[Temporal order deterioration and circadian disruption with age. 2. Systemic mechanisms and correction].

Part 2 of the present review highlights the impact of aging on mechanisms involved in response of the circadian system to different photic and non-photic factors, especially zeitgebers. Promising strategies to prevent age-dependent circadian disruption using internal and external factors that may entrain circadian rhythms are presented. In particular, benefits of bright light, melatonin and other chronobiotics, the circadian body temperature rhythm, physical activity and regular feeding schedules to preserve the temporal order of aged organisms are discussed, emphasizing especially a personalized approach based on the assessment of individual overt rhythms parameters.

[TEMPORAL ORDER DETERIORATION AND CIRCADIAN DISRUPTION WITH AGE].

The present review summarizes the current knowledge of gradual deterioration of temporal order in aging humans and other mammals. An obvious consequence of age-dependent circadian disruption in complex mechanisms is extra-circadian dissemination (ECD) that can be observed in overt rhythmic functions. ECD is a variance transposition from circadian to ultradian and infradian frequencies accompanied by a loss of interdaily phase stability. Moreover, heterochronic changes in central and peripheral tissue-specific cellular mechanisms are involved in circadian desychronization. A multitude of internal factors accounts for cumulative clockwork misalignment. Age-related circadian disruption is a consequence of weaker rhythm generation and the loss of proper orchestration on molecular, tissue and systemic levels, disabling their circadian synchrony and resonance.

Progressive retinal ganglion cell loss in primary open-angle glaucoma is associated with temperature circadian rhythm phase delay and compromised sleep.

Advanced primary open-angle glaucoma (POAG) is characterized by progressive retinal ganglion cell complex (RGCC) damage that may cause subsequent disruption of the circadian rhythms. Therefore, we evaluated circadian body temperature (BT) rhythm and sleep characteristics of 115 individuals (38 men and 77 women) diagnosed with POAG. GLV (global loss volume; %), a measure of RGCC damage, was estimated by high-definition optical coherence tomography, and RGC functional ability was assessed by pattern electroretinogram amplitude (PERGA). Depending on dynamics of POAG progression criteria, two groups were formed that were distinctively different in GLV: Stable POAG group (S-POAG; GLV = 5.95 ± 1.84, n = 65) and Progressive POAG group (P-POAG; GLV = 24.27 ± 5.09, n = 50). S-POAG and P-POAG groups were not different in mean age (67.61 ± 7.56 versus 69.98 ± 8.15) or body mass index (24.66 ± 3.03 versus 24.77 ± 2.90). All subjects performed 21 around-the-clock BT self-measurements during a 72-h period and kept activity/sleep diaries. Results showed pronounced disruption of circadian physiology in POAG and its progression with increasing severity of the disease. The daily mean of BT was unusually low, compared to age-matched controls. Moreover, our results revealed distinctive features of BT circadian rhythm alterations in POAG development and POAG progression. S-POAG is associated with lowered BT circadian rhythm robustness and inter-daily phase stability compared to controls. In the P-POAG group, the mean phase of the circadian BT rhythm was delayed by about 5 h and phases were highly scattered among individual patients, which led to reduced group mean amplitude. Circadian amplitudes of individuals were not different between the groups. Altogether, these results suggest that the body clock still works in POAG patients, but its entrainment to the 24-h environment is compromised. Probably because of the internal desynchronization, bedtime is delayed, and sleep duration is accordingly shortened by about 55 min in P-POAG compared to S-POAG patients. In the entire POAG cohort (both groups), later sleep phase and shorter mean sleep duration correlate with the delayed BT phase (r = 0.215; p = 0.021 and r = 0.322; p = 0.0004, respectively). An RGCC GLV of 15% apparently constitutes a threshold above which a delay of the circadian BT rhythm and a shortening of sleep duration occur.

Voluntary exercise stabilizes photic entrainment of djungarian hamsters (Phodopus sungorus) with a delayed activity onset.

