Hadas Lewy

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.

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.

Seasonality of birth month of children with celiac disease differs from that in the general population and between sexes and is linked to family history and environmental factors.

Background: Patients with autoimmune diseases, such as type 1 diabetes mellitus, atopic dermatitis, autoimmune thyroid diseases, and multiple sclerosis have a different seasonality of month of birth (MOB) from the general population. This study was undertaken to determine the seasonality of MOB in children with celiac disease (CD), an autoimmune-mediated enteropathy. Patients and Methods: The medical records of 431 children with CD (239 girls, 192 boys) were included in the study; 138 girls and 81 boys were under the age of 24 months. Data were analyzed by the cosinor method, which, in addition to statistical significance, provides parameters of rhythms. Statistical differences between groups were also analyzed by the χ2 test. Results: Patients with CD showed different patterns from that in the general population, which peaks in September. Boys and girls with CD were found to have a different seasonality of MOB (P < 0.02). Girls whose CD was diagnosed before age 24 months (peak July–August) had a different seasonality of MOB from those whose CD was diagnosed after age 24 months (no rhythm; P < 0.005) and showed a different seasonality from boys whose CD was diagnosed above 24 months (peak July; P < 0.02). In addition, we found a different seasonality of MOB in children with a family history of CD compared with those with no family history (P < 0.001). Conclusions: Girls with the diagnosis of CD and patients of both sexes with a family history of CD have a different pattern of seasonality of birth from the general population. This is suggestive of a perinatal virus infection as a plausible candidate for the primary trigger.

From ultradian to infradian rhythms: LH release patterns in vitro.

In the present study, we examined in vitro luteinizing hormone (LH) release patterns from pituitaries and from pituitary cell cultures (3 and 7 days in culture) to elucidate the endogenous period generated by the gonadotroph cell population and to evaluate the relationship between the basic period generated at the cellular level and the output pattern observed at the organ level. In addition, we examined the effect of photic environmental signals perceived by the animals on LH release patterns from pituitaries in vitro. When the animals were exposed to circadian photoperiodic signals, the in vitro LH release pattern from the pituitaries exhibited ultradian, circadian, and infradian frequencies. When the animals were exposed to continuous illumination, the in vitro patterns exhibited only ultradian and infradian frequencies. Furthermore, free running is a process, not a state. This process is driven by a change in the relative dominance of different frequencies that construct the pattern without changing the basic period length. Evaluation of the relative dominance of the different frequencies that construct the pattern indicates that, although infradian oscillators may take part in shaping the output pattern, the basic rhythm generated by the pituitary cells is in the ultradian domain. The results obtained from the examined system suggest that an endogenous oscillator is a cellular entity with ultradian periodicity, and that the rhythmic output of many biological variables is structured by various ultradian components that construct the circadian and infradian output rhythms.

Seasonality of month of birth differs between type 1 diabetes patients with pronounced beta‐cell autoimmunity and individuals with lesser or no beta‐cell autoimmunity*

Objective:  To establish whether children with type 1 diabetes mellitus (T1D) with signs of pronounced beta‐cell‐specific autoimmunity as reflected by high autoantibody titers or positivity for several beta‐cell‐specific autoantibodies show a different pattern of month of birth (MOB) compared with children with T1D and low beta‐cell autoimmunity and that of the general population.

Differences between males and females in the seasonality of birth and month of clinical onset of disease in children with type 1 diabetes mellitus in Ireland.

The aim was to study the monthly rhythm of birth and clinical onset in 303 children with type 1 diabetes mellitus (DM1) aged 0-15 years (156 males, 147 females) born between 1980 and 1996 in Ireland and compare to 951,717 infants born in the general population during the same period. Analysis was performed using the cosine fit for rhythm and t-test between the seasons of the year. Whereas the males showed a rhythmic pattern of month of birth, peaking in the summer (p < 0.05), similar to that in the general population, the females showed no seasonal differences in either month of birth or month of onset. A mirror image pattern, nadir in spring and summer (p < 0.01), was observed in month of clinical onset, also only in males. If we assume a viral infectious etiology of DMI, females seem to be less susceptible than males to the environmental infectious influences.

CIRCADIAN PATTERN OF SIMULATED FLIGHT PERFORMANCE OF PILOTS IS DERIVED FROM ULTRADIAN COMPONENTS

Studies suggest some physiologic, cognitive, and behavioral 24h rhythms are generated by cyclic components that are shorter in period than circadian. The aim of this study was to examine the hypothesis that 24h human performance rhythms arise from the integration of high-frequency endogenous components and to quantify the contribution of each higher frequency component to the phenotype of the rhythm. We monitored the performance of 9 experienced pilots by employing an array of cognitive-based tests conducted in a flight simulator so that, over the 6-day experiment, data were obtained for each 2h interval of the 24h. The activity-rest schedule of the subjects, no matter the exact clock time schedule of sleep and activity, always consisted of 14h activity (when they carried out regular professional duties) and 10h rest, with at least 8h of sleep. The simulated combat scenarios consisted of simple and complex tasks associated with target interception, aircraft maneuvering, and target shooting and downing. The results yielded two indices: the number of prominent periodicities in the time series and the relative magnitude of the amplitude of each relative to the construction of the composite 24h waveform. Three cyclic components (8h, 12h, and 24h) composed the observed 24h performance pattern. The dominant period and acrophase (peak time) of the compound output rhythm were determined by the interplay between the amplitudes of the various individual ultradian components. Task complexity (workload) increases the expression of the ultradian entities in the 24h pattern. We constructed a model composed of the multiple ultradian components; the composite output defined a “time span” (of 2h–4h duration) as opposed to an exact “time point” of high and low performance, endowing elevated functional capability. (Chronobiology International, 18(6), 987–1003, 2001)

