Israel E. Ashkenazi

Internal Desynchronization of Circadian Rhythms and Tolerance to Shift Work

Intolerance to shift work may result from individual susceptibility to an internal desynchronization. Some shift workers (SW) who show desynchronization of their circadian rhythms (e.g., sleep‐wake, body temperature, and grip strength of both hands) exhibit symptoms of SW intolerance, such as sleep alteration, persistent fatigue, sleep medication dependence, and mood disturbances, including depression. Existing time series data previously collected from 48 male Caucasian French SW were reanalyzed specifically to test the hypothesis that internal synchronization of circadian rhythms is associated with SW intolerance and symptoms. The entry of the subjects into the study was randomized. Three groups were formed thereafter: SW with good tolerance (n=14); SW with poor tolerance, as evident by medical complaints for at least one year (n=19); and former SW (n=15) with very poor tolerance and who had been discharged from night work for at 1.5 yr span but who were symptom‐free at the time of the study. Individual and longitudinal time series of selected variables (self‐recorded sleep‐wake data using a sleep log, self‐measured grip strength of both hands using a Colin Gentile dynamometer, and oral temperature using a clinical thermometer) were gathered for at least 15 days, including during one or two night shifts. Measurements were performed 4–5 times/24 h. Power spectra that quantify the prominent period (τ) and t‐test, chi square, and correlation coefficient were used as statistical tools. The mean (±SEM) age of SW with good tolerance was greater than that of SW with poor tolerance (44.9±2.1 yrs vs. 40.1±2.6 yrs, p<.001) and of former SW discharged from night work (very poor tolerance; 33.4±1.7, p<.001). The shift-work duration (yrs) was longer in SW with good than poor tolerance (19.9±2.2 yrs vs. 15.7±2.2; p<0.002) and former SW (10.7±1.2; p<.0001). The correlation between subject age and shift-work duration was stronger in tolerant SW (r=0.97, p<.0001) than in non‐tolerant SW (r=0.80, p<0.001) and greater than that of former SW (r=0.72, p<.01). The mean sleep‐wake rhythm τ was 24 h for all 48 subjects. The number of desynchronized circadian rhythms (τ differing from 24 h) was greater in non‐tolerant than in tolerant SW (chi square=38.9, p<.0001). In Former SW (i.e., 15 individuals assessed in follow‐up studies done 1.5 to 20 yrs after return to day work), both symptoms of intolerance and internal desynchronization were reduced or absent. The results suggest that non‐tolerant SW are particularly sensitive to the internal desynchronization of their circadian time organization.

Seasonality of birth and onset of clinical disease in children and adolescents (0-19 years) with type 1 diabetes mellitus in Canterbury, New Zealand.

AIMS To determine the seasonality of clinical disease onset and month of birth in type 1 diabetes mellitus (DM) in the southern hemisphere. PATIENTS Two hundred and seventy-five children with type 1 DM in the South Island of New Zealand were studied. The total live births (91,394) of the same period were used as control data. METHODS Seasonal rhythms were analyzed using the 12 month cosinor method. RESULTS The month of birth pattern of the patients with DM showed a statistically significant peak (p < 0.01) in summer, whereas the disease onset had a significant peak in winter (p < 0.01), similar to that registered in countries of the northern hemisphere, but in different months of the year. The total live births had no significant rhythm. The different seasonality of birth of the children who subsequently developed type 1 DM from that of the total live births is suggestive of the initiation of the autoimmune process in utero or perinatally.

Euchronism, Allochronism, and Dyschronism: Is Internal Desynchronization of Human Circadian Rhythms a Sign of Illness?