The Djungarian hamsters of our breeding colony show unstable daily activity patterns when kept under standard laboratory conditions. Moreover, part of them develops a delayed activity onset (DAO) or an arrhythmic phenotype. In former studies, we have shown that the system of photic entrainment works at its limits. If the period length (tau) increases, which is the case in DAO hamsters, the light-induced phase advances are too small to compensate the daily delay of the activity rhythm caused by tau being longer than 24 h. Accordingly, under natural conditions, there must be further (environmental) factors to enable a stable entrainment. One of these may be the higher level of motor activity. Animals must cover long distances to search for food, sexual partners and others. In the laboratory, hamsters are kept singly in small cages. This does restrict animals' options for motor activity. Also, there is less need for moving around as the hamsters are fed ad libitum. In the present study, a series of experiments was performed to investigate the putative effect of the activity level. To begin with, wild type (WT) and DAO animals were given access to running wheels. 50% of DAO hamsters developed a WT activity pattern. As the main reason for the DAO phenomenon is their long tau together with a too weak photic phase response, the effect of wheel running on these parameters was investigated in further experiments. With higher activity level, tau decreased in WT hamsters but increased in DAO animals even though the increase for the activity onset was only close to significance. Moreover, the photic phase responses were weaker though significant only for the activity offset of DAO hamsters. Based on the assumptions that running wheel activity will affect the phase response and/or the free running period, the results of the present paper do not provide an explanation for why part of DAO hamsters developed a WT phenotype when they had access to running wheels. Obviously, mechanisms downstream from the suprachiasmatic nuclei must be taken into account when investigating the stabilizing, improving circadian entrainment effect of motor activity.

Photic and non-photic effects on the daily activity pattern of Mongolian gerbils.

The paper analyses the daily activity pattern of Mongolian gerbils with and without access to a running wheel. To evaluate the synchronizing and the masking effects of light, experiments were performed under different photoperiods (L:D=14:10 h and 10:14 h), and light and dark pulses were applied at different phases of the day-night cycle. In order to get a more direct estimate of the central pacemaker of the circadian system, the body temperature rhythm was investigated via implanted transmitters. Without access to a running wheel, the daily activity pattern was bimodal. One peak occurred in the first half of the light time, the other one around the light-dark transition. Also, the gerbils were more active during the light phase as compared to the dark phase. After unlocking the running wheel, the gerbils were active mainly during the dark time. The activity peak in the first half of the light phase remained, the second one shifted by a phase delay into the dark time. These results were found under both LD-regimens. Light during the night nearly completely suppressed running wheel activity, switching off the light during the day time induced wheel running. Whereas wheel running was clearly affected by light and dark pulses, the general activity was not. The body temperature rhythm also shows two peaks, with the second one being bigger and coinciding with the endogenous component of the circadian body temperature rhythm. It was found around light-off. After unlocking the running wheel, the maximum of the body temperature rhythm shifted to the night. This was not primarily a consequence of the changed activity pattern as shown by means of purification analysis. Removing the direct effects of motor activity led to a body temperature curve that could be described by a cosine function, and the delay shift was found also for the purified data, a better estimate of the endogenous circadian component. The wheel-associated increase in nocturnality is not only due to masking effects of wheel-running activity on the body temperature and activity rhythms. It also involves clock-related processes. Changes in the phase preference may serve as an adaptation mechanism to the changes in the animal's natural environment.

Deep brain stimulation in the subthalamic area is more effective than nucleus ventralis intermedius stimulation for bilateral intention tremor.

