Wearable devices- from healthy lifestyle to active ageing.

As wearable and mobile technologies are becoming more available and can provide more information and knowledge to users, new challenges and opportunities opens for industry and healthcare organizations. The future use of wearable by health and wellbeing users, from fitness tracking, to chronic disease management and independent living will create ecosystem for the population that will be adapted to their changing needs along lifespan in health and disease. This will also drive a change in healthcare delivery models and the relationship between patient and healthcare providers. It raises challenges for the healthcare systems as well as for the industry in implementing these new technologies, data privacy and security, regulation, adaptation of the systems to the individual and the growing amount of information in clinical practice and workflows. In this paper the vision, barriers, the gaps and opportunities will be discussed.

Time dependent protection of amifostine from renal and hematopoietic cisplatin induced toxicity.

Efficacy of chemotherapy may be maximized and its toxicity can be minimized if drugs would be administered at specified daily times. The present study was aimed to examine if the protection of amifostine against cisplatin toxicity is time dependent. Amifostine is an organic thiophosphate that protects selectively normal tissues, but not tumors, against the cytotoxicity of DNA binding chemotherapeutic agents such as cisplatin. ICR male mice which were entrained to Light:Dark (L:D) 14:10 were injected (intrapritoneal bolus) for 5 consecutive days with either: cisplatin, cisplatin plus amifostine (administered 30 minutes prior to cisplatin). Injections were given at either 08:00, 13:00, 20:00 or 01:00. Five days later, on day 10, each set of mice was sacrificed (at the same hour corresponds to the injection hour), blood count, blood creatinine and blood urea nitrogen (BUN) were assayed. Cisplatin treated mice exhibited nephrotoxicity, as indicated by increased blood urea nitrogen values and by high blood urea nitrogen to creatinine ratios, as well as myelotoxicity that was indicated by low levels of hemoglobin and platelets. Co-administration of amifostine-cisplatin reversed both, the nephrotoxicity of cisplatin, and its myelosuppressive effects. For BUN, hemoglobin and platelets, maximal protections were observed at 08:00, (p <0.05, p <0.01 and p <0.01 respectively). For BUN/Cr ratio (p <0.05), maximal protections was observed at 13:00. These findings show that amifostine exhibits time dependent protection against cisplatin toxicity and thus it is recommended to use the protector when treatments are given during morning hours. The results also further validate the notion that chronochemotherapy is advantageous at least in reducing drug toxicity and thus should be integrated in the design of clinical protocols.

Prolactin rhythms-oscillators' response to photoperiodic cues is age and circadian time dependent.

In vivo prolactin release patterns exhibit a compound rhythm with circadian (24 h), semicircadian (12 h) and ultradian (6-8 h) periods. Changes in these rhythmic patterns were observed at different photoperiodic conditions, and in elderly. Since in vitro prolactin release was related to the photoperiodic history of the animal, we studied the effect of varying photoperioda upon the in vitro rhythmic output of prolactin release from young and old male rat pituitaries, isolated at different circadian times from animals housed at LD 12:12, 18:6 for 10 days or 6 weeks. The results indicate that, both, mean levels and rhythmic prolactin release in vitro are determined by the age of the animal, the circadian time of pituitary isolation, the photoperiodic conditions in which the animal was housed, and the duration of housing in the long day conditions. The change of the rhythmic output pattern is gradual, reflecting a process by which the oscillators respond to the external cues to fit prolactin release pattern to the environmental conditions. Each of the oscillators (e.g. circadian, semicircadian, ultradian) shows different sensitivity to the changing photoperiodic signal and is regulated at the level of phase and amplitude but not the period. In old rats the response of the oscillators to the change in photoperioda is attenuated and not sufficient to induce a change in the output of prolactin release suggesting a loss in adaptation ability.

Evidence for biological rhythm in spermatogenesis in the pubertal hamster (Mesocricetus auratus): a flow cytometric study.