The authors define a subject as euchronic when the circadian parameters—tau (τ=period), Ø (acrophse or peak time), A (amplitude), and M (MESOR=24 h rhythm‐adjusted mean)—of a set of circadian variables are within the confidence limits of appropriate reference values of healthy subjects (HS). We define internal desynchronization as a state in which the circadian τ of a set of rhythms differs from 24 h and when the τ of a given variable differs from that of other variables. Such a state was first observed in singly isolated HS without access to time cues and clues. Herein, data and analyses are presented demonstrating that internal desynchronization appears to be a rather common phenomenon in HS dwelling in their natural environment (i.e., in the presence of usual zeitgebers). This has been documented by longitudinal studies (n≅15 days) of the circadian rhythm in sleep‐wakefulness, body temperature, right‐ and left‐hand‐grip strength, and reaction time involving a total of 246 HS and 134 shift workers (SW), with 45.5% showing good and 54.5% poor SW tolerance. The presence of internal desynchronization observed in SW was associated SW intolerance, with symptoms being sleep alteration/disturbances, sleeping‐pill dependence, persisting fatigue (asthenia), mood alteration, and digestive complaints. Internal desynchronization was also documented in groups of HS and tolerant SW, though it was almost the rule among the intolerant SW. The authors introduce two new terms: allochronism to describe the time organization of those SW who evidence internal desynchronization without detectable clinical symptoms, and dyschronism to describe the time organization of those SW who exhibit internal desynchrobization plus the symptoms of SW intolerance or medical illness. The condition of allochronism is not restricted only to SW tolerance, as it was detected in 112 HS without medical complains when exposed to various experimental conditions, including medications and placebos, sojourn in the high Arctic summer, intensive sport training, and task‐loaded cognitive performance testing. Dyschronism in SW who are sleep‐deprived is associated with persisting fatigue. An unpublished Gallup survey found that 47% of 2478 respondents experienced a state of asthenia during the previous 12 months, with symptoms mimicking those of SW intolerance. In one‐third of the cases, the origin of the asthenia was undetermined. Taking into account the high incidence of internal desynchronization found in past investigations and the clinical observation that sleep deprivation is a consequence of many acute and chronic medical conditions (nocturnal pain, nocturnal asthma, etc.), it is suggested that dyschronism may be responsible for the asthenia of unknown origin, at least for some persons. The interindividual (including sex‐related) variability in the propensity to exhibit an altered temporal organization, whether it be transient or persistent (i.e., reversible or non‐reversible) suggests the involvement of genetic factors. The Dian‐Circadian genetic model previously proposed by the authors seems pertinent to conceptualize and explain the various levels and output of internal desynchronization.

Mechanism of GnRH receptor signaling on gonadotropin release and gene expression in pituitary gonadotrophs

Gonadotropin releasing hormone (GnRH), the first key hormone of reproduction, is synthesized and secreted from the hypothalamus in a pulsatile manner and stimulates pituitary gonadotrophs (5-10% of the pituitary cells) to synthesize and release gonadotropin luteinizing hormone (LH) and follicle stimulating hormone (FSH). Gonadotrophs consist of 60% multihormonal cells (LH+FSH) and 18% LH- and 22% FSH-containing cells. LH and FSH, members of the glycoprotein hormone family, stimulate spermatogenesis, folliculogenesis, and ovulation. Although GnRH plays a pivotal role in gonadotropin synthesis and release, other factors such as gonadal steroids and gonadal peptides exert positive and negative feedback mechanisms, which affect GnRH actions. GnRH actions include activation of phosphoinositide turnover as well as phospholipase D and A2, mobilization and influx of Ca2+, activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). A complex crosstalk between the above messenger molecules mediates the diverse actions of GnRH. Understanding the signaling mechanisms involved in GnRH actions is the basis for our understanding of basic reproductive functions in general and gonadotropin synthesis and release in particular.