BACKGROUND: The ventro-lateral thalamus is the stereotactic target of choice for severe intention tremor. Nevertheless, the optimal target area has remained controversial, and targeting of the subthalamic area has been suggested to be superior. PATIENTS AND METHODS: Eleven patients with disabling intention tremor of different etiology (essential tremor (n = 8), multiple sclerosis (n = 2) and one with, spinocerebellar ataxia) were implanted bilaterally with DBS electrodes targeted to the ventro-lateral thalamus using micro-recording and micro-stimulation. Among five tracks explored in parallel optimal tracks were chosen for permanent electrode implantation. Postoperative tremor suppression elicited by individual electrode contacts was quantified using a lateralised tremor rating scale at least 3 months (in most patients >1 year) after implantation. The position of electrode contacts was determined retrospectively from stereotactic X-ray exams and by correlation of pre- and postoperative MRI. RESULTS: In all patients, DBS suppressed intention tremor markedly. On average, tremor on the left and right side of the body was improved by 68% (+/-19; standard deviation) and 73% (+/-21), respectively. In most patients, distal electrode contacts located in the subthalamic area proved to be more effective than proximal contacts in the ventro-lateral thalamus. In stereotactic coordinates, the optimal site was located 12.7 mm (+/-1.4; mean +/- standard deviation) lateral, 7.0 (+/-1.6) mm posterior, and 1.5 (+/-2.0) mm ventral to the mid-commissural point. In general, the best contacts could be selected for permanent stimulation. Nevertheless, in some instances, more proximal contacts had to be chosen because of adverse effects (paraesthesiae, dysarthria, gait ataxia) which were more pronounced with bilateral stimulation resulting in slightly less tremor suppression on the left and right side of body (63 +/- 18 and 68 +/- 19%, respectively). CONCLUSION: Direct comparison of different stimulation sites in individual patients revealed that DBS in the subthalamic area is more effective in suppressing pharmacoresistant intention tremor than the ventro-lateral thalamus proper. Anatomical structures possibly involved in tremor suppression include cerebello-thalamic projections, the prelemniscal radiation, and the zona incerta.

Disrupted circadian rhythms of body temperature, heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus.

We report a progressive disruption of 24-h rhythms in fasting blood glucose (FBG), body temperature (BT) and heart rate (HR) associated with metabolic dysfunction and the development of prediabetes (PD) and type 2 diabetes mellitus (T2DM) in overweight middle-aged (40-69 years old) humans. Increasing BT and HR mean values and declining 24-h BT and HR amplitudes accompany adverse changes in metabolic state. Increased nocturnal BT and a phase delay of the 24-h BT rhythm, deviant 24-h HR profile and a phase advance of the 24-h HR and FBG rhythms are early signs of the PD metabolic state. In T2DM, the 24-h FBG rhythm is no longer detectable, and the 24-h amplitudes of BT and HR are greatly diminished. In addition, lepton and creatinine values were lowered in T2DM. Moreover, positive correlations between FBG and body mass index, BMI, and negative correlations between the 24-h amplitude of FBG and BMI indicate that overweight is an additional factor causing disruption of the circadian rhythms. Further studies on circadian disruption as a consequence of metabolic dysfunction are necessary. The quantitative analysis of changing circadian BT and HR rhythms may provide prognostic markers of T2DM and therapeutic targets for its prevention and correction.

Activity, sleep and ambient light have a different impact on circadian blood pressure, heart rate and body temperature rhythms.

The aim of the present study was to investigate the impact of endogenous and exogenous factors for the expression of the daily rhythms of body temperature (BT), blood pressure (BP) and heart rate (HR). One hundred and seventy-three young adults (YA), 17-24 years old (y.o.), of both genders were studied under a modified constant-routine (CR) protocol for 26 h. Participants were assigned randomly to groups with different lighting regimens: CR-LD, n = 77, lights (>400 l×) on from 09:00 to 17:00 h and off (<10 l×) from 17:00 to 09:00 next morning; CR-LL, n = 81, lights on (>400 l×) during the whole experimental session; CR-DD, n = 15, constant dim light (<10 l×) during the whole experiment. Systolic (SBP) and diastolic (DBP) BP, HR and BT were measured every 2 h. For comparison, the results of the former studies performed under conditions of regular life with an activity period from 07:00 to 23:00 h and sleep from 23:00 till 07:00 h (Control) were reanalyzed. Seven-day Ambulatory Blood Pressure Monitoring (ABPM) records from 27 YA (16-38 y.o.) and BT self-measurement data from 70 YA (17-30 y.o.) taken on ≥ 3 successive days at 08:00, 11:00, 14:00, 17:00, 20:00, 23:00 and 03:00 were available. The obtained daily patterns were different between Control and CR-DD groups, due to effects of activity, sleep and light. The comparison of Control and CR-LD groups allowed the effects of sleep and activity to be estimated since the lighting conditions were similar. The activity level substantially elevated SBP, but not DBP. Sleep, on the other hand, lowered the nighttime DBP, but has no effect on SBP. HR was affected both by activity and sleep. In accordance with previous studies, these results confirm that the steep BP increase in the morning is not driven by the circadian clock, but rather by sympathoadrenal factors related to awakening and corresponding anticipatory mechanisms. The effect on BT was not significant. To investigate the impact of light during the former dark time and darkness during the former light time, the CR-LL and CR-DD groups were each compared with the CR-LD group. Light delayed the evening decrease of BT, most likely via a suppression of the melatonin rise. Besides, it had a prominent arousal effect on SBP both in the former light and dark phases, a moderate effect on DBP and no effect on HR. Darkness induced decline in BT. BP values were decreased during the former light time. No effects on HR were found. Altogether, the results of the present paper show that BT, BP and HR are affected by exogenous factors differently. Moreover, the effect was gender-specific. Especially, the response of BT and BP to ambient light was evident only in females. We suppose that the distinct, gender-specific responses of SBP, DBP and HR to activity, sleep and ambient light do reflect fundamental differences in the circadian control of various cardiovascular functions. Furthermore, the presented data are important for the elaboration of updated reference standards, the interpretation of rhythm disorders and for personalized chronotherapeutic approaches to prevent adverse cardiovascular events more effectively.

