Influence of alpha stimulants and beta blockers on yohimbine toxicity

1. Potentiation of yohimbine-induced sublethality has been largely used to predict antidepressant action. 2. Several products were tested in order to understand the mechanism of this toxicity better: an alpha-1 central stimulant (adrafinil); an alpha-2 central stimulant (clonidine); and 4 beta-blockers (propranolol, atenolol, penbutolol and metoprolol). 3. It was found that atenolol and adrafinil could not antagonize toxicity, whereas clonidine and the other 3 beta-blockers could. 4. It is suggested that a central beta-origin toxicity exists since only beta-blockers which cross the blood-brain barrier are capable of antagonizing this activity. 5. The fact that clonidine also antagonized this toxicity may be explained by the beta-antagonist action of this substance at the high doses used.     

Adrafinil: effects on behavior and cognition in aged canines

1. Adrafmil is a novel vigilance promoting agent developed in France by Louis Lafon Laboratories. 2. Adrafinil causes increased locomotion without producing stereotypical activity in canines tested in an open field. 3. The effectiveness of a single treatment is long-lasting, and the effectiveness persists over repeated treatments. 4. Acquisition of a size discrimination problem is enhanced by adrafinil. This may be linked to performance motivation. 5. Adrafinil causes a long-lasting increase in high frequency electroencephalographic activity recorded from cortical electrodes. 6. These results indicate that adrafinil is novel behavioral stimulant with cognitive enhancing potential. The underlying mechanisms of action are still unknown.     

Modafinil: its discovery,the early European and North American experience in the treatment of narcolepsy and idiopathic hypersomnia,and its subsequent use in other medical conditions

Adrafinil, a new molecule identified by a French drug company, L. Lafon Ltd, in 1974, was found to cause a significant dose-dependent increase in motor activity in mice, without exerting peripheral sympathomimetic effects. As early as 1977–78, Michel Jouvet prescribed adrafinil to narcoleptic patients, but without consistent results. Meanwhile the kinetics of adrafinil led to the identification of an active metabolite, modafinil. In 1983, Jouvet and Bastuji prescribed modafinil to narcoleptic and idiopathic hypersomnia patients and obtained a significant decrease of excessive daytime sleepiness and sleep attacks in a majority of patients. L. Lafon Ltd was initially not interested in developing this molecule for market however, thanks to Jouvet's insistance, it decided to start clinical trials in both healthy volunteers and narcoleptic patients as well as conduct animal studies. Results were excellent and led to the use of modafinil by the French army during the Gulf War in January–February 1991, as well as to the official registration of the drug in France in 1992. Subsequent multicenter controlled clinical trials in North America confirmed the findings in Europe. Modafinil was later used to treat sleepiness, somnolence and fatigue in a large number of medical conditions.     

Two-year maintenance treatment with citalopram, 20 mg, in unipolar subjects with high recurrence rate

BACKGROUND: The efficacy of citalopram, 20 to 60 mg/day, in relapse prevention in major depression was demonstrated in 6-month placebo-controlled studies. The authors tested the efficacy of citalopram, 40 mg/day, in relapse prevention over a 4-month period and citalopram, 20 mg/day, in recurrence prevention over a 24-month period. METHOD: Fifty inpatients with recurrent major depressive disorder (DSM-IV criteria) who had had at least one depressive episode during the 18 months preceding the index episode were openly treated with citalopram, 40 mg/day. Thirty-six subjects had a stable response to citalopram and remained in the continuation treatment with citalopram, 40 mg/day, for 4 months as outpatients. At the time of recovery, 32 patients gave their written informed consent before entering the 24-month maintenance period with citalopram, 20 mg/day. They were evaluated monthly by trained psychiatrists on the basis of the 21-item Hamilton Rating Scale for Depression. Every 3 months, patients were given the Sheehan Disability Scale, a self-rating instrument, to assess their psychosocial adjustment. RESULTS: No relapse was observed in the 4-month continuation period. Sixteen (50%) of 32 patients who entered the 24-month maintenance period had a new recurrence. Patients with recurrence showed a persistent moderate disability on Sheehan Disability Scale score, while no further differences were highlighted in clinical and demographic characteristics between patients with and without recurrence. CONCLUSION: In agreement with previous findings, these data suggest that a full dose of antidepressant is strongly recommended in prophylactic therapy of patients with recurrent major depression. Moreover, it appears that psychosocial impairment may increase the risk of recurrence, thus conditioning a poor outcome.     

The case of a newspaper phobia in a 9-year-old child.

