Severe impairment of circadian rhythm in Alzheimer's disease.

Circadian rhythmicity was repeatedly determined in a patient with Alzheimer's disease by measuring his core temperature with a rectal thermistor and motor activity by an ambulatory activity monitor. The first recording, performed 9 years after he was diagnosed with Alzheimer's disease, showed well organized 24 hr circadian rhythm of core body temperature. The second recording, made four months later, showed very poor fit of core body temperature to 24 hour rhythm, but excellent fit with 36 hour rhythm. The third recording, made two months later, showed again good fit of core body temperature with 24 hour cycle. The last recording, which was performed 5 months later, showed almost complete disappearance of circadian rhythm of body temperature. These changes probably reflect gradual lengthening of the circadian cycle that at one point became extremely lengthened before returning to the 24 hr cycle.

Maynard Smith: amplifying the reasons for signal reliability.

One of the many questions to which John Maynard Smith contributed was that of why most animal signals are reliable. He initially rejected the "handicap" argument but gradually accepted it, a process I briefly describe. This episode illustrated his preference for mathematical models over verbal ones, and the generosity with which he could change his mind. Even after accepting that some signals are reliable because of their strategic costs, he argued for a pluralistic approach to signal reliability. Signal complexity was a developing interest when he died. Signals usually involve several components, some of which appear to amplify other signal components. The terms "amplifier" and "index" require more thought to reduce the scope for semantic confusion. I conclude by describing Maynard Smith's fascination with peacocks Pavo cristatus.

Sundowning and circadian rhythms in Alzheimer's disease.

OBJECTIVE: The goal of this study was to determine changes of circadian rhythms induced by Alzheimer's disease and to explore relationships among rhythm disturbances, sundowning, and sleep disturbances in patients with Alzheimer's disease. "Sundowning" is the occurrence or exacerbation of behavioral symptoms of Alzheimer's disease in the afternoon and evening. METHOD: Circadian rhythms of core body temperature and motor activity were measured in 25 patients with diagnoses of probable Alzheimer's disease and in nine healthy individuals. The subjects with Alzheimer's disease were divided according to the occurrence of sundowning as determined by staff reports. RESULTS: The subjects with Alzheimer's disease had less diurnal motor activity, a higher percentage of nocturnal activity, lower interdaily stability of motor activity, and a later activity acrophase (time of peak) than did the healthy individuals. They also had a higher mesor (fitted mean) temperature, higher amplitude of the fitted cosine temperature curve, and later temperature acrophase than did the healthy subjects. The severity of sundowning was associated with later acrophase of temperature, less correlation of circadian temperature rhythm with a 24-hour cycle, and lower amplitude of temperature curve. CONCLUSIONS: These data indicate that Alzheimer's disease causes disturbances of circadian rhythms and that sundowning is related to a phase delay of body temperature caused by Alzheimer's disease.

Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration.

BACKGROUND: Caregiver exhaustion is a frequent consequence of sleep disturbance and rest-activity rhythm disruption that occurs in dementia. This exhaustion is the causal factor most frequently cited by caregivers in making the decision to institutionalize patients with dementia. Recent studies have implicated dysfunction of the circadian pacemaker in the etiology of these disturbances in dementia. METHODS: We studied the activity and core-body temperature rhythms in a cohort of 38 male patients with a clinical diagnosis of probable Alzheimer disease (AD) approximately 2 years before death. These patients were later given a confirmed diagnosis of AD (n = 23), frontotemporal degeneration (FTD) (n = 9), or diffuse Lewy body disease (DLB) with mixed AD or FTD pathologies (n = 6) after autopsy and neuropathological examination. Physiological rhythms of patients with AD and FTD were then compared with a group of normal, elderly men (n = 8) from the community. RESULTS: Alzheimer patients showed increased nocturnal activity and a significant phase-delay in their rhythms of core-body temperature and activity compared with patients with FTD and controls. The activity rhythm of FTD patients was highly fragmented and phase-advanced in comparison with controls and apparently uncoupled from the rhythm of core-body temperature. CONCLUSIONS: Patients with AD and patients with FTD show different disturbances in their rhythms of activity and temperature compared with each other and with normal elderly patients.