The circadian body temperature rhythm in the elderly: effect of single daily melatonin dosing.

The present study is part of a more extensive investigation dedicated to the study and treatment of age-dependent changes/disturbances in the circadian system in humans. It was performed in the Tyumen Elderly Veteran House and included 97 subjects of both genders, ranging from 63 to 91 yrs of age. They lived a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted 3 wks. After 1 control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen) daily at 22:30 h for 2 wks. The other 34 subjects were given placebo. Axillary temperature was measured using calibrated mercury thermometers at 03:00, 08:00, 11:00, 14:00, 17:00, and 23:00 h each of the first and third week. Specially trained personnel took the measurements, avoiding disturbing the sleep of the subjects. To evaluate age-dependent changes, data obtained under similar conditions on 58 young adults (both genders, 17 to 39 yrs of age) were used. Rhythm characteristics were estimated by means of cosinor analyses, and intra- and inter-individual variability by analysis of variance (ANOVA). In both age groups, the body temperature underwent daily changes. The MESOR (36.38+/-0.19 degrees C vs. 36.17+/-0.21 degrees C) and circadian amplitude (0.33+/-0.01 degrees C vs. 0.26+/-0.01 degrees C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001). The mean circadian acrophase was similar in both age groups (17.19+/-1.66 vs. 16.93+/-3.08 h). However, the inter-individual differences were higher in the older group, with individual values varying between 10:00 and 23:00 h. It was mainly this phase variability that caused a decrease in the inter-daily rhythm stability and lower group amplitude. With melatonin treatment, the MESOR was lower by 0.1 degrees C and the amplitude increased to 0.34+/-0.01 degrees C, a similar value to that found in young adults. This was probably due to the increase of the inter-daily rhythm stability. The mean acrophase did not change (16.93 vs. 16.75 h), although the inter-individual variability decreased considerably. The corresponding standard deviations (SD) of the group acrophases were 3.08 and 1.51 h (p<0.01). A highly significant correlation between the acrophase before treatment and the phase change under melatonin treatment indicates that this is due to a synchronizing effect of melatonin. Apart from the difference in MESOR, the body temperature rhythm in the elderly subjects undergoing melatonin treatment was not significantly different from that of young adults. The data clearly show that age-dependent changes mainly concern rhythm stability and synchronization with the 24 h day. A single daily melatonin dose stabilizes/synchronizes the body temperature rhythm, most probably via hypothermic and sleep-improving effects.

Individual recognition of social rank and social memory performance depends on a functional circadian system.