The case of E, a 9-year-old, male, with a newspaper phobia, is presented. The phobia developed over a 4-year period and gradually spread until it included many significant areas of E's life. Treatment took place over a 4-month period. It involved use of a token economy administered by E's parents. Cognitively, the treatment involved the concepts of the acquisition of perceived self-control as a consequence of the token economy agreement. This included volition, attention, and self-control by E as well as parental reinforcement.     

A prospective natural history study of inclusion body myositis: implications for clinical trials

Eleven patients with untreated inclusion body myositis (IBM) were prospectively studied during a 6-month period that included muscle strength, lean body mass, and muscle mass measurements. There was an overall quantifiable mean decline in percent of predicted normal muscle strength of 4% from baseline in a 6-month period, but one third of patients showed no change or slight improvements in strength. Short-term treatment trials in IBM will require large numbers of patients to detect slowing, arrest, or even slight improvement in muscle strength.     

Increases in a marker of immune system reconstitution are predated by decreases in 24-h urinary cortisol output and depressed mood during a 10-week stress management intervention in symptomatic HIV-infected men

BACKGROUND: Stress management interventions reduce distress symptoms and hypothalamic-pituitary-adrenal (HPA) axis hormones such as cortisol, which has been related to a down-regulation of immune system components relevant to the human immunodeficiency virus (HIV) infection. We previously showed that HIV+ men assigned to a 10-week cognitive behavioral stress management (CBSM) intervention showed more CD4+CD45RA+CD29+ lymphocytes, an indicator of immune system reconstitution, at a 6- to 12-month follow-up compared with controls. Here, we tested whether reductions in urinary cortisol output and depressed mood during the 10-week CBSM intervention period mediated its effects on this immune system reconstitution marker at follow-up. METHODS: Twenty-five HIV-infected men randomized to either a 10-week CBSM intervention or a wait-list control provided 24-h urine samples and psychological responses pre- to postintervention, which were related to changes in immune status over a 6- to 12-month follow-up period. RESULTS: Greater reductions in cortisol output and depressed mood during CBSM appeared to mediate the effects of this intervention on this indicator of immune system reconstitution over the 6- to 12-month follow-up period. Changes in mood were maintained over the follow-up period, although these did not add explanatory information beyond the cortisol and mood changes that were observed during the 10-week intervention period. These findings were not explained by the changes in medications or health behaviors during follow-up. CONCLUSION: A time-limited CBSM intervention may affect the rate of immune system reconstitution in HIV-infected men by modifying the stress of symptomatic disease. This intervention may work by decreasing depressed mood and normalizing HPA axis functioning.     

Behavioral and Histopathological Analysis of Domoic Acid Administration in Marmosets

Summary:  Purpose: To induce status epilepticus (SE) followed by the subsequent onset of spontaneous recurrent seizures, thus characterizing a new model of temporal lobe epilepsy in a nonhuman primate.
Methods: Male and female marmosets ( Callithrix jacchus ) (n = 18), ages between 2 and 8 years, were injected with domoic acid (0.5–4 mg/kg, i.p.) or saline, and behaviorally assessed with regard to the presence of acutely induced seizures and for ≤6 months for spontaneous seizures. Injection of doses ranging from 3.5 to 4 mg/kg either did not induce SE or resulted in fatal SE. Even a 5-min SE duration (SE blockade resulting from diazepam injection) proved lethal to marmosets within 1 h of domoate administration, regardless of intensive care and monitoring of the animals. Animals injected with doses ranging from 0.5 to 3 mg/kg that developed only a few minor convulsive signs were allowed a 6-month survival period for the assessment of spontaneous epileptic events. At the end of the experiment, 6-month period, or acute intoxication associated with SE induction, animals were deeply anesthetized and had their brains subjected to histologic processing for Nissl and delta-FosB.
Results: For the animals injected with domoate that did not develop SE (i.e., those that survived), we could not detect any behavioral signs of spontaneous epileptic seizures in the 6-month observation period, and only minor indications of neuropathologic changes (i.e., neuronal death) over Nissl-stained sections, as well as some small changes in the staining for delta-FosB in a few of the animals.
Conclusions: Systemic administration of domoic acid to marmosets is not effective for the generation of a model of chronic temporal lobe epilepsy. Administration of domoic acid at doses that do not lead to SE also did not lead to the development of temporal lobe epilepsy or clear-cut behavioral changes over a 6-month period.     

Spinal muscular atrophy: new thoughts on the pathogenesis and classification schema.

