A clinical, pharmacologic, and polysomnographic study of sleep benefit in Parkinson's disease

We assessed the effect of sleep benefit on motor performance in Parkinson's disease (PD) and analyzed its relation to pharmacologic and sleep measures. The sleep benefit phenomenon-motor improvement after sleep before drug intake-in patients with PD has been addressed by questionnaire studies, but objective data are scarce. Ten PD patients with sleep benefit were pairwisely matched to 10 PD patients without sleep benefit for gender, age, PD symptom duration, and medications. We examined motor performance at night before sleep, during morning baseline state immediately after spontaneous awakening, and continuously after intake of the usual levodopa dose. Plasma levodopa concentrations were measured serially and all-night polysomnography was performed. Between night and morning evaluations, motor state improved slightly in patients with sleep benefit and deteriorated slightly in patients without sleep benefit. The difference between both groups proved to be significant. After levodopa induced "on" state, patients with sleep benefit had more severe interdose "off" than those without. Levodopa concentrations and polysomnographic findings were similar in both conditions, although there was a trend toward more abnormal sleep measures in sleep benefit patients. Sleep benefit is a small but significant phenomenon. It does not clearly relate to a specific sleep variable; however, patients with sleep benefit showed a different response profile to levodopa. Subjective perception or possibly sensory mechanisms could play an additional role in sleep benefit in PD.     

Parkinson's disease: improved function with GM1 ganglioside treatment in a randomized placebo-controlled study

BACKGROUND/OBJECTIVE: Studies in animal models of Parkinson's disease (PD) suggest that GM1 ganglioside treatment can restore neurologic and dopaminergic function. In view of positive preclinical findings and the results of a previous open-label study demonstrating efficacy of GM1 in PD patients, this study compared effects of GM1 ganglioside and placebo on motor functions in PD patients. METHODS: Forty-five patients with mild to moderate PD were studied. The primary efficacy measure was change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. After three independent baseline assessments, patients received IV infusion of the test drug (1,000 mg GM1 or placebo) and then self-administered either GM1 or placebo twice daily (200 mg/day, subcutaneously) for 16 weeks. Patients were examined during monthly follow-up visits. RESULTS: There was a significant difference between groups in UPDRS motor scores at 16 weeks (p=0.0001). The activities of daily living portion of the UPDRS (off-period assessment) also showed a significant effect in favor of the GM1-treated patients (p=0.04). GM1-treated patients also had significantly greater mean improvements than placebo-treated patients in performance of timed motor tests including tests of arm, hand, and foot movements, and walking. GM1 was well tolerated and no serious adverse events were reported. CONCLUSIONS: This study demonstrates that GM1 ganglioside treatment enhances neurologic function significantly in PD patients. Further study is warranted to evaluate long-term effects of GM1 in PD patients and to elucidate further the mechanisms underlying patient improvements.     

Levodopa improves motor function without impairing cognition in mild non-demented Parkinson's disease patients. Parkinson Study Group

OBJECTIVE: The objective of the study was to determine the effects of short-term levodopa administration on motor, cognitive, and psychiatric aspects of Parkinson's disease (PD). BACKGROUND: The effects of levodopa on mental processes in PD are controversial. Opinions range from the claim that levodopa improves cognition to the opposite view that levodopa causes or exacerbates dementia, delusions, and hallucinations. Of the 800 idiopathic PD patients enrolled in the original DATATOP study, 387 reached the end point of functional disabilities sufficiently severe to require levodopa treatment. There were 263 men and 124 women who were comparable with regard to age, symptom duration of PD, and measures of PD severity. We compared test scores on motor performance, cognitive function, and psychiatric status before levodopa and again within 6 months after initiation of levodopa therapy. RESULTS: Levodopa administration improved all motor functions significantly. The improvement was significantly greater in women than in men. Levodopa administration did not worsen scores on any cognitive tests, and there were quantitatively small but significant improvements in tests of frontal lobe function. Levodopa exerted only minor effects on psychiatric measures. There were small but significant decreases in scores for depression, and increases in vivid dreams and hallucinations. CONCLUSIONS: Levodopa administration for up to 6 months in dosages sufficient to improve motor function has only small effects on cognitive function and psychiatric status in mild to moderate PD patients. We conclude that motor symptoms in early PD, which result from dopamine depletion, are dissociable from cognitive functions and psychiatric status, which may be more dependent on nondopaminergic mechanisms.     