Stress induced disorganization of circadian and ultradian rhythms: comparisons of effects of surgery and social stress.

Persistent autonomic disturbances following stressful events suggest that the rhythmical nature of homeostatic functioning may be disrupted by these experiences. We assessed the effects of two different stressors on circadian and ultradian rhythms of Long-Evans rats by using nonlinear multi-oscillator cosinor analysis. Heart rate and intraperitoneal temperature were monitored continuously in 5-min intervals in two groups of animals via radio-telemetry for 15 days after surgery (n = 9) and 15 days following social defeat (n = 6). Circadian amplitude of heart rate and temperature increased significantly for the first nine days of the recovery from surgery but only circadian temperature amplitude increased following social defeat. Circadian acrophase of temperature but not heart rate changed significantly for a similar period following the surgery but not after the social defeat. A mathematical model incorporating the first five harmonics of the circadian rhythm was found to fit the data significantly better than a circadian model alone with rhythms of 3 and 5 cycles/day in temperature and heart rate entraining significantly to the light-dark schedule. Full recovery of the circadian and ultradian rhythms did not occur until a minimum of nine to twelve days after surgery or social defeat. The results suggest that rhythms with multiple periodicities are involved in homeostatic functioning and that models incorporating these rhythms may aid in understanding an organisms adaptive response to surgical intervention and social defeat, long after the challenges have terminated.

Controlled comparison of two fluorometholone formulations in the antigen challenge model of allergic conjunctivitis.

We compared the safety and efficacy of MethaSite, a gel-forming suspension (0.1% fluorometholone), to a commercially available 0.1% fluorometholone ointment, FML S.O.P., using an antigen challenge model. Subjects with known allergic histories were exposed to increasing concentrations of cat dander, ragweed, or grass at visits 1 and 2. Allergic responses of conjunctival injection, chemosis, and subjective itching were quantified on a scale from zero to 3; the sum of these ratings constituted the total allergic score. At visit 3, 105 subjects with total scores of > or = 5 received a drop of MethaSite in one eye and a 0.5 inch ribbon of FML ointment in the other eye. Three and 6 hours postdose, the eyes were challenged with the antigen concentration that provoked significant allergic response at visit 2. We determined safety by evaluating changes in visual acuity, intraocular pressure, and biomicroscopy that occurred between visits 1 and 3. Eyes treated with MethaSite and FML responded similarly to the antigen challenges. Both groups demonstrated suppression of allergic response 3 and 6 hours postdose through equivalent and significant reductions in total allergy scores and individual ratings of injection, chemosis, and itching. In this population, MethaSite was equivalent to FML ointment in safety and efficacy.

Flurbiprofen 0.03% for the control of inflammation following cataract extraction by phacoemulsification.

We conducted a double-masked, vehicle-controlled study to evaluate the anti-inflammatory effect of topical flurbiprofen in cataract surgery by phacoemulsification and implantation of a posterior chamber intraocular lens. The 233 patients were randomized to receive either flurbiprofen or vehicle immediately prior to and for two weeks following surgery. No concomitant corticosteroid use was allowed. The flurbiprofen group had significantly less anterior chamber cells and flare at day 7 and significantly less conjunctival erythema, corneal edema, and lid edema at day 14. The investigator's global effectiveness rating was higher in the flurbiprofen group at day 14. Blood-aqueous barrier disruption, as measured by aqueous fluorophotometry, was statistically significantly diminished in the flurbiprofen group. Burning and stinging were rated significantly greater in the flurbiprofen group than in the vehicle group. Foreign-body sensation and photophobia were significantly more severe in the vehicle group than in the flurbiprofen group. Flurbiprofen provided postsurgical anti-inflammatory efficacy in clinical signs of inflammation and in blood-aqueous barrier disruption, and also showed improved subjective signs.

Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia.

The administration of intravenous agents is the most commonly used method in Canada and the United States to produce sedation or general anesthesia for dental procedures. Ketamine, a dissociative anesthetic, has several advantageous physical, pharmacokinetic, and pharmacodynamic properties. It can be used to induce anesthesia, sedation, analgesia, and amnesia. Ketamine can maintain functional residual capacity, induce bronchodilation, and avoid cardiovascular depression. However, adverse effects have been demonstrated, such as cardiovascular stimulation and unpleasant emergence phenomena, both of which may be modulated by supplementation with benzodiazepines. An increase in the use of ketamine for ambulatory anesthesia has recently been advocated. This review of the literature supports the use of ketamine as an effective agent for selected anesthetic procedures.

Malignant hyperthermia and the general dentist: current recommendations.

Malignant hyperthermia is a potentially fatal disease that may be triggered by the administration of specific drugs or by stress. Although most often associated with general anesthesia, stress can be a significant stimulus and is therefore of concern to the general dentist. The decision as to how and where to treat these patients is complicated by conflicting recommendations from various sources. The aim of this article is to propose a protocol for the dentist to use in the treatment of patients with a history of malignant hyperthermia. The dentist must assess the patient for both their susceptibility to a crisis and the degree of stress of the planned procedure. For non-stressful treatment, it is reasonable to assume that the general dental practitioner can treat these patients in his office. For stressful treatment, advanced preparation is advised.

Skeletal muscle deformation in the lateral muscle of the intact rainbow trout Oncorhynchus mykiss during fast start maneuvers.

Although there is an extensive body of information on the kinematics of the fast start response in teleosts, there is little information on the deformation of the skeletal muscle which produces the changes in body position during a fast start. This study presents preliminary information on the determination of skeletal muscle deformation with implanted ultrasonic dimension gauges in the intact fish during startle behavior. Deformation was measured in the lateral epaxial musculature of the rainbow trout Oncorhynchus mykiss during stage one of fast starts. The results show that ultrasound transit time dimension gauges can be implanted in the skeletal muscle of rainbow trout with minimum trauma and used to record local deformation along the length of the fish. Measurements remained stable over 4-8 h of implantation. Preliminary results show that: (1) muscle at different positions along the fish reaches its minimum length (average 9.6% shortening) at approximately the same time and coincident with the end of stage one of the fast start response; (2) the onset of concave curvature of the entire fish precedes the onset of local shortening at more caudal sites; (3) muscle on the convex side of a bend lengthens while muscle on the concave side shortens, and the two deformations follow a similar time course. These results indicate an asynchronous onset of skeletal muscle contraction in fast starts and support the hypothesis that local skeletal muscle deformation is transmitted caudally through skeletal or other structures.

Lack of differential effect by Ultracaine (articaine) and Citanest (prilocaine) in infiltration anaesthesia.

It has been claimed that anaesthesia of mandibular pulpal and lingual soft tissue, as well as maxillary palatal soft tissue, results following buccal infiltration of the local anaesthetic Ultracaine (articaine HC1). However, this has never been scientifically proven and the aim of this investigation was to test these claims by comparing articaine to a standard anaesthetic, Citanest (prilocaine HC1). In order to study this, a double blind, randomized trial was conducted in healthy adult volunteers. In these subjects, the ability to induce maxillary and mandibular anaesthesia following buccal infiltration with articaine (as compared to prilocaine given contralaterally), was determined by measuring sensation to electrical stimulation at the tooth, buccal and lingual soft tissue at each of the four non-carious, non-restored, second molars. Results showed that there were no statistically significant differences between articaine and prilocaine in their ability to induce anaesthesia for any tissue at any of the six sites (p greater than 0.05) as determined by chi-square analysis. Analysis of effect on sensation for 25 minutes post-administration also failed to demonstrate a difference between the two drugs. Therefore, these data are not consistent with superior anaesthesia efficacy by articaine at any site, including the mandibular pulpal, lingual or maxillary palatal tissues, in the second molars studied.

