to mimic non-leucoreduced levels of leucocytes. The spiked RCC/medium was divided into three equal units and treated with gamma irradiation at the US Food and Drug Administration (FDA)-approved dose of 25 Gy, with 0.1% v/v PEN110 at 22 degrees C for 24 h, or stored at 4 degrees C as a control. The treated and control cells were recovered and tested using infectivity, viability and polymerase chain reaction (PCR) assays. RESULTS: Gamma-irradiated CMV-infected cells produced active virus, as shown by both infectivity assays and PCR quantification of viral DNA. PCR analysis demonstrated higher CMV DNA levels in gamma-irradiated, latently infected monocytic THP-1 cells than untreated control cells. The increased virus production in gamma-irradiated cells was paralleled by an increased metabolic rate and the development of enlarged multinuclear cells. In contrast, PEN110 treatment terminated virus replication and completely inactivated the infected cell. CONCLUSIONS: These results demonstrate that gamma irradiation, at levels currently used to treat RCC, has the capacity to induce expression of CMV, whereas PEN110 inhibits CMV replication and efficiently inactivates the infected cells.

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Attention deficit/hyperactivity disorder (ADHD) is often a lifelong condition. When untreated or undertreated, it appears to have a deleterious impact upon the daily functioning of the majority of adults that were diagnosed with this condition during childhood. Effective treatment, under the best circumstances, is multi-modal. The recent MTA study staged by the United States government confirmed the primary role of psychostimulants for children with this condition. The findings from this study have been generalised to adults that also have ADHD, particularly in cases where there is a well-defined longitudinal history dating back to early childhood. Psychostimulants remain a viable first-choice strategy for adults with ADHD. There are idiosyncratic differences in response to the various psychostimulants for any given individual with ADHD. Furthermore, the emergence of long-acting, once daily psychostimulant medications is likely to improve the calibre of care for adults with ADHD. A number of alternative pharmacotherapies have been studied, or are being developed, for adults with ADHD. These pharmacotherapies include antidepressant medications that affect dopaminergic and noradrenergic bioavailability, as well as cholinergic agents. In addition, agents that manipulate histaminergic and glutaminergic receptors are being studied as possible non-stimulant alternatives in the management of adult ADHD. More information is needed before any definitive statements can be made concerning the feasibility and utility of these non-stimulant medication approaches.

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BACKGROUND: Effective treatments for attention-deficit/hyperactivity disorder (ADHD) in adults are still being defined. Pediatric studies have suggested that a mixed amphetamine salt product (Adderall) is safe and effective in the treatment of childhood forms of ADHD. Presently, there are no reports in the scientific literature concerning the safety and efficacy of Adderall in adults with ADHD, which is the focus of this study. METHOD: Twenty-four outpatients (mean age = 33.3 years) with DSM-IV ADHD were administered Adderall in an open-label fashion, starting at 5 mg p.o. b.i.d., with titration according to clinical response, across a 16-week period. Relatives or spouses of each patient completed serial checklists (including the Copeland Symptom Checklist and the Brown Attention-Deficit Disorder Scales). Prospectively collected data were analyzed retrospectively. RESULTS: Thirteen patients (54%) responded in a positive manner to Adderall, based on Clinical Global Impressions-Improvement scale scores. The mean end dose for responders was 10.77 mg/day (0.14 mg/kg/day). An intent-to-treat analysis revealed a decrease in the mean Copeland score from 99.05 to 63.3 (p < .001), while the mean Brown score dropped from 76.75 to 50.85 (p < .0001). Nine patients (38%) were poor responders or nonresponders to Adderall. Acute anxiety symptoms occurred in 4 of 7 patients with a comorbid anxiety diagnosis. CONCLUSION: Adderall may be an effective agent for the treatment of adult forms of ADHD, with positive responses occurring at relatively low doses, at least for some individuals. However, Adderall may precipitate anxiety in vulnerable individuals. Further study is required.

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PURPOSE: Methods of determining muscle usage for exercises involving rotator cuff muscles are limited. Therefore, this investigation used magnetic resonance imaging (MRI) to evaluate the effect of three different exercises used for rehabilitation of the rotator cuff. METHODS: Five normal volunteer subjects (3 men, 2 women, mean age 31.4 yr) were studied. The exercises were scaption with internal rotation (SIR), military press (MP), and side-lying 45 degrees abduction (SLA). MR imaging was performed immediately before and after exercise using a "fast" spin echo STIR sequence and oblique coronal plane imaging. Changes in signal intensity pre- and post-exercise were measured at comparable section locations for the MR images of the supraspinatus, infraspinatus, teres minor, subscapularis, deltoid, and trapezius. RESULTS: The SLA showed the greatest increase in signal intensity in all the muscles (percent change, P < 0.01) except for the trapezius, which was used more by the MP and SIR. None of the exercises activated the teres minor (percent change, P = not significant). CONCLUSION: These findings have important implications in efficacy of physical rehabilitation of the rotator cuff and avoidance of subacromial impingement exercise motions.

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INTRODUCTION: Guanfacine hydrochloride is an alpha-2 adrenergic agonist, which has gained recent attention in the field of child and adolescent psychiatry. This medication has been described as effective in the management of attention-deficit hyperactivity and tic disorders, with minimal side effects. METHODS: Presented here are five cases of behavioral activation in children treated with guanfacine. RESULTS: In each instance the clinical presentation resembled an acute hypomanic or manic episode. The dose of guanfacine was 0.5 mg/day. Later investigation revealed that all of the youngsters had clear risk factors (clinical and/or familial) for bipolar disorder. CONCLUSIONS: It appears as though guanfacine may be capable of precipitating secondary mania in vulnerable children.

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Infidelity of DNA synthesis by human immunodeficiency virus, type 1 reverse transcriptase (HIV-1 RT) is a presumptive determinant of HIV-1 hypervariability and is incompletely understood at the mechanistic and structural levels. Amino acid substitution at only three residues, including Asp-76 (Kim, B., Hathaway, T. R., and Loeb, L. A. (1996) Biochemistry 37, 5831-5839), is known to increase fidelity. We report here that substitution at Arg-78 can also increase accuracy. Mutant R78A RT showed reduced primer extension in misincorporation assays lacking a complementary dNTP and exhibited a 9-fold decrease in mutation frequency in the M13mp2 lacZ forward mutation assay. Previous structural studies indicate that Arg-78 and Asp-76 lie in a region that interacts with template nucleotides. Interestingly, R78A RT exhibited 6- to 8-fold decreases in binding affinity (K(d)) for RNA and DNA templates relative to wild type RT. In contrast, D76V RT, which also increases fidelity (Kim et al., 1996), showed a 6- to 7-fold increased affinity. The processivity of R78A RT on both RNA and DNA templates was substantially reduced relative to wild type RT, whereas the processivity of D76V RT was increased. We discuss relationships of fidelity, template binding, and processivity in these and other HIV RT mutants.

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Many autistic patients with mental retardation have difficulties with explosivity and aggression. They often prove resistant to various pharmacotherapeutic interventions. In this study, 11 male outpatients (mean 18.3 years) were administered risperidone in an open-label fashion. The risperidone was started at 0.5 mg daily, and titrated upwards until maximum clinical benefit occurred. Serial clinical interviews were conducted, and Conners Parent-Teacher Questionnaires (short form) were completed by the caretakers. Substantial clinical improvement was noted almost immediately in each patient, with aggression, self-injury, explosivity, and poor sleep hygiene most improved. The modal dose for optimal response was 0.5 mg bid. Weight gain was a significant side effect (average velocity of 0.47 kg per week), while none of the patients experienced extrapyramidal side effects.

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