A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group

OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations. BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset. METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial. RESULTS: A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations.     

Prevalence of thyroid cancer in hot nodules

Five parkinsonian patients with motor fluctuations and dyskinesia after long-term treatment with levodopa were treated with subcutaneous lisuride infusion (0.24-0.42 mg/day) together with oral levodopa for a mean period of 27 (range 13-36) months. All 5 patients showed marked initial improvement in mobility. Mild psychiatric side effects were observed in three patients; however, these side effects disappeared with reduction in the dosage of lisuride to 0.06 mg per day without a significant increase in motor fluctuations. A low dose of subcutaneous lisuride infusion with oral levodopa is an effective treatment for fluctuations of motor performance in parkinsonian patients without adverse psychiatric effects.     

Safety and tolerance of zolpidem in the treatment of disturbed sleep: a post-marketing surveillance of 16944 cases

The subjective response to treatment with zolpidem, an imidazopyridine hypnotic, was assessed in patients with insomnia under normal treatment conditions in an outpatients' practice in Germany. The uncontrolled clinical surveillance study included 16944 outpatients with subjective difficulties in initiating and/or maintaining sleep. Office-based neurologists, psychiatrists, internists and general practitioners were asked individually to adjust the dosage of zolpidem (age < or = 65 years, 10-20 mg; age > 65 years, 5-10 mg) over a recommended period of 3-4 weeks. In total, 82.8% of patients completed the survey (36% men, 64% women, mean age 58.8 +/- 14.9 years; 58.6% without previous hypnotic medication; duration of sleep complaints > 6 months in 40.6%, 1-6 months in 27.8%). Most patients (63.9%) took zolpidem on a daily basis. The average dose was 10 mg zolpidem per night in 74.8%, 5 mg in 19.8%, 20 mg in 2.4% and > 20 mg in 10 cases. Most physicians (87.6%) rated the efficacy of zolpidem as 'very good' or 'good'. One hundred and eighty-two (1.1%) of the 16 944 patients reported 268 adverse events (one adverse event in 113 cases, two adverse events in 53 cases and more than two adverse events in 16 cases). One hundred and eighteen (64.8%) of these patients (0.006% of all participating patients) discontinued treatment because of adverse events. Nausea (n = 36), dizziness (n = 35), malaise (n = 23), nightmares (n = 20), agitation (n = 19), and headache (n = 18) were the most common adverse events. There was one serious adverse reaction in a 48-year-old women who developed paranoid symptoms during the documentation phase. No life-threatening adverse event occurred. The adverse event profile reflected the pharmacological properties of zolpidem and underlined the cumulative good experience with the drug internationally.     

Neuropsychiatric adverse effects of antiparkinsonian drugs. Characteristics, evaluation and treatment

Parkinson's disease (PD) is a progressive neurological condition that causes considerable disability in the elderly. Drugs used to treat PD, such as levodopa, offer symptomatic relief but often have neuropsychiatric adverse effects, most prominently psychosis and delirium. Aged patients and those with dementia are particularly vulnerable to these adverse effects. Evaluating PD patients with drug-induced neuropsychiatric adverse effects is made difficult by their complex clinical presentations. The treatment of drug-induced psychosis and delirium begins with manipulating the antiparkinsonian drug regimen, but this frequently worsens motor function. Atypical antipsychotics such as clozapine have been successfully employed to treat the psychosis without worsening the motor disability. Patient intolerance of clozapine therapy has prompted open-label studies with newer agents such as risperidone, remoxipride, zotepine, mianserin and ondansetron.     

Compulsory collegial guidance. What do candidates in general practice think about training of practical procedures?