Comparison of articaine and prilocaine anesthesia by infiltration in maxillary and mandibular arches.

Claims that labial infiltration of the local anesthetic articaine HCl (Ultracaine DS) results in anesthesia of mandibular pulpal as well as maxillary and mandibular lingual soft tissue have never been scientifically substantiated. The aim of this investigation was to evaluate these claims, by comparing articaine to a standard anesthetic, prilocaine HCl (Citanest Forte). To investigate this, a double blind, randomized study was conducted in healthy adult volunteers. In each volunteer, the ability to induce maxillary and mandibular anesthesia following labial infiltration with articaine was compared to prilocaine given contralaterally. Anesthesia was determined by measuring sensation to electrical stimulation at the tooth, labial and lingual soft tissue for each of the 4 non-carious, non-restored, canines. Results showed that mandibular canine pulpal anesthesia had a success rate of 65% for articaine and 50% for prilocaine. Success rates for palatal and lingual anesthesia averaged 5% for each agent. As determined by chi-square analysis, no statistically significant differences were found between articaine and prilocaine for any tissue at any of the 6 sites (P greater than 0.05). A time-course assessment also failed to demonstrate a difference between the two drugs. Therefore these data are not consistent with superior anesthesia efficacy being produced by articaine at any site, including the mandibular pulpal, lingual or maxillary palatal tissues, in the canine teeth studied.

[Dipivefrin: its mechanism of action, clinical efficacy and good tolerance]. / Dipivéfrine, son mécanisme d'action, son efficacité clinique, sa bonne tolérance.

Dipivefrin (DPE) is the first prodrug in general use in ophthalmology. We will discuss the metabolism of DPE to epinephrine within the eye, and the efficacy and safety of DPE in the treatment of elevated intraocular pressure. In addition, we will address the incidence of adverse systemic effects, ocular tolerance and allergy, and the ocular hypotensive efficacy when DPE is used alone or in combination with other antiglaucoma medications.

The evolution of aggression: can selection generate variability?

Three models--the war of attrition, the size game and the badges of dominance game--are described, in which natural selection can maintain genetic variability for aggression. The models differ in whether or not the traits that settle contests are costly in contexts other than fighting, and also in whether signals are used. It is concluded that contests will be settled by non-costly traits only if the value of the contested resource is small relative to the cost of fighting, and that 'honest' signalling of aggressiveness is stable only if individuals giving signals that are inconsistent with their behaviour suffer costs. The literature on 'badges of dominance' in birds is reviewed. New data on great tits, greenfinches and corn buntings show that there is plumage variability within age and sex that sometimes serves to settle contests, and that, in the first two species but not the third, the badges are uncorrelated with size, and settle contests only over trivial resources.

Prevalence of increased intraocular pressure in Graves' disease--evidence of frequent subclinical ophthalmopathy.

Graves' exophthalmos is frequently associated with elevated intraocular pressure on upgaze. Eighty patients with Graves' disease were evaluated prospectively by applanation tonometry to assess the prevalence of ophthalmopathy in this disorder. Whereas 21 (26 per cent) of the 80 patients had exophthalmos, 61 (76 per cent) had abnormal intraocular pressure (delta greater than or equal to 3 mm Hg). All patients with exophthalmos had elevated intraocular pressure on upgaze; 40 (68 per cent) of 59 patients without proptosis had abnormal pressure readings. The mean interval between the onset of Graves' disease and this study was 6.3 +/- 1.0 years (S.E.M.) for those patients who had exaggerated positional changes in intraocular pressure, as compared with 3.0 +/- 1.0 years for those with normal intraocular pressure (P less than 0.005). All but 1 of 15 patients in whom the diagnosis of Graves' disease had been documented 10 or more years earlier had increased intraocular pressure on upgaze. We conclude that Graves' ophthalmopathy is more common than is recognized clinically and that eye involvement is an inevitable complication of the disease.