In a natural environment, social abilities of an animal are important for its survival. Particularly, it must recognize its own social rank and the social rank of a conspecific and have a good social memory. While the role of the circadian system for object and spatial recognition and memory is well known, the impact of the social rank and circadian disruptions on social recognition and memory were not investigated so far. In the present study, individual recognition of social rank and social memory performance of Djungarian hamsters revealing different circadian phenotypes were investigated. Wild type (WT) animals show a clear and well-synchronized daily activity rhythm, whereas in arrhythmic (AR) hamsters, the suprachiasmatic nuclei (SCN) do not generate a circadian signal. The aim of the study was to investigate putative consequences of these deteriorations in the circadian system for animals cognitive abilities. Hamsters were bred and kept under standardized housing conditions with food and water ad libitum and a 14l/10 D lighting regimen. Experimental animals were assigned to different groups (WT and AR) according to their activity pattern obtained by means of infrared motion sensors. Before the experiments, the animals were given to develop a dominant-subordinate relationship in a dyadic encounter. Experiment 1 dealt with individual recognition of social rank. Subordinate and dominant hamsters were tested in an open arena for their behavioral responses towards a familiar (known from the agonistic encounters) or an unfamiliar hamster (from another agonistic encounter) which had the same or an opposite social rank. The investigation time depended on the social rank of the WT subject hamster and its familiarity with the stimulus animal. Both subordinate and dominant WT hamsters preferred an unfamiliar subordinate stimulus animal. In contrast, neither subordinate nor dominant AR hamsters preferred any of the stimulus animals. Thus, disruptions in circadian system result in an impaired individual recognition of social rank. A social recognition/discrimination task was used in Experiment 2 to quantify social memory performance. In a training session, the hamsters were confronted with two unfamiliar stimulus animals. In the test session, one of the two animals was replaced. The training-test interval was 2min or 24h. The times animals did explore the novel and the familiar stimulus animal were recorded, and the discrimination index as a measure of cognitive performance was calculated. Behavioral tests revealed that after 2min both subordinate and dominant WT hamsters were able to discriminate between familiar and novel stimulus animals but after 24h only the subordinate animals. On contrary in AR hamsters, only subordinates were able to perform the social recognition/discrimination task and only after a training-test interval of 2min. The results show that the social rank and the circadian system have an impact on the cognitive abilities of Djungarian hamsters. Disruptions of circadian rhythms impair individual recognition and social memory performance.

Indicators for post-surgery recovery in Mongolian gerbils (Meriones unguiculatus).

Telemetric investigations of various parameters are widely used to estimate an animal's state. However, the implantation of the transmitters includes anaesthesia and surgery and has short and longer lasting impacts on the studied object. The aim of the present paper was to evaluate these effects in Mongolian gerbils, namely the hypothermia caused by the anaesthetic and the enduring disturbance of daily rhythmicity until complete recovery. The surgery associated with the implantation of the transmitters differed both in severity and type of anaesthesia. Whereas normal values of body temperature were restored within hours, restoration of daily rhythm required several days, depending on the severity of the surgical procedure. Also, the sensitivity of the body temperature to activity changes was different until the rhythms were re-established. A method based on the rhythm magnitude and shape was proposed to estimate the time until complete recovery of the animals.

Seasonal adaptation of dwarf hamsters (Genus Phodopus): differences between species and their geographic origin.

The genus Phodopus consists of three species--P. campbelli (Pc), P. sungorus (Ps), and P. roborovskii (Pr). They inhabit steppes, semi-deserts, and deserts in continental Asia with a climate changing from a moderate to a hard Continental one with extreme daily and seasonal variations. These different environmental challenges are likely to have consequences for hamsters' morphology, physiology, and behavior. Hamsters of all three species were investigated during the course of the year in the laboratory though using natural lighting and temperature conditions. Motor activity and body temperature were measured continuously, and body mass, testes size, and fur coloration every 1-2 weeks. With regard to the pattern of activity, nearly twice as many Pc as Ps hamsters (25 vs. 14%) failed to respond to changes of photoperiod, whereas all Pr hamsters did. Body mass and testes size were high in summer and low in winter, with the biggest relative change in Ps and the lowest in Pr hamsters. Changes of fur coloration were found in Ps hamsters only. All responding animals (that is excluding Pr), exhibited regular torpor bouts during the short winter days. In autumn, seasonal changes started considerably earlier in Ps hamsters. To investigate the putative causes of these different time courses, a further experiment was performed, to identify the critical photoperiod. Hamsters were kept for 10 weeks under different photoperiods, changing from 16 to 8 h light per day. Motor activity was recorded continuously, to identify responding and non-responding animals. Body mass was measured at the beginning and the end of the experiment, testes mass only at the end. The critical photoperiod was found to be similar in all three species. Though in a further experiment, Pc and Pr hamsters showed a delayed response, whereas the changes in Ps hamsters started immediately following transfer to short-day conditions. The results show that interspecific differences in seasonal adaptation exist, even between the closely related Ps and Pc hamsters, possibly due to different conditions in their natural habitat. Also, the impact of environmental factors like climatic conditions and food resources may differ between species.