Sleep disorders are common and well documented in patients with Parkinson's disease (PD). However, most data on sleep in patients with PD are derived from selected patient populations. This community-based survey evaluated the prevalence of and risk factors for sleep disturbances in an unselected group of 245 patients with PD and two control groups of similar age and sex distribution: 100 patients with another chronic disease (diabetes mellitus) and 100 healthy elderly persons. Nearly two thirds of the patients with PD reported sleep disorders, significantly more than among patients with diabetes (46%) and healthy control subjects (33%). About a third of the patients with PD rated their overall nighttime problem as moderate to severe. The most common sleep disorders reported by the patients with PD were frequent awakening (sleep fragmentation) and early awakening. Sleep initiation showed no significant difference compared with the control groups. Pain and cramps were not more prevalent among the patients with PD, but they were more likely to report sleep disturbed by myoclonic jerks. Use of sedatives was common in all three groups but significantly higher in the PD group than in the healthy elderly. Symptoms of depression and duration of levodopa treatment showed a significant correlation with sleep disorders in the PD group. This community-based study confirms that sleep disorders are common and distressing in patients with PD. The strong correlation between depression and sleep disorders in patients with PD underlines the importance of identifying and treating both conditions in these patients.     

Arachidonyl ethanolamide (anandamide) activates the parvocellular part of hypothalamic paraventricular nucleus

A total of 335 patients with early Parkinson's disease (PD) were enrolled in a multicenter, randomized, double-blind trial designed to assess the efficacy and safety of pramipexole. Entry was restricted to patients with idiopathic PD who were not receiving levodopa. Pramipexole was administered according to an ascending dose schedule up to 4.5 mg/d. During the 7-week dose-escalation phase, each subject was titrated to his or her maximally tolerated dose of study medication. This was followed by a 24-week period of maintenance therapy. The mean daily dose during the maintenance period was 3.8 mg. Pramipexole significantly reduced the severity of PD symptoms and signs compared with placebo, as measured by decreases in parts II (Activities of Daily Living) and III (Motor Examination) of the Unified Parkinson's Disease Rating Scale at week 24 compared with baseline (p < or = 0.0001). Differences between the active drug and placebo groups emerged at week 3 (1.5 mg/d) in the ascending-dose interval and persisted throughout the maintenance phase (p < or = 0.0001). The majority of patients completed the study (pramipexole 83%, placebo 80%). In the assessment of adverse events, nausea, insomnia, constipation, somnolence, and visual hallucinations occurred more frequently in the pramipexole treatment group compared with placebo patients. No clinically significant changes were noted in blood pressure or pulse rate. Overall, these results indicate that pramipexole is safe and effective in the treatment of early PD.     

Genetic polymorphism of AHSG, FXIIIB, HP and PLG serum proteins in six Jewish groups in Israel

This study was designed to evaluate the conventional techniques of assessing sleep, nursing and patient report, of inpatients on a clinical psychiatric unit. Nurses assessed sleep/wake status at hourly checks and patients completed a sleep diary. For three nights patients wore a wrist actigraph, a portable instrument which provides objective data about sleep/wake activity. The nursing and patient data obtained were compared with actigraphy data. Nursing staff evaluated sleep with satisfactory agreement (76.5% night 1 and 81.6% night 3) that improved over the first three nights of hospitalization (p < 0.03). When the nurses' report did not agree with the actigraph, they tended to overestimate sleep. Patients tended to underestimate their total sleep time and total time awake after sleep onset. Time in bed and initial sleep latency were overestimated. There was great intersubject variability, making determination of agreement impossible. This data suggest that treatment teams on psychiatric units should in general consider nursing reports of sleep more accurate than patient self-report. However, since nursing staff and patients observe different aspects of sleep, both sources of data are important to inpatient treatment teams on clinical units.     