We have established the first prospective, collaborative study of spinal muscular atrophy, the second most common neuromuscular disease of childhood. One hundred and forty-one patients have been evaluated on at least four occasions over a 3-year period. The patients have been grouped by age of onset, as well as by function at the time of initial evaluation. The muscle strength of 96 patients aged 5 years or older was evaluated at 6-month intervals using a fixed myometry system. The new observations made are: (1) The present classification schema is not valid; for example, 49 patients with onset of weakness before 6 months of age (type I or Werdnig-Hoffmann disease), whose life span is said to be only 2 to 4 years, participated in the study and are 4 months to 31 years of age. (2) Thirty-seven patients were evaluated over an 18-month period. None lost strength during this time but four lost function. Although the period of observation was short, the results suggest that the loss of function in patients with spinal muscular atrophy might be explained by a process other than cell death that allows patient strength to be maintained and simultaneously prevents the motor unit from achieving its normal adult potential.     

MRI brain volume changes in relapsing-remitting multiple sclerosis patients treated with interferon beta-1a

The aim of this study was to investigate changes of brain volume as measured by magnetic resonance imaging (MRI) in relapsing-remitting multiple sclerosis (MS) patients under treatment with interferon beta-1a. Moreover, the relationship between brain volume changes and standard MR or clinical outcome variables was determined. After a 6-month pretreatment period, 52 patients with relapsing-remitting MS were assigned to receive interferon beta-1a (Rebif-Serono) during a 24-month treatment period MRI scans were performed monthly during the 6-month pretreatment period and for the first 9 months of the treatment period. A final MRI scan was also performed at the end of the 12- and 24-month treatment period. Over 24 months of IFNbeta-1a treatment, a significant decrease of hyperintense lesion volume was found (-18.0%; p<0.0001) compared to the last pretreatment scan, while T1 hypointense volume showed a slight nonsignificant increase (+2.2%), and brain volume showed a significant decrease (-2.2%; p<0.0001). The mean volume of enhancing lesions over the 6-month pretreatment period was significantly related to absolute (p=0.02; r=-0.32) and per cent change (p=0.03; r=-0.30) of brain volume during 24-month treatment period. No correlations between changes in brain volume and changes in T2 hyperintense volume or T1 hypointense volume were observed. Neither was there a relationship between brain volume and changes of Expanded Disability Status Scale (EDSS) or frequency in clinical relapses. Of the group in whom was detected a significant decrease of brain volume, 13 out of 26 (50%) had a sustained change in EDSS while in the group that did not have a significant decrease of brain volume, only 3 out of 26 (11.5%) had a sustained EDSS change (p=0.02). In this study a decrease of brain volume was found in relapsing-remitting MS patients treated with IFNbeta-1a over 2 years. The only parameter that predicted brain volume decrease by 2 years of IFNbeta-1a treatment was the mean volume of enhancing lesions over the 6-month pretreatment period.     

Mental Health Factors in the Utilization of Pediatric Primary Care

The relationship of mental health factors to use of pediatric medical care in a 12-month period is examined using cross-sectional and prospective data from a community-based cohort of children (aged 4–8 years at baseline) and their families. Results from this study demonstrate that mother's self-reported mental health is statistically significantly related to the number of pediatric visits. In the cross-sectional analysis, the effect of mothers's mental health on children with 5 or more pediatric visits is moderated by poverty and mothers with depressive symptoms are much more likely than those without such symptoms to have children who are very high service users (10 visits or more). In the longitudinal analysis, an inconsistent pattern of mothers' mental health problems over a 24-month period increases the likelihood of high use in the third year and the persistence of maternal mental health problems increases the likelihood of very high use.     

Motor root conduction block in traumatic brachial plexopathy

A 31-year old man sustained severe left brachial plexus traction injury. Electrical stimulation demonstrated multilevel motor root conduction block, which reversed after a 4-month period. Motor root conduction studies are useful diagnostic and prognostic adjuncts in the management of brachial plexopathy.     

The canine model of human cognitive aging and dementia: pharmacological validity of the model for assessment of human cognitive-enhancing drugs

For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimer's disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.     

Goal-Directed Fantasy and the Performance of Hypnotic Test Suggestions†

Rejection sensitivity has been found to confer risk for depression. The process through which this occurs remains unclear. This risk factor also has been associated with negative behavioral tendencies and interpersonal difficulties. Drawing on these different lines of research, the current investigation aimed to evaluate stress generation, the tendency for depression-prone individuals to experience higher rates of life stressors that are at least in part influenced by their own behavior, as a potential mechanism mediating the link between rejection sensitivity and subsequent depressive symptoms. Sixty-six adults with a history of depression were followed over a 4-month interval and completed assessments of rejection sensitivity and depressive symptoms at baseline, and depressive symptoms, a diagnostic interview for depression, and a contextual threat life stress interview at 4-month follow-up. Consistent with the stress generation hypothesis, rejection sensitivity predicted higher rates of dependent stressors, but not independent ones, over the 4-month prospective follow-up period. Furthermore, prospectively occurring dependent stressors mediated the relationship between baseline rejection sensitivity and depressive symptoms at follow-up. The finding that stress generation may operate as a mediating mechanism underlying the pathway between rejection sensitivity and depression lends preliminary support for the importance of targeting maladaptive behavioral tendencies in rejection-sensitive individuals in clinical settings.     