Circadian variation of nitric oxide synthase activity in mouse tissue

Endogenous nitric oxide (NO) is an important mediator in the processes that control biological clocks and circadian rhythms. The present study was designed to elucidate if NO synthase (NOS) activity in the brain, kidney, testis, aorta, and lungs and plasma NOx levels in mice are controlled by an endogenous circadian pacemaker. Male BALB/c mice were exposed to two different lighting regimens of either light–dark 14:10 (LD) or continuous lighting (LL). At nine different equidistant time points (commencing at 09:00h) blood samples and tissues were taken from mice. The plasma and tissue homogenates were used to measure the levels of NO2+ NO3− (NOx) and total protein. The NOx concentrations were determined by a commercial nitric oxide synthase assay kit, and protein content was assessed in each homogenate tissue sample by the Lowry method. Nitric oxide synthase activity was calculated as pmol/mg protein/h. The resulting patterns were analyzed by the single cosinor method for pre-adjusted periods and by curve-fitting programs to elucidate compound rhythmicity. The NOS activity in kidneys of mice exposed to LD exhibited a circadian rhythm, but no rhythmicity was detected in mice exposed to LL. Aortic NOS activity displayed 24h rhythmicity only in LL. Brain, testis, and lung NOS activity and plasma NOx levels displayed 24h rhythms both in LD and LL. Acrophase values of NOS activity in brain, kidney, testis, and lungs were at midnight corresponding to their behavioral activities. Compound rhythms were also detected in many of the examined patterns. The findings suggest that NOS activity in mouse brain, aorta, lung, and testis are regulated by an endogenous clock, while in kidney the rhythm in NOS activity is synchronized by the exogenous signals.

Interindividual Differences in the Flexibility of Human Temporal Organization: Pertinence to Jet Lag and Shiftwork

Interindividual variability in the human temporal structure is seldom taken into account, especially in studies devoted to the effects of shiftwork and jet lag. The understated postulate is that humans can be treated as a pure strain species. This paper reviews some facts and concepts with special reference to interindividual changes in the rhythm period tau and the resulting dyschronism. The following points are addressed. (1) Subjects and methods (importance of longitudinal field studies on shift workers). (2) Criteria for tolerance to shiftwork and jet lag. (3) Interindividual differences and shiftwork problems (subject type; the association between good shiftwork tolerance and stable temporal structure; dychronism with tau s differing from 24h and from variable to variable. (4) The genetic background of circadian dyschronism. The Dian-circadian genetic model of biological rhythms. It allows understanding of ones susceptibility to dyschronism, which was actually observed in approximately equal to 30% of subjects studied longitudinally. (5) Practical implications of interindividual differences (dissociate problems of passengers after a transmeridian flight-who have to adjust their temporal structure to local time-from problems of shiftworkers-who need to prevent alteration of their temporal structure; the advantage for the latter of participating in a rapid rotation system rather than a weekly rotation; emphasis that the suitability of a given subject for a given shiftworking condition is likely to be estimated only after a trial span of time including longitudinal study of a set of rhythms.

Epidemiologic Surveys of Deleterious Genes in Different Population Groups in Israel

THE geographic distribution of genetic traits of human populations is influenced by many factors, the most important of which are (in the light of the present knowledge) the ethnic origin of the population, the degree of its isolation and the rate of consanguineous marriages, and the environmental conditions acting upon the advantageous or the detrimental selective values of the traits. The contemporary Jewish community of Israel presents a unique opportunity for gathering important data for the study of these factors. The Jewish people, who were dispersed for 20-25 centuries throughout wide geographic areas and lived among different ethnic groups, gathered in Israel during the last 50 years, and particularly within the last decade. During the long period of dispersal strong religious and cultural bonds enabled the Jewish communities in the Diaspora to survive, preventing their assimilation among the local populations. The inferior social status which they occupied in many countries, as well as the enmity toward their religion, prevented in most cases a large-scale influx Bracha Ramot, M.D.; Avinoam Adam, M.Sc.;

Circadian rhythm period in reaction time to light signals: difference between right- and left-hand side.