Retinal vessel dilatation and elongation precedes diabetic macular oedema

Rolandic discharge (RD), noted in the electroencephalography (EEG) of patients with benign epilepsy in childhood with centrotemporal spikes (BECCT) has several unique features. One feature is that the amount or frequency of RDs does not correlate well with the incidence of seizures in BECCT although it is a key finding in the diagnosis of this epileptic syndrome. In this study, we examined the efficacy of antiepileptic drugs focusing on the disappearance of RDs in relationship with seizure control. Forty patients with BECCT who were not medically treated prior to this study were randomly sorted into three groups. Twenty patients were assigned for clonazepam (CZP) treatment, 10 patients for valproate (VPA) and the remaining 10 patients for carbamazepine (CBZ). Each drug was administered for 4 consecutive weeks. EEGs were recorded twice during the study, before and 4 weeks after the medication trial. The effects of each treatment on RDs were assessed. RDs disappeared in 15 of the 20 cases treated with CZP (75%) within 4 weeks while the same was observed in only one of the 10 cases treated with VPA (10%). CBZ failed to demonstrate any effect on RD. In the group treated with CZP, there were no differences in seizure incidence, seizure type and blood concentration of CZP between the patients whose RDs disappeared and those whose RDs remained.     

Patients' perceptions of care and safety within psychiatric settings.

There is growing concern over institutional measures of control (e.g., seclusion, restraint) and other potentially harmful or traumatic experiences within psychiatric hospitals. The purpose of the present study was to examine the relationship between demographic variables, potentially harmful and/or traumatic psychiatric experiences, and patients' perceptions of care and safety in psychiatric settings among 142 public-sector psychiatric patients. Data revealed 45.1% of patients reported they had been to a psychiatric facility they would never want to return to, and the majority of patients did not communicate with staff after a distressing event occurred. There were no significant differences in perceptions of care and safety by race, gender, or age. However, patients who reported potentially harmful or traumatic psychiatric events were significantly more likely to report that they had been to a psychiatric facility they would not want to return to. Encouragingly, most patients (84.5%) reported that psychiatric facilities have become safer in recent years. These data suggest the need to better understand how adverse psychiatric events influence how patients view their care and their subsequent engagement in that care. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Development of guidelines to designate alleles using an STR multiplex system

A random sample of 876 subjects aged 65-79 years were investigated by means of a questionnaire concerning sleep and related factors. Sleep problems were reported by 23.8% of females and 13.3% of males. Moderate or major complaints of maintaining sleep were reported by 43.5% of subjects, early morning awakening 33.4% and difficulties falling asleep 31.4%. Daytime sleepiness was more common among males, and a relationship between daytime sleepiness and perceived poor sleep was found. Daytime napping was common, but not related to poor sleep. The prevalence of regular sleeping pill users was 7.6% for females and 3.0% for males and a relationship between sleep problems, sleeping pill usage and psychiatric symptoms was established. Among the regular sleeping pill users 39.1% had possible depression (PD) and 63.0% had possible anxiety disorder (PA). Among respondents with sleep complaints 29.8% had PD and 48.7% had PA. Sleep problems were also related to impaired physical health. Various medical illnesses contributed to sleep complaints among males, and depression affected sleep the most among females.     

Growth suppression mediated by transfection of wild-type hMLH1 in human cancer cells expressing endogenous truncated hMLH1 protein

Eosinophils contribute to the inflammatory process in a variety of chronic inflammatory bowel diseases. Ketotifen is beneficial in experimental models of colitis and in patients with eosinophilic gastroenteritis. Therefore, we investigated the efficacy of ketotifen therapy for the treatment of active ulcerative colitis. Children with newly or previously diagnosed ulcerative colitis with mild-moderate disease activity were treated with ketotifen at a dosage of 4 mg daily for eight weeks. Efficacy was determined by a physician disease severity index and by endoscopic and histologic examinations. Ten patients were enrolled. Symptoms improved in four patients and resolved completely in one patient. There was endoscopic improvement in three patients and histologic improvement in one. Increased eosinophils on rectal biopsy at entry were present in two of the responders. Five patients withdrew due to a lack of symptomatic improvement. No adverse events were identified. Low-dose ketotifen offers a limited therapeutic advantage in active ulcerative colitis that may be enhanced in the subgroup of patients with a high eosinophil count in the colonic mucosa. Further study of therapeutic efficacy with increased dosages of the mast cell stabilizer for acute and maintenance therapy is warranted.     

Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group

BACKGROUND: Despite widespread use of aminosalicylates as maintenance treatment for ulcerative colitis (UC), patients still report troublesome symptoms, often nocturnally. AIM: To compare the efficacy and safety of balsalazide (Colazide) with mesalazine (Asacol) in maintaining UC remission. METHODS: A randomized, double-blind comparison of balsalazide 3 g daily (1.04 g 5-ASA) and mesalazine 1.2 g daily for 12 months, in 99 (95 evaluable) patients in UC remission. RESULTS: Balsalazide patients experienced more asymptomatic nights (90% vs. 77%, P=0.0011) and days (58% vs. 50%, N.S.) during the first 3 months. Balsalazide patients experienced more symptom-free nights per week (6.4+/-1.7 vs. 4.7+/-2.8; P=0.0006) and fewer nights per week with blood on their stools or on the toilet paper, mucus with their stools or with sleep disturbance resulting from symptoms or lavatory visits (each P < 0.05). Fewer balsalazide patients relapsed within 3 months (10% vs. 28%; P=0.0354). Remission at 12 months was 58%, in both groups. Similar proportions of patients reported adverse events (61% balsalazide vs. 65% mesalazine). There were five serious adverse events (two balsalazide, three mesalazine) and four withdrawals due to unacceptable adverse events (three balsalazide, one mesalazine), of which one in each group was also a serious adverse event. CONCLUSIONS: Balsalazide 3 g/day and mesalazine 1.2 g/ day effectively maintain UC remission and are equally well tolerated over 12 months. At this dose balsalazide prevents more relapses during the first 3 months of treatment and controls nocturnal symptoms more effectively.     

Nerve damage in leprosy: an epidemiological and clinical study of 396 patients in west Nepal--Part 1. Definitions, methods and frequencies

A historic cohort study was performed to determine the prevalence and incidence rates of nerve function impairment (NFI) as demonstrated by sensory testing with a nylon monofilament and standard tests of motor function. The records of 396 new leprosy patients registering at Green Pastures Hospital, Pokhara, between January 1988 and January 1992 were analysed. The mean follow-up period was 21 months. In all, 36% (141/396) of patients had either sensory or motor function impairment at their initial examination. For each nerve the prevalence of sensory and motor impairment is reported separately. The posterior tibial nerve was the most frequently affected (sensory) nerve (21%). Sensory impairment of the ulnar nerve was found in 17% of the patients; 8.8% had sensory impairment of the median nerve. The overall incidence rate of motor function impairment was 7.5 (5.4-10) per 100 person years at risk (PYAR). Sensory impairment had a significantly higher rate of 13 (10-17)/100 PYAR (rate ratio (1.8 (1.2-2.7), p = 0.0076). Bl patients had a significantly higher incidence rate of nerve function impairment than BT patients (rate ratio 2.3 (1.4-3.7), p = 0.006). Altogether 152/396 (39%) of the patients required corticosteroid treatment for 'recent' or 'acquired' impairment, and 78 of the patients (20%) developed severe nerve function impairment during or after antileprosy treatment. Analysis of potential risk factors for nerve function impairment showed a significant association with the extent of clinical disease expressed as the number of body areas (out of 9) with primary or secondary signs of leprosy (rate ratio 5.0 (1.5-17), p = 0.0091). It was concluded that nerve function impairment is a serious problem, often occurring during or after multidrug therapy. The extent of clinical disease expressed as a count of body areas involved, or of skin or nerve lesions may identify patients who are at increased risk of nerve damage.     

Understanding adverse experiences in the psychiatric institution: The importance of child abuse histories in iatrogenic trauma.