THE BIRTH OF CHRONOBIOLOGY: JULIEN JOSEPH VIREY 1814

Julien-Joseph Virey (1775–1846) held the position of pharmacist-in-chief at the Val-de-Grâce, a military hospital. He was an innovative pharmacist, naturalist, anthropologist, and philosopher and a prolific author. His writings encompassed a wide range of topics, although many of his ideas were sometimes harshly questioned. Interest in Vireys work today stems from renewed appreciation of his doctoral thesis in medicine, which was completed in 1814 in Paris and was the first devoted to biological rhythms. Virey envisioned biological rhythms to be innate in origin and controlled by living clocks entrained by periodic environmental changes, such as the day-night alternation in light and darkness. He also reported that the effects of drugs vary according to their administration time. But, above all, he collected and published quantified time series that demonstrated human circadian and annual mortality rhythms. Statistical analysis of Vireys data using modern time series methods confirms his deduction that human mortality exhibits rhythmicity. Comparison of his findings with those derived from analyses of more recent human mortality time series shows the characteristics of these rhythms have changed little since 1807 despite differences in environmental conditions. Virey deserves credit for establishing the field of chronobiology based on his insights and writings. (Chronobiology International, 18(2), 173–186, 2001)

Gonadotropin releasing hormone (GnRH) and estradiol (E2) regulation of cell cycle in gonadotrophs

The number of pituitary cells, their size, hormonal content and release and response to external cues varies between day and night and during the estrus cycle. Previous studies have demonstrated that pituitary cells proliferate rhythmically and that estradiol (E(2)) is a mitogen of alpha T3 cells. We, therefore, studied the effect of gonadotropin releasing hormone (GnRH) and E(2), on the cell cycle in primary cultures of mouse pituitary cells and in the gonadotroph cell line L beta T2. We found that GnRH and E(2) modulate the cell cycle in a time dependent manner and induce proliferation in cultures of mouse pituitary and L beta T2 cells. GnRH induces proliferation in cells isolated in the morning of the estrus day and increases the number of cells in G2 stage when isolated in noon and evening. However, the transition into the G1 stage is enabled only by co-addition of E(2) and GnRH. GnRH stimulates LH release from L beta T2 cells after 2 days via exocytosis while after 4 days in culture, the increase in LH release may be accounted for by the increase in cell number. E(2) enhanced the GnRH response after 2 days, and abolished it after 4 days in culture. Furthermore, E(2) has no effect on LH release and cell number after 2 days in culture, however, after 4 days in culture, E(2) had no effect on the total amount of LH released but inhibited LH release per cell due to increase in cell number. Our results show that GnRH and E(2) function to shorten the cell cycle and regulate the cell number of each stage of the cell cycle. The effect of GnRH and E(2) on the cell cycle is dependent on the circadian time. This mechanism may serve to modulate the size and function of the pituitary cell population and consequently the function of pituitary gonadotrophs regulating the surge of LH release before ovulation.

Seasonality of month of birth of children and adolescents with type 1 diabetes mellitus in Berlin differs from the general population

Children with auto-immune diabetes have an abnormal seasonality of birth Research performed in recent years in different populations on the seasonality of births revealed that the pattern in children, adolescents and young adults who subsequently developed type 1 diabetes mellitus (T1-DM) differed from that of total live births in the same populations [1, 2, 6]. It was therefore of interest to find out whether the seasonality in North Germany is of a similar pattern. A total of 570 patients with T1-DM (324 males and 246 females) diagnosed between ages 0–18 years at the Charite Children’s Hospital, Humboldt University of Berlin between the years 1990–2000, were included in this study. In all of them the month of birth and date of the onset of clinical disease could be ascertained. The monthly distribution of total live births in Berlin (n=250531) for the same period was obtained from the Bureau of Statistics of the City of Berlin. Seasonality of month of birth and onset of disease in the diabetic population and in the total live births was analysed using the Cosinor fit analysis adjusted for a pre-determined period [4]. The monthly pattern of onset of disease is shown in Fig. 1 (upper panel). The smallest number of newly diagnosed patients occured in spring and summer (P<0.01) as was previously observed also in South Germany and many other populations. In contrast, the pattern of month of birth of the same cohort of patients showed a significant biphasic increase during spring and summer (P<0.001) (Fig. 1) (lower panel). This pattern is similar to that found by others in European countries [1,6] and by us [2]. The monthly rhythmn of the total live births was statistically non significant. Analysis of the seasonality of month of birth of children and adolescents in Berlin who subsequently developed T1-DM revealed that there was a significant increase during spring and summer, differing from the seasonal pattern of onset of clinical disease, peaking in autumn and winter, and different from the pattern of the total live births. These significant differences, similar to Eur J Pediatr (2002) 161: 291–292 DOI 10.1007/s00431-002-0941-9