The number of cells in the S-phase fraction of the cell cycle reflects proliferative activity. Using flow cytometry histograms and the Phoenix M+ cell cycle program, the percent of cells in the S-phase fraction was measured in single cell suspensions prepared from testes of hamsters of different ages. A cyclical pattern with a period of 9 days, superimposed on another rhythm with a 38 day period was observed (p < 0.01) during hamster maturation and it disappeared after the second spermatogenic wave, where the S phase values reached a plateau. It was concluded that maturing animals passed through a stage in which testicular biological rhythm was involved. Therefore it was concluded that it takes approximately two spermatogenic waves before the proliferation rate in the testis reached a steady state.

Magnetic field (50 Hz) increases N-acetyltransferase, hydroxy-indole-O-methyltransferase activity and melatonin release through an indirect pathway.

PURPOSE: To examine whether magnetic fields (MF) affect N-acetyltransferase (NAT) and hydroxy-indole-O-methyltransferase (HIOMT) activity directly or exert their effect through a cellular pathway that indirectly regulates the activity of these enzymes and melatonin release. MATERIALS AND METHODS: The pineal glands from Wistar rats were isolated at 10:00 h and exposed to MF (50 Hz, 1 mT) for 4 h in vitro, with or without 1 micro M norepinephrine. An additional group of pineals was exposed to MF 30 min before norepinephrine addition. The direct effect of MF on the activity of the enzymes was studied in sonicated glands exposed to MF. NAT activity, HIOMT activity and melatonin release were determined. RESULTS: In pineal glands isolated in the morning, 4-h in vitro exposure did not affect the basal release of melatonin from the pineal gland as well as the basal NAT and HIOMT activities. Pineal gland exposure to MF 30 min before norepinephrine addition significantly (p<0.05) increased NAT activity, HIOMT activity and melatonin release (p<0.05). These effects were not observed in pineals co-treated with MF and norepinephrine or in sonicated glands exposed to MF. CONCLUSIONS: The results suggest that in pineals isolated in the morning, 4-h MF exposure changes melatonin release by affecting the signal transduction pathway leading from the norepinephrine receptor to NAT and HIOMT and not via a direct effect at the enzyme levels.

Temporal pattern of LH secretion: regulation by multiple ultradian oscillators versus a single circadian oscillator.

The possibility that the 24h rhythm output is the composite expression of ultradian oscillators of varying periodicities was examined by assessing the effect of external continuously or pulsed (20-minute) Gonadotropin-releasing hormone (GnRH) infusions on in vitro luteinizing hormone (LH) release patterns from female mouse pituitaries during 38h study spans. Applying stepwise analyses (spectral, cosine fit, best-fit curve, and peak detection analyses) revealed the waveform shape of LH release output patterns over time is composed of several ultradian oscillations of different periods. The results further substantiated previous observations indicating the pituitary functions as an autonomous clock. The GnRH oscillator functions as a pulse generator and amplitude regulator, but it is not the oscillator that drives the ultradian LH release rhythms. At different stages of the estrus cycle, the effect of GnRH on the expression of ultradian periodicities varies, resulting in the modification of their amplitudes but not their periods. The functional output from the system of ultradian oscillators may superimpose a "circadian or infradian phenotype" on the observed secretion pattern. An "amplitude control" hypothesis is proposed: The temporal pattern of LH release is governed by several oscillators that function in conjunction with one another and are regulated by an amplitude-controlled mechanism. Simulated models show that such a mechanism results in better adaptive response to environmental requirements than does a single circadian oscillator.

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.

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 Virey's 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 Virey's 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.

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 (1) to examine the hypothesis that 24h human performance rhythms arise from the integration of high-frequency endogenous components and (2) 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.

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.

Mechanism of GnRH receptor signaling: from the membrane to the nucleus.

The purpose of this review is to update the information concerning the intracellular effect of GnRH. Binding of GnRH to a G-protein coupled receptor leads to stimulation of Gq and/or G11 protein and to activation of phospholipase C beta. Inositol 1-4-5-triphosphate and early diacylylycerol are the second messengers required for conventional protein kinase C activation. Activation of phospholipase A2 and phospholipase D are also involved, as demonstrated by the liberation of Arachidonic Acid and Phosphatidic Acid. Pituitary cells also express atypical protein kinase C isoforms which mode of activation is not known. Hypothesis concerning transcriptional regulation are presented.

Rhythmicity of luteinizing hormone secretion expressed in vitro.