Psychiatric institutions are intended to be places of treatment and sanctuary. However, iatrogenic events in the hospital may interfere with treatment delivery and adherence (Shaw, McFarlane, & Bookless, 1997); additionally, a history of childhood abuse may increase vulnerability to negative emotional reactions to later adverse or threatening events (Chisholm, Freeman, & Cooke, 2006). The present study extends previous research on the frequency and impact of negative hospital events using the Psychiatric Experiences Questionnaire (Cusack et al., 2003), specifically considering the rate of negative events and consumers' perceptions of their treatment experiences. Questionnaires were administered to 43 participants with a history of at least one inpatient psychiatric hospitalization. Results indicated that 98% of participants had experienced at least one negative event in the psychiatric hospital. Child abuse history was significantly related to number of reported negative hospital events, so that those with a history of child abuse reported experiencing a greater number of negative hospital events and a higher level of subjective distress. Implications for research, clinical practice, and policy to improve trauma-sensitive assessments and treatments are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of excitation of sensory pathways on the membrane potential of cat masseter motoneurons before and during cholinergically induced motor atonia

Electrical stimulation of the nucleus pontis oralis during wakefulness enhances somatic reflex activity; identical stimuli during the motor atonia of active (rapid eye movement) sleep induces reflex suppression. This phenomenon, which is called reticular response-reversal, is based upon the generation of excitatory postsynaptic potential activity in motoneurons during wakefulness and inhibitory postsynaptic potential activity during the motor atonia of active sleep. In the present study, instead of utilizing artificial electrical stimulation to directly excite brainstem structures, we sought to examine the effects on motoneurons of activation of sensory pathways by exogenously applied stimuli (auditory) and by stimulation of a peripheral (sciatic) nerve. Accordingly, we examined the synaptic response of masseter motoneurons prior to and during cholinergically induced motor atonia in a pharmacological model of active sleep-specific motor atonia, the alpha-chloralose-anesthetized cat, to two different types of afferent input, one of which has been previously demonstrated to elicit excitatory motor responses during wakefulness. Following the pontine injection of carbachol, auditory stimuli (95 dB clicks) elicited a hyperpolarizing potential in masseter motoneurons. Similar responses were obtained upon stimulation of the sciatic nerve. Responses of this nature were never seen prior to the injection of carbachol. Thus, stimulation of two different afferent pathways (auditory and somatosensory) that produce excitatory motor responses during wakefulness instead, during motor atonia, results in the inhibition of masseter motoneurons. The switching of the net result of the synaptic response from one of potential motor excitation to primarily inhibition in response to the activation of sensory pathways was comparable to the phenomenon of reticular response-reversal. This is the first report to examine the synaptic mechanisms whereby exogenously or peripherally applied stimuli that elicit motor excitation during wakefulness instead elicit inhibitory motor responses during the motor atonia of active sleep. Thus, not only are motoneurons tonically inhibited during active sleep, but the selective elicitation of inhibitory motor responses indicates that this inhibition can be phasically increased in response to sensory stimuli, possibly in order to maintain the state of active sleep. The data provided the foundation for the hypothesis that, during naturally occurring active sleep, there is a change in the control of motor systems so that motor suppression occurs in response to stimuli that would otherwise, if present during other behavioral states, result in the facilitation of motor activity.     