Dynamic changes of the spinal canal in patients with cervical spondylosis at flexion and extension using magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors determine the dynamic changes of the spinal canal during flexion and extension in patients with cervical spondylosis. METHODS: Forty-six patients were studied inside a whole-body magnetic resonance (MR) scanner with between 50 degrees of flexion and 30 degrees of extension, using a positioning device. At neutral position (0 degree) and maximum flexion and extension sagittal T2-weighted turbo spin echo sequences were acquired. RESULTS: A significant (P < or = 0.05) increase of spinal stenosis was found at extension (48%, 22 of 46 patients) when compared with flexion (24%, 11 of 46). Cervical cord compression was diagnosed at flexion in 5 patients (11%) and at extension in 9 patients (20%). Concerning the number of patients with cervical cord compression at flexion and extension, significant differences (P < or = 0.05) were found in patients with degenerative changes at four segments compared with patients with one segment involvement. CONCLUSIONS: Magnetic resonance imaging identified a significant percentage of increased spinal stenosis at flexion and, especially, at extension, which was not observed at neutral position (0 degree). Flexion and extension MR imaging demonstrates additional information using a noninvasive technique concerning the dynamic factors in the pathogenesis of cervical spondylotic myelopathy.

Exacerbated pain in cervical radiculopathy at axial rotation, flexion, extension, and coupled motions of the cervical spine: evaluation by kinematic magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors evaluate the functional changes in patients with cervical radiculopathy and increasing symptoms after provocative maneuvers at flexion, extension, axial rotation, and coupled motions of the cervical spine. METHODS: Twenty-one patients with cervical disc herniation (n = 17) or cervical spondylosis (n = 4) in whom symptoms were elicited at flexion, extension, axial rotation, and coupled motions of the cervical spine were studied. The patients were examined inside a positioning device by using a circular surface coil for signal reception. At neutral position (0 degrees) and at provocative positions sagittal T2-weighted turbo spin-echo, axial T2-weighted two-dimensional flash sequence, sagittal three-dimensional (3D) fast imaging with steady state precision sequence and coronal 3D double-echo-in-the-steady-state sequences were obtained. The 3D sequences were reformatted in the axial and oblique coronal planes perpendicular to the exiting nerve roots. The images were evaluated for the size of disc herniations, the foraminal size and cervical cord rotation or displacement at provocative position compared with neutral position (0 degrees). RESULTS: Compared with neutral position (0 degrees), change in size of disc herniation was not found in any (0%) of the provocative positions. In five (24%) patients cervical cord rotation or displacement was noted at axial rotation. The foraminal size increased at flexion, axial rotation to the opposite side of pain and flexion combined with axial rotation to the opposite side of the pain. The foraminal size decreased at extension combined with axial rotation to the side of the pain. A decrease or no change in foraminal size was observed at either extension or axial rotation to the side of the pain. CONCLUSIONS: In patients with cervical disc herniation or cervical spondylosis, exacerbated pain at defined provocative maneuvers is related more to changes in the foraminal size and to nerve root motion with, in some cases, cervical cord rotation or displacement than to changes in the size of herniated discs.

Predisposition to urinary tract epithelial metaplasia in Schistosoma haematobium infection.