The study was designed to test the hypothesis that the prominent rhythm period tau of simple reaction time (SRT) and three-choice reaction time (CRT) to light signals may vary between the dominant (DH) and non-dominant (NDH) hand. Eleven healthy subjects, 8 males (16-74 years, including two left-handed) and 3 females (18-43 years), synchronized with a diurnal activity (approximately 07.00 h to approximately 23.00 h) and a nocturnal rest, volunteered for the study. A battery-powered ambulatory device was used to self-record SRT to a yellow light signal and CRT to yellow, green and red signals. Tests were performed 4-7 times/24 h during a 12- to 15-day span. Power spectra, ANOVA, cosinor, chi2 and correlation tests were used to individually analyze time series. Tau = 24 h in SRT rhythms of DH (8/11 cases) and NDH (6/11 cases) with chi2 = 3.5 and p > 0.05. In CRT rhythms, tau = 24 h for DH (8/11 cases) while tau = 8 h for NDH (7/11 cases), a difference which was statistically significant (chi2 = 9.4 with p < 0.02). Concordant results were obtained with other statistical tests leading to the conclusion that the rather complex cognitive task (CRT) and, to a certain extent, SRT of certain individuals, were associated with tau = 24 h for DH and tau = 8 h for NDH. These findings are in favor of the hypothesis that functional clocks are present in the human brain cortex, associated with the possible expression of rhythms with a prominent period differing from the right- and left-hand side.

Activity rhythms of enzymes in human red blood cell suspensions

Abstract We have established the presence of a rhythm in the activity of 4 enzymes in in‐vitro cell suspensions of human red blood cells. Glucose 6‐phosphate dehydrogenase and glutamate oxaloacetate transaminase demonstrated semicircadian patterns of activity, while acid phosphatese and acetylcholine esterase exhibited circadian activity rhythms. The ratios between the highest to lowest activities varied from 2:1 to 10:1 among the various enzymes. The affinity of glucose 6 phosphate dehydrogenase to its substrate and coenzyme remained constant throughout the cycle. No evidence was obtained for the presence of a soluble inhibitor at the lower levels of the activity. Sonication of hemolysates with low glucose 6 phosphate dehydrogense activity yielded additional activity comparable to that of the peak activity. Sonication of hemolysates from the time of the peak activity did not change the original activity. The observations point to a role of the cell membrane in the biological clock.

Right- and left-brain hemisphere. rhythm in reaction time to light signals is task-load-dependent: Age, gender, and handgrip strength rhythm comparisons

In healthy mature subjects simple reaction time (SRT) to a single light signal (an easy task) is associated with a prominent rhythm with τ=24 h of dominant (DH) as well as nondominant (NDH) hand performance, while three-choice reaction time (CRT), a complex task, is associated with τ=24 h of the DH but τ<24 h of the NDH. The aims of the study were to assess the influence of age and gender on the difference in τ of the NDH and DH, as it relates to the corresponding cortical hemisphere of the brain, in comparison to the rhythm in handgrip strength. Healthy subjects, 9 (5 M and 4 F) adolescents 10–16 yr of age and 15 (8 M and 7 F) adults 18–67 yr of age, active between 08:00±1 h and 23:00±1:30 h and free of alcohol, tobacco, and drug consumption volunteered. Data were gathered longitudinally at home and work 4–7 times daily for 11–20 d. At each test time the following variables were assessed: grip strength of both hands (Dynamometer: Colin–Gentile, Paris, France); single reaction time to a yellow signal (SRT); and CRT to randomized yellow, red, or green signal series with varying instruction from test to test (Psycholog-24: Biophyderm, France). Rhythms in the performance in SRT, CRT, and handgrip strength of both DH and NDH were explored. The sleep–wake rhythm was assessed by sleep-logs, and in a subset of 14 subjects it was also assessed by wrist actigraphy (Mini-Motionlogger: AMI, Ardsley NY). Exploration of the prominent period τ of time series was achieved by a special power spectra analysis for unequally spaced data. Cosinor analysis was used to quantify the rhythm amplitude A and rhythm-adjusted mean M of the power spectral analysis determined trial τ. A 24h sleep–wake rhythm was detected in almost all cases. In adults, a prominent τ of 24 h characterized the performance of the easy task by both the DH and NDH. In adults a prominent τ of 24 h was also detected in the complex CRT task performed by the DH, but for the NDH the τ was <24 h. This phenomenon was not gender-related but was age-related since it was seldom observed in adolescent subjects. Hand-side differences in the grip strength rhythms in the same individuals were detected, the τ being ultradian rather than circadian in adolescent subjects while in mature subjects the τ frequently differed from that of the rhythm in CRT. These findings further support the hypothesis that functional biological clocks exist in both the left and right hemispheres of the human cortex.