Origin and evolution of sleep: roles of vision and endothermy

The origin of both sleep and memory appears to be closely associated with the evolution of mechanisms of enhancement and maintenance of synaptic efficacy. After the origin of activity-dependent synaptic plasticity, whereby single activations of synapses led to short-term efficacy enhancements, lengthy maintenance of the enhancements probably was achieved by repetitive activations ("dynamic stabilization"). These are thought to have occurred either in the course of frequent functional use, or to have been induced spontaneously within the brain to maintain synaptic efficacies in circuits that were in infrequent use. The latter repetitive activations are referred to as 'non-utilitarian' dynamic stabilization. With the evolution of increasing repertories and complexities of behavioral and sensory capabilities-with vision usually being the vastly preeminent sense-brain complexity increased markedly. Accompanying the greater complexity, needs for storage and maintenance of hereditary and experimental information (memories) also increased greatly. It is suggested that these increases led to conflicts between sensory input processing during restful waking and concomitant 'non-utilitarian' dynamic stabilization of infrequently used memory circuits. The selective pressure for the origin of primitive sleep may have been a need to achieve greater depression of central processing of sensory inputs-largely complex visual information-than occurs during restful waking. The electrical activities of the brain during sleep (aside from those that subserve autonomic activities) may function largely to maintain sleep and to dynamically stabilize infrequently used circuitry encoding memories. Sleep may not have been the only evolutionary adaptation to conflicts between dynamic stabilization and sensory input processing. In some ectothermic vertebrates, sleep may have been postponed or rendered unnecessary by a more readily effected means of resolution of the conflicts, namely, extensive retinal processing of visual information during restful waking. By this means, processing of visual information in central regions of the brain may have been maintained at a sufficiently low level to allow adequate concomitant dynamic stabilization. As endothermy evolved, the skeletal muscle hypotonia of primitive sleep may have become insufficient to prevent sleep-disrupting skeletal muscle contractions during 'non-utilitarian' dynamic stabilization of motor circuitry at the accompanying higher body temperatures and metabolic rates. Selection against such disruption during dynamic stabilization of motor circuitry may have led to the inhibition of skeletal muscle tone during a portion of primitive sleep, the portion designated as "rapid-eye-movement sleep." Many marine mammals that are active almost continuously engage only in unihemispheric non-rapid-eye-movement sleep. They apparently do not require rapid-eye-movement sleep and accompanying 'non-utilitarian' dynamic stabilization of motor circuitry because this circuitry is in virtually continuous use. Studies of hibernation by arctic ground squirrels suggest that each hour of sleep stabilizes brain synapses for as long as four hours.     

Possible involvement of free radicals in lipopolysaccharide-induced labyrinthitis in the guinea pig: a morphological and functional investigation

BACKGROUND: There are few published placebo-controlled clinical trials demonstrating the efficacy of the newer antidepressants in markedly or severely depressed hospitalized patients. This study demonstrates the efficacy of nefazodone compared with placebo in the treatment of patients hospitalized for major depression. METHOD: Nefazodone and placebo treatment were compared in a 6-week trial of 120 patients hospitalized for DSM-III-R diagnosed major depression (without psychosis) at 2 study centers. Efficacy was evaluated using standard psychiatric rating scales, and patients were monitored for safety. RESULTS: Nefazodone treatment resulted in a significant reduction (p < .01) of the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score compared with placebo from the end of the first treatment week through the end of the study (-12.2 nefazodone vs. -7.7 placebo). At the end of the trial, significantly more nefazodone-treated patients (50%) than placebo-treated patients (29%) had responded, as indicated by their Clinical Global Impressions-Improvement score (p = .021) or by a > or = 50% reduction in their HAM-D-17 scores (p = .017). Significantly more patients treated with nefazodone (36%) than placebo-treated patients (14%) had a HAM-D-17 score < or = 10 at the end of treatment (p = .004). Significant treatment differences (p < .01) in favor of nefazodone were also seen in the Montgomery-Asberg Depression Rating Scale; the HAM-D retardation, anxiety, and sleep disturbance factors; and HAM-D item 1 (depressed mood). Patients with dysthymia in addition to major depression also showed significant improvement (p < .05) when treated with nefazodone, with significant differences in response rates seen as early as week 2 and through the end of the trial. The mean nefazodone dose was 491 mg/day at the end of week 2 and 503 mg/day at the end of treatment. Nefazodone was well tolerated, and the number of patients discontinuing owing to adverse events was small, with no significant safety issues noted in either treatment group. Fewer nefazodone-treated than placebo-treated patients discontinued owing to lack of efficacy. CONCLUSION: Nefazodone was superior to placebo in the treatment of marked to severe major depression in patients requiring hospitalization. The clinical benefit of nefazodone was evident as early as the first week of treatment as judged by several measures of efficacy, with significant differences from placebo sustained throughout the trial.