Although there is strong epidemiologic evidence linking Schistosoma haematobium infection with carcinoma of the bladder, the utility of cytologic screening for urinary tract cancer has not been critically evaluated in S. haematobium-endemic populations. The present cross-sectional study examined urine cytology findings among 1,014 residents (ages 1 to 91) of the S. haematobium-endemic Msambweni area of Coast Province, Kenya. Among 705 evaluable cytology specimens, prevalence of inflammation (39%), hyperkeratosis (30%), metaplasia (33%), and frank atypia (0.4%) was notably higher than in previously studied, non-endemic populations. Overall, S. haematobium infection was strongly associated with increased risk for cytologic abnormality (> 2.8-fold relative risk of metaplasia or hyperkeratosis; P < 0.001). Age-group analysis confirmed parallel increases in metaplasia and S. haematobium infection prevalence early in life (from age I to 15 for both boys and girls). However, above age 20, metaplasia prevalence persisted at 33-45% prevalence despite a decline in infection prevalence and intensity. Prevalence of advanced (moderate or severe) metaplasia showed two age-related peaks: the first at 10-14 years of age (at the time of peak infection), and the second among subjects > or = 60 years old. No cancers were detected in the study population either on cytology or on follow-up ultrasound examination. These data suggest an age-dependent progression of cellular abnormalities in the urinary epithelium that is associated with chronic S. haematobium infection, which becomes independent of concurrent infection intensity as subjects grow older. Implications for cancer screening are discussed.

Thalamic, pallidal, or subthalamic surgery for Parkinson's disease?

Levodopa is a highly effective treatment of all motor symptoms of Parkinson's disease. However, long-term treatment with levodopa can lead to motor fluctuations and levodopa-induced dyskinesias. Motor side effects can become so disabling as to warrant surgical treatment. Both ablative surgery and deep brain stimulation (DBS) for Parkinson's disease (PD) can be performed in different target areas. Thalamic surgery mainly improves tremor, and to a lesser extent also rigidity and dyskinesias, whereas pallidal and subthalamic nucleus surgery improves all motor symptoms and levodopa-induced dyskinesias. The efficacy and safety of unilateral pallidotomy is well established. DBS has a lower morbidity and is safe enough to be performed bilaterally. The subthalamic nucleus (STN) presently seems to be the most promising target for DBS in advanced stage PD.

Classification system based on kinematic MR imaging in cervical spondylitic myelopathy.

BACKGROUND AND PURPOSE: Functional myelographic studies are often used to evaluate the dynamic changes of the cervical spinal canal during flexion and extension. The purposes of this study were to use kinematic MR imaging to assess the dynamic changes of the cervical spine in patients at different stages of degenerative disease and to describe a classification system based on static and dynamic factors in the pathogenesis of cervical spondylitic myelopathy. METHODS: Eighty-one patients with different stages (I-IV) of degenerative disease of the cervical spine were examined with MR imaging. In the neutral position (0 degrees) and at maximum flexion and extension, spinal stenosis was classified for each segment according to the following grading system: 0 = normal, 1 = partial obliteration of the anterior or posterior subarachnoid space, 2 = complete obliteration of the anterior or posterior subarachnoid space, and 3 = cervical cord compression or displacement. RESULTS: At flexion and extension, the prevalence of spinal stenosis and cervical cord impingement increased as the stage of degenerative disease progressed. With regard to a pincer effect (anterior and posterior cord impingement) and cord encroachment at multiple segments, statistically significant differences were observed at stages III and IV as compared with stages I and II. Significant increase in cord impingement was seen in 22 (27%) of 81 patients at extension, as compared with four (5%) of 81 patients at flexion. CONCLUSION: Regardless of the stage of degenerative disease and grade of spinal stenosis at the neutral position (0 degrees), cervical spinal motion may contribute to the development of cervical spondylitic myelopathy.

Diurnally changing effects of locomotor activity on body temperature in laboratory mice.

