The genesis of adiabatic shear bands.

Adiabatic shear banding (ASB) is a unique dynamic failure mechanism that results in an unpredicted catastrophic failure due to a concentrated shear deformation mode. It is universally considered as a material or structural instability and as such, ASB is hardly controllable or predictable to some extent. ASB is modeled on the premise of stability analyses. The leading paradigm is that a competition between strain (rate) hardening and thermal softening determines the onset of the failure. It was recently shown that microstructural softening transformations, such as dynamic recrystallization, are responsible for adiabatic shear failure. These are dictated by the stored energy of cold work, so that energy considerations can be used to macroscopically model the failure mechanism. The initial mechanisms that lead to final failure are still unknown, as well as the ASB formation mechanism(s). Most of all - is ASB an abrupt instability or rather a gradual transition as would be dictated by microstructural evolutions? This paper reports thorough microstructural characterizations that clearly show the gradual character of the phenomenon, best described as a nucleation and growth failure mechanism, and not as an abrupt instability as previously thought. These observations are coupled to a simple numerical model that illustrates them.

Dynamic recrystallization as a potential cause for adiabatic shear failure.

Dynamic recrystallization (DRX) is almost universally observed in the microstructure of adiabatic shear bands. It is usually admitted that DRX results from the large temperatures that develop in the band along with very high local strains. This paper reports the observation of dynamically recrystallized nanograins in Ti6Al4V alloy specimens that were impact loaded to only half the failure strain at which the adiabatic shear band develops. This observation shows that DRX not only precedes adiabatic shear failure but it is also likely to be a dominant micromechanical factor in the very generation of the band. This result means that adiabatic shear failure is not only a mechanical instability but also the outcome of strong microstructural evolutions leading to localized material softening prior to any thermal softening.

Long-term sertraline treatment of children and adolescents with obsessive-compulsive disorder.

OBJECTIVE: To evaluate the safety and effectiveness of sertraline in the long-term treatment of pediatric obsessive-compulsive disorder (OCD). METHOD: Children (6-12 years; n= 72) and adolescents (13-18 years; n = 65) with DSM-III-R-defined OCD who had completed a 12-week, double-blind, placebo-controlled sertraline study were given open-label sertraline 50 to 200 mg/day in this 52-week extension study. Concomitant psychotherapy was allowed during the extension study Outcome was evaluated by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), National Institute of Mental Health Global Obsessive-Compulsive Scale, and Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) scores. RESULTS: Significant improvement (p < .0001) was demonstrated on all four outcome parameters on an intent-to-treat analysis for the overall study population (n = 132), as well as the child and the adolescent samples. At endpoint, 72% of children and 61% of adolescents met response criteria (>25% decrease in CY-BOCS and a CGI-I score of 1 or 2). Significant (p < .05) improvements were also demonstrated from the extension study baseline to endpoint on all outcome parameters in those patients who received sertraline during the 12-week, double-blind acute study. Long-term sertraline treatment was well tolerated, and there were no discontinuations due to changes in vital signs, laboratory values, or electrocardiograms. CONCLUSION: Sertraline (50-200 mg/day) was effective and generally well tolerated in the treatment of childhood and adolescent OCD for up to 52 weeks. Improvement was seen with continued treatment.

Rehabilitation. Does it make a difference?

Stroke is a major cause of disability. Comprehensive multidisciplinary assessment and treatment programs have been proven to improve survival and functional outcome compared with less organised systems of stroke care. Patients who undergo such rehabilitative programs are more likely to be alive and living at home 1 year later.

Deep vein thrombosis: prevention in stroke patients during rehabilitation.

Deep vein thrombosis (DVT) and subsequent pulmonary embolism (PE) is a major source of mortality and morbidity in stroke patients. This study was designed to determine the effectiveness of different prophylactic treatments in the prevention of DVT after a stroke in patients undergoing rehabilitation. An additional objective was the identification of risk factors for DVT in stroke in patients during rehabilitation. Three hundred and sixty patients, over a 3-year period, were randomly assigned to one of four groups: adjusted dose heparin, intermittent pneumatic compression (IPC), functional electrical stimulation (FES), or control. There was no significant difference in the development of DVT by treatment group. Patients with DVT on admission (prevalent, n = 61) were compared with the study patients (n = 360). Time interval (from stroke to admission) and lactic dehydrogenase (LDH) concentration were significant risk factors, as well as predictors, for development of DVT (p < .000). These results suggest that the longer a patient remains without DVT prophylaxis after a stroke, the greater the risk of developing DVT and this supports early prophylaxis before rehabilitation.

Serotonergic (5-HT2) mediation of anxiety-therapeutic effects of serazepine in generalized anxiety disorder.