In the present study we explored the possibility that the pituitary functions as an autonomous clock and is capable of generating rhythms of luteinizing hormone (LH) release independently of hypothalamic control. Pituitaries from estrous or diestrous day 1 female mice were perifused separately with Medium-199. Effluent samples were collected at 10-min intervals and assayed for LH levels. Fourier analysis and curve-fit analysis served to elucidate the presence of prominent periods whose significance was then determined by best-fit cosinor. The latter method was used to determine additional parameters for the significant rhythm. All perifused pituitaries exhibited LH release patterns that were composed of significantly long ultradian rhythms (approximately 16 and 8 h, p < 0.001). Continuous stimulation with gonadotropin-releasing hormone (GnRH) or estradiol did not alter the periods of the observed rhythms but affected other rhythm parameters. Gonadotropin-releasing hormone increased the mesor of the rhythm and estradiol increased the amplitude. The results indicate that pituitary gonadotropes are capable of producing rhythms of LH release for a long duration in vitro, in the absence of hypothalamic control. Both GnRH and estradiol affect different rhythm parameters but do not change the periods of these rhythms.

Dissociation between release and gene expression of gonadotropin alpha-subunit in gonadotropin-releasing hormone-stimulated alpha T3-1 cell line.

The alpha T3-1 cell line which was derived by targeted tumorigenesis in transgenic mice [Windle et al. (1990) Mol. Endocrinol. 4, 597-603] possesses high-affinity binding sites for GnRH analogs coupled to enhanced phosphoinositide turnover and phospholipase D activity. Incubation of alpha T3-1 cells with [D-Trp6]-GnRH analog (GnRH-A) resulted in a rapid increase in gonadotropin alpha-subunit mRNA levels which was detected already at 30 min of incubation (0.1 nM GnRH-A, 3-fold, p < 0.01). The effect diminished with time to reach basal levels at about 12 h of incubation, with a secondary rise in alpha mRNA levels between 12 and 24 h of incubation. Addition of the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 ng/mL) or the Ca2+ ionophore ionomycin (1 microM) to alpha T3-1 cells also resulted in a rapid increase in alpha-subunit mRNA levels. Surprisingly, GnRH-induced alpha-subunit release was detected only after a lag of 4 h of incubation. Thus, dissociation between exocytosis and gene expression can be demonstrated in GnRH-stimulated alpha T3-1 cell line.

Paradoxical signal transduction mechanism of endothelins and sarafotoxins in cultured pituitary cells: stimulation of phosphoinositide turnover and inhibition of prolactin release.

Endothelins (ET-1, ET-2, ET-3 and vasoactive intestinal contractor, VIC) and sarafotoxins (SRTX-b and SRTX-c) appear to bind with high affinity to a homogeneous class of binding sites in cultured rat pituitary cells. All of these ligands seem to interact with the same receptor (ETA-R), except for SRTX-c which apparently binds to a separate receptor. Binding was followed by phosphodiesteric cleavage of phosphoinositides, resulting in the formation of inositol phosphates. No consistent effect on basal or gonadotropin-releasing hormone (GnRH)-induced release of luteinizing hormone (LH) was exerted by ET or SRTX during 2 h of static incubation. On the other hand, both groups of vasoactive peptides inhibited basal and thyrotropin-releasing hormone (TRH)-induced prolactin secretion. Surprisingly, activation of phosphoinositide turnover by TRH in pituitary mammotrophs led to stimulation of prolactin secretion, whereas activation of the same pathway by ET or SRTX resulted in inhibition of prolactin secretion. ET and SRTX stimulated inositol phosphate formation in GH3 cell line and in the gonadotroph-like cell line alpha T-3 (which is capable of producing the alpha subunit of the gonadotrophins), indicating that the peptides interact with both pituitary mammotrophs and gonadotrophs. The very low concentrations (nM range) needed to stimulate phosphoinositide turnover and to inhibit prolactin secretion, as well as the recent finding that ETs are present in the hypothalamo-pituitary axis suggest that ET might participate in the neuroendocrine modulation of pituitary functions. One such possibility is that ETs might be members of the prolactin inhibiting factors (PIFs) family.