In mice circadian body temperature curves are masked due to the effect of motor activity. However, body temperature will not immediately reflect activity, but rather the integrated activity over IT minutes (integration time) and after a certain delay (lag), and the sensitivity to such masking may change throughout the circadian cycle. The aims of the present investigation were to estimate IT and lag, to quantify the effect of motor activity on body temperature at different times of the day, and, using these results, to draw temperature curves that are closer to the endogenous one. Activity and body temperature of adult male laboratory mice were recorded telemetrically at 10-min intervals. Animals were housed in air-conditioned rooms (T = 22+/-2 degrees C; relative humidity: 55-65%) with a light-dark cycle of 12 h:12 h (light from 0700 to 1900 hours) and food and water available ad lib. The diurnal activity and body temperature rhythms were similar with a main maximum during the dark time and a secondary maximum immediately following lights-on. Nearly all changes of activity were reflected in body temperature. IT and lag were established on the basis of the best correlation between body temperature and activity (overlapping 4-h sections of 12 days) for all combinations of IT from 10 to 90 min and lag from 0 to 50 min (10-min steps each). The overall means of IT and lag were 40 and 0 min, respectively. During the dark time the values were somewhat larger, but not significantly so. The correlation between activity and body temperature was significantly better in the light time compared to the dark time. The sensitivity of the body temperature to changes in activity was investigated by linear regression analysis for every hour over 12 days (IT = 40 min, lag = 0 min). The gradients assessed by regression analysis showed a diurnal pattern with maximal values during the light time (p < 0.01). Thus, body temperature was raised by activity more during the light time (minimum of body temperature and activity) than during the dark time. The intercepts showed a nearly sinusoidal diurnal pattern with maximal values in the middle of the dark time. Accepting that the intercepts correspond to zero activity at a certain time of day, one might use them to get a curve that is closer to the endogenous body temperature rhythm. Mechanisms (circadian and thermoregulatory) that might cause the diurnally changing sensitivity of body temperature to activity are discussed.

Daily activity and body temperature rhythms do not change simultaneously with age in laboratory mice.

Daily rhythms of locomotor activity (AR) and body temperature (TR) were investigated in juvenile, adult, and senile female laboratory mice (5, 16, or 65 weeks old). All daily patterns were bimodal, with a main maximum in the dark and a secondary one immediately following lights on. The juvenile mice showed the highest magnitude of oscillation of the AR but the lowest magnitude of the TR; the magnitudes of the TR of adult and senile animals were not different, whereas those of AR in senile mice approached zero. For the AR, but not the TR, a phase advance with age was observed. The effect of locomotor activity on the body temperature was higher during the light time (minimum of motor activity) than during the dark time (maximum activity), and was least in juvenile mice. The calculated daily temperatures corresponding to zero activity gave rhythms that showed no age-dependent differences in daily mean or magnitude. This implies that the age-dependent changes of the TR were due mainly to masking effects.

Age-dependent changes of the circadian system.

This review summarizes the current knowledge on changes of the circadian system in advanced age, mainly for rodents. The first part is dedicated to changes of the overt rhythms. Possible causes are discussed, as are methods to treat the disturbances. In aging animals and humans, all rhythm characters change. The most prominent changes are the decrease of the amplitude and the diminished ability to synchronize with a periodic environment. The susceptibility to photic and nonphotic cues is decreased. As a consequence, both internal and external temporal order are disturbed under steady-state conditions and, even more, following changes in the periodic environment. Due to the high complexity of the circadian system, which includes oscillator(s), mechanisms of external synchronization and of internal coupling, the changes may arise for several reasons. Many of the changes seem to occur within the SCN itself. The number of functioning neurons decreases with advancing age and, probably, so does the coupling between them. As a result, the SCN is unable, or at least less able, to produce stable rhythms and to transmit timing information to target sites. Initially, only the ability to synchronize with the periodic environment is diminished, whereas the rhythms themselves continue to be well pronounced. Therefore, the possibility exists to treat age-dependent disturbances. This can be done pharmacologically or by increasing the zeitgeber strength. So, some of the rhythm disturbances can be reversed, increasing the magnitude of the light-dark (LD) zeitgeber. Another possibility is to strengthen feedback effects, for example, by increasing the daily amount of activity. By this means, the stability and synchronization of the circadian activity rhythm of old mice and men were improved.