Serotonin 1a and serotonin-2 receptors are implicated in anxiety. Serazepine (CGS-15040A, (R,S)-1,3,4,16b-Tetrahydro-2-methyl-2H,10H-indolo[2,1-c] Pyrazino-[1,2-a][1,4] benzodiazepine-16-carboxylic acid, methyl ester hydrochloride]) is a representative of a novel pentacyclic ring system containing a stabilized indole. In chemical assays it was a highly specific inhibitor of serotonin (5-HT2) binding, and it was active in preliminary preclinical assays of anxiolytic potential. This multicenter trial of CGS-15040A in patients with generalized anxiety disorder demonstrated clinical anxiolytic effects consistent with established preclinical effects. Doses greater than or equal to 10 mg reduced Hamilton Anxiety Scale scores. However, the dose-response relationship was nonlinear. Effects appeared primarily related to the psychic components of anxiety.

A clinical test of noradrenergic involvement in the therapeutic mode of action of an experimental antidepressant.

The noradrenaline (NA) hypothesis of depression is founded primarily on preclinical and clinically indirect evidence. In two three-compartment randomized parallel clinical trials conducted serially, we examined the significance of NA uptake for antidepressant activity. The racemic compound oxaprotiline (hydroxymaprotiline) is a highly specific inhibitor of NA uptake, whereas its R-(-) enantiomer levoprotiline is totally devoid of this property. Oxaprotiline significantly resembled amitriptyline in its antidepressant potential. Conversely, levoprotiline significantly resembled placebo in antidepressant potential. Therefore, NA uptake was necessary for the observed therapeutic effect of this experimental antidepressant.

Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder--a multicenter trial.

Children and adolescents with obsessive compulsive disorder were studied in an 8-week, multicenter, double-blind, parallel groups trial of clomipramine hydrochloride (CMI) versus placebo. Efficacy assessments included the child version of the Yale-Brown Obsessive Compulsive Scale and the National Institute of Mental Health Global rating scale. At the end of 8 weeks, CMI-treated patients showed a mean reduction in Yale-Brown Obsessive Compulsive Scale score of 37% compared to 8% in the placebo group. Side effects were typical of tricyclic antidepressants. In a 1-year open label treatment, CMI continued to be effective and well tolerated.

Deep vein thrombosis in rehabilitating stroke patients. Incidence, risk factors and prophylaxis.

A total of 503 consecutive cases of suspected stroke were examined for potential eligibility based on recent development of a paralyzed limb. Of 123 otherwise eligible subjects, 22 were found by ultrasound to have deep vein thrombosis (DVT) on admission. Therefore, 101 patients were assigned randomly to one of the treatment groups or to the control group. The three treatments were adjusted-dose heparin, external pneumatic compression and functional electrical muscle stimulation. An ultrasound examination of the lower extremities was conducted twice a week on each patient until completion of the study (28 days or discharge, whichever came first). Electrical muscle stimulation was discontinued after 4 mo of the study because of discomfort, blister formation and high drop-out rate. Ten patients developed DVT during the study period. In 17 of the 32 cases of DVT, venography was performed, which confirmed the ultrasound findings in every case. The 32 cases of DVT differed from those without DVT by having a higher prevalence of hypertension (P = 0.02), cholesterol (P = 0.08) and a longer time interval between stroke and admission (P less than 0.05). We conclude that ultrasound is effective for DVT detection in the rehabilitation setting, and two-thirds of such cases are detectable on admission.

Clomipramine in obsessive-compulsive disorder.

The effects of clomipramine hydrochloride (CMI) versus placebo upon DSM-III-defined obsessive-compulsive disorder (OCD) were assessed in a 10-week double-blind multicenter trial and in a corresponding 1-year double-blind extension study. The NIMH global O-C scale, a 15-point ordinal severity scale, incorporating categorical features specific to OCD, was used to evaluate the severity of obsessive compulsive symptoms over the course of treatment, and a physician's rating of global therapeutic effect was used to assess overall change from baseline. In the core study, patients receiving placebo demonstrated minor and nonsystematic changes, whereas patients who received CMI had clinically and statistically significant reductions in the global severity of their disorder. Findings from the extension study were consistent with continuing efficacy for CMI, whereas corresponding data for patients receiving long-term placebo were difficult to interpret. Based upon shifts in categorical severity, symptoms for over half those patients who received CMI were rendered subclinical or within a range of normal functioning. In contast, less than 5% of patients receiving placebo had their symptoms reduced to a subclinical level. Generally, both treatments were well tolerated. Previous studies have indicated therapeutic potential for CMI in obsessive compulsive disorder. These findings confirm and extend previous observations.

Normal latency of the P300 event-related potential in mild-to-moderate Alzheimer's disease and depression.

A two-tone-discrimination task was used to elicit the P300 component of event-related (brain) potentials (ERPs) from patients with presumed Alzheimer's dementia of mild or moderate severity, depressed patients of older age, and cognitively normal individuals. Although the average P300 latency of the Alzheimer patients was greater than that of the depressed patients, which in turn was greater than that of older aged normals, none of the group differences in latency were statistically significant. Moreover, when latency was examined on an individual basis, less than one-quarter of the Alzheimer patients had an abnormally delayed P300 for their age. Reaction times and the percentage of correct behavioral responses to the tones did distinguish the Alzheimer from the normal group; on both measures the patients' scores were significantly worse. It was concluded that the performance of a simple tone discrimination task requiring a button-press response does not sufficiently tax those cognitive functions impaired in the earlier stages of Alzheimer's dementia to result in abnormally slowed cognitive processing of the kind reflected in P300 latency.