Robot-aided sensorimotor arm training improves outcome in patients with chronic stroke

Thirty patients with chronic stroke received 6 weeks of sensorimotor robotic training in a pilot study that targeted motor function of the affected shoulder and elbow. The impairment and disability scores were stable during a 2-month observation/measurement period, improved significantly by program completion, and remained robust in the 3-month follow-up. Task-specific motor training attenuated a chronic neurologic deficit well beyond the expected period for improvement after stroke.     

Case series: brief parent-child group therapy for childhood anxiety disorders using a manual-based cognitive-behavioral technique

OBJECTIVE: To report on a brief parent-child group therapy program for children with anxiety disorders. METHOD: Twenty-four children with an anxiety disorder and their parents participated in a 10-session treatment. Children were evaluated at pretreatment (T1), posttreatment (T2), 12-month follow-up (T3), and 36-month follow-up (T4). Ten children were also assessed on entering a waiting period (T0). RESULTS: There were no significant symptomatic changes between T0 and T1. Anxiety symptoms decreased significantly during the treatment and follow-up periods. Depressive symptoms changed only during the follow-up period. The percentage of children with no current anxiety disorder was 71% at T2 and 91% at T4. Children of mothers with an anxiety disorder improved more than children of nonanxious mothers, whereas the anxiety level of anxious mothers remained stable. CONCLUSIONS: Brief parent-child group psychotherapy may serve as a time-limited, cost-effective, and efficient intervention.     

Hypothermia and multiple sclerosis. A case with 3 episodes of transient hypothermia

On three occasions over a 21-month period, a woman with multiple sclerosis presented with hypothermia accompanied by altered consciousness, neurological signs and inappropriate antidiuretic hormone secretion. One of the episodes included hypoglycaemia. Although repeated MRI examinations, one of them with gadolinium injection, gave negative results, hypothalamic demyelination was suspected. The 4-year follow-up of this patient suggests that this lesion has no prognostic value.     

Risk for depression in families over time: a pilot epidemiologic study

A random sample of 34 families from the general population were studied over a 15-month period to determine their risk for depression over time. Adults and children in the families were interviewed three times during the 15-month period. Risk for depression was evaluated using four screening instruments, including the Diagnostic Interview Schedule. At the original interview, 40 percent of the families contained one or more members at risk for depression. The 15-month family incidence rate for risk for depression was 26 percent and of continued good mental health 74 percent. The mental health status of 35 percent of the families changed during the 15-month period, suggesting that longitudinal studies can provide a more accurate profile of family mental health than studies of families at a single point in time.     

Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography

Introduction

CT Pulmonary Angiography has been shown to be equivalent to Ventilation/ Perfusion scanning in 3-month outcome studies, but it detects more pulmonary emboli. Isolated subsegmental pulmonary emboli are thought to account for some of the increase in diagnosis, but it is not known whether these emboli represent a harbinger for future thromboembolic events. The objective of this study was to determine the 3-month clinical outcomes of a cohort of patients diagnosed with isolated subsegmental pulmonary emboli.

Materials and Methods

Review of 10,453 consecutive CTPA radiology reports over 74-month period since the implementation of Multidetector CT Pulmonary Angiography identified a cohort of 93 patients found to have acute pulmonary embolism isolated to subsegmental pulmonary arteries without other evidence of deep venous thrombosis at one institution. The study measured 3-month clinical outcomes (anticoagulation use, recurrence, death, hemorrhage) determined by review of records and telephone interviews with physicians.

Results

Seventy-one patients (76%) were treated with anticoagulation and/or IVC filter, while 22 (24%) were observed without therapy. One patient (1/93, 1.05%; 95% CI: 0-6.6%) who was treated with anticoagulants and a vena caval filter had a recurrent subsegmental pulmonary embolus. No patients died of pulmonary embolism. There were 8 hemorrhages, including 5 (5.3%) major hemorrhages without any hemorrhage-related mortality.

Conclusions

Patients diagnosed with isolated subsegmental pulmonary emboli have favorable 3-month outcomes. Short-term prognosis for recurrent thromboembolism may be lower than the risk of adverse events with anticoagulation in patients at high risk of hemorrhage.