Clinical predictors of treatment response in obsessive compulsive disorder: exploratory analyses from multicenter trials of clomipramine.

Two multicenter, double-blind trials were conducted in adults with DSM-III (American Psychiatric Association 1980) defined Obsessive Compulsive Disorder (OCD), comparing clomipramine (Anafranil, CMI) up to 300 mg daily with placebo. Of 519 patients evaluated, 260 received CMI for up to 10 weeks. More than half of the CMI treated patients were significantly improved, approximately 30 percent were minimally improved, and 15 percent showed no improvement after CMI treatment. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess treatment effects and attempts were made to correlate change in Y-BOCS score from baseline with a number of baseline characteristics, including age, sex, duration of OCD, baseline Y-BOCS score, baseline Hamilton Rating Scale for Depression (HAM-D) score, presence or absence of secondary depression, and predominance of obsessions or compulsions. Pearson and/or Spearman correlations failed to reveal any statistically significant correlations between outcome and any of the baseline characteristics studied. While the differences were not statistically significant, it did appear that male patients and patients with a longer duration of illness may be less likely to respond to CMI treatment; however, the overall conclusion from this analysis is that none of the variables studied is a reliable predictor of responses to treatment with CMI.

Regional cerebral blood flow measurements in the diagnosis of dementia.

The Xenon-133 regional cerebral blood flow technique (rCBF) was used to assess cortical perfusion in a group of 15 elderly patients (mean age = 79.1, SD = 8.7) with a probable diagnosis of Dementia of the Alzheimer type (DAT). Nine had mild DAT and six were in the moderate stages of DAT. These patients were compared with 15 age and sex matched normal elderly controls (mean age = 75.1, SD = 5.6). RCBF was measured in each patient and control at rest with eyes closed. The DAT patients had significantly lower mean global CBF than normal controls (t = -4.63, p less than 0.0001). In addition, a further 15 normal elderly subjects aged 60 to 92 were assessed and combined with the original 15 to allow calculation of a normal range of rCBF for elderly individuals. Seventy-three per cent of the DAT patients fell below the lower limit of the normal range (39.3 - 59.3 ISI units). These results show the possible usefulness of rCBF as an aid in the diagnosis of early DAT.

The P300 event-related potential and regional cerebral blood flow in patients with Alzheimer's disease.

A number of studies have reported that an abnormal delay in the latency of the P300 event-related potential (ERP) is characteristic of the majority of patients with a dementing process. Another body of research suggests regional cerebral blood flow (rCBF) is significantly reduced in Alzheimer's disease (AD). No previous study has compared the effectiveness of these 2 measures in identifying the same patients with AD. Furthermore, most of the studies on which the above findings are based examined patients in the moderate to severe stages of the disorder. In this study we examined P300 latency and rCBF in 10 patients with mild to moderate Alzheimer's disease, and compared their responses with those of normal subjects of similar age. The P300 component was not evident in 2 of the patients: the remaining 8 had a latency within normal limits for their age. On the other hand, 8 of the patients had abnormally reduced rCBF. These results suggest rCBF measures may be useful for identifying AD in its early stages.

Preliminary results from a multicenter trial of clomipramine in obsessive-compulsive disorder.

Two multicenter, double-blind, placebo-controlled clinical trials were conducted to evaluate the effectiveness of 10 weeks of treatment with up to 300 mg daily of clomipramine in nondepressed patients with OCD. There were 575 patients enrolled in these clinical trials, and preliminary analyses of data from 384 of these patients demonstrate a virtual absence of placebo response, a very low rate of premature discontinuation, and for patients receiving clomipramine, a statistically and clinically significant improvement in OCD symptoms (40%-45% mean improvement with clomipramine vs. 4%-5% mean improvement with placebo). In general, clomipramine was well tolerated in doses of up to 300 mg daily.

The P300 event related potential component in the diagnosis of dementia.

Several studies have suggested that delays in the latency of the P300 ERP component are highly sensitive and specific to dementia and that ERP measurements may become a useful clinical tool in aiding diagnosis. This study examines the sensitivity of P300 measurements to dementia and addresses several methodological issues that limit previous research. Twenty-four patients with dementia diagnosed according to ICD-10 criteria were compared with 100 normal controls, 31 of whom were older than 60. An auditory oddball paradigm was employed to elicit the P300. Mean P300 latency did not differ significantly between the two groups. When individual subjects were examined only 13% of patients with dementia fell outside the two standard error band of the regression of P300 latency on age derived from controls. Thus, this study has not demonstrated clinically useful abnormalities of the P300 component in dementia.