Circadian Disruption as a Risk Factor for Development of Cardiovascular and Metabolic Disorders - From Animal Models to Human Population.

The lifestyle of human society is drifting apart from the natural environmental cycles that have influenced it since its inception. These cycles were fundamental in structuring the daily lives of people in the pre-industrial era, whether they were seasonal or daily. Factors that disrupt the regularity of human behaviour and its alignment with solar cycles, such as late night activities accompanied with food intake, greatly disturb the internal temporal organization in the body. This is believed to contribute to the rise of the so-called diseases of civilization. In this review, we discuss the connection between misalignment in daily (circadian) regulation and its impact on health, with a focus on cardiovascular and metabolic disorders. Our aim is to review selected relevant research findings from laboratory and human studies to assess the extent of evidence for causality between circadian clock disruption and pathology. Keywords: Circadian clock, Chronodisruption, Metabolism, Cardiovascular disorders, Spontaneously hypertensive rat, Human, Social jetlag, Chronotype.

Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN.

BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.

Rapid test for fecal calprotectin levels in children with Crohn disease.

Assessment of fecal calprotectin, a surrogate marker of mucosal inflammation, is a promising means to monitor therapeutic response in pediatric inflammatory bowel disease, especially if the result is readily available. We tested the performance of a novel calprotectin rapid test, Quantum Blue, versus the conventional enzyme-linked immunosorbent assay in 134 stool samples from 56 pediatric patients with Crohn disease. The intraclass correlation coefficient analysis reflected good agreement (intraclass correlation coefficient 0.97 [95% confidence interval 0.95-0.98]) but agreement was better in lower values, where dilutions were not required. Using a cutoff of 100 µg/g for normal values, the percentage agreement between the 2 tests was 87%. The optimal cutoff values to guide clinical decisions in the therapy of inflammatory bowel disease have yet to be determined.

Restricted feeding regime affects clock gene expression profiles in the suprachiasmatic nucleus of rats exposed to constant light.

The master circadian clock located in the suprachiasmatic nuclei (SCN) is dominantly entrained by external light/dark cycle to run with a period of a solar day, that is, 24 h, and synchronizes various peripheral clocks located in the body's cells and tissues accordingly. A daily restricted normocaloric feeding regime synchronizes the peripheral clocks but has no effect on SCN rhythmicity. The aim of this study was to elucidate whether feeding regime may affect the molecular mechanism generating SCN rhythmicity under conditions in which the rhythmicity is disturbed, as occurs under constant light. The rats were maintained under constant light for 30 days and were either fed ad libitum during the whole period, or their access to food was restricted to only 6 h a day during the last 2 weeks in constant light. Locomotor activity was monitored during the whole experiment. On the last day in constant light, daily expression profiles of the clock genes Per1, Per2, Bmal1, and Rev-erbα were determined in the SCN of both groups by in situ hybridization. Due to their exposure to constant light, the rats fed ad libitum became completely arrhythmic, while those exposed to the restricted feeding were active mostly during the time of food availability. In the SCN of behaviorally arrhythmic rats, no oscillations in Rev-erbα and Bmal1 gene expression were detected, but very low amplitude, borderline significant, oscillations in Per1 and Per2 persisted. Restricted feeding induced significant circadian rhythms in Rev-erbα and Bmal1 gene expression, but did not affect the low amplitude oscillations of Per1 and Per2 expression. These findings demonstrate that, under specific conditions, when the rhythmicity of the SCN is disturbed and other temporal entraining cues are lacking, the SCN molecular clockwork may likely sense temporal signals from changes in metabolic state delivered by normocaloric food.

Circadian molecular clocks tick along ontogenesis.

The circadian system controls the timing of behavioral and physiological functions in most organisms studied. The review addresses the question of when and how the molecular clockwork underlying circadian oscillations within the central circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and the peripheral circadian clocks develops during ontogenesis. The current model of the molecular clockwork is summarized. The central SCN clock is viewed as a complex structure composed of a web of mutually synchronized individual oscillators. The importance of development of both the intracellular molecular clockwork as well as intercellular coupling for development of the formal properties of the circadian SCN clock is also highlighted. Recently, data has accumulated to demonstrate that synchronized molecular oscillations in the central and peripheral clocks develop gradually during ontogenesis and development extends into postnatal period. Synchronized molecular oscillations develop earlier in the SCN than in the peripheral clocks. A hypothesis is suggested that the immature clocks might be first driven by external entraining cues, and therefore, serve as "slave" oscillators. During ontogenesis, the clocks may gradually develop a complete set of molecular interlocked oscillations, i.e., the molecular clockwork, and become self-sustained clocks.

Ontogenesis of photoperiodic entrainment of the molecular core clockwork in the rat suprachiasmatic nucleus.

The molecular mechanism underlying a generation of circadian rhythmicity within the suprachiasmatic nucleus (SCN) is based on interactive negative and positive feedback loops that drive the rhythmic transcription of clock genes and translation of their protein products. In adults, the molecular mechanism is affected by seasonal changes in day length, i.e., photoperiod. The photoperiod modulates phase, waveform, and amplitude of the rhythmic clock genes expression as well as the phase relationship between their profiles. To ascertain when and how the photoperiod affects the circadian core clock mechanism during ontogenesis, the rhythmic expression of clock genes, namely of Per1, Per2, Cry1 and Bmal1 was determined in 3-, 10- and 20-day-old rat pups maintained under either a long photoperiod with 16 h of light and 8 h of darkness per day (LD 16:8) or under a short, LD 8:16 photoperiod. The daily profiles in the level of clock genes mRNA were studied in constant darkness. The photoperiod affected the profile of Per1 and Per2 mRNA in 20- and 10- but not yet in 3-day-old pups. Expression of Cry1 was affected only in 20-day-old pups, whereas expression of Bmal1 was not yet affected even in 20-day-old rats. The results demonstrate no effect of the photoperiod on 3-day-old pups, only partial entrainment of the molecular core clockwork in 10-day-old pups and a more mature, though not yet fully complete, entrainment in 20-day-old pups as compared with adult animals. The developmental interval when the photoperiod begins to entrain the core clock mechanism completely might thus occur around the time of weaning.

Seasonal molecular timekeeping within the rat circadian clock.

In temperate zones duration of daylight, i.e. photoperiod, changes with the seasons. The changing photoperiod affects animal as well as human physiology. All mammals exhibit circadian rhythms and a circadian clock controlling the rhythms is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consists of two parts differing morphologically and functionally, namely of the ventrolateral (VL) and the dorsomedial (DM). Many aspects of SCN-driven rhythmicity are affected by the photoperiod. The aim of the present overview is to summarize data about the effect of the photoperiod on the molecular timekeeping mechanism in the rat SCN, especially the effect on core clock genes, clock-controlled genes and clock-related genes expression. The summarized data indicate that the photoperiod affects i) clock-driven rhythm in photoinduction of c-fos gene and its protein product within the VL SCN, ii) clock-driven spontaneous rhythms in clock-controlled, i.e. arginine-vasopressin, and in clock-related, i.e. c-fos, gene expression within the DM SCN, and iii) the core clockwork mechanism within the rat SCN. Hence, the whole central timekeeping mechanism within the rat circadian clock measures not only the daytime but also the time of the year, i.e. the actual season.

Quality of life after breast carcinoma surgery: a comparison of three surgical procedures.

BACKGROUND: Because breast-conserving surgery (BCS), mastectomy alone, and mastectomy with reconstruction are equally effective for the treatment of early stage breast carcinoma, women's choice among them often focuses on quality-of-life (QOL) issues. Information regarding QOL after these surgical treatments could help women with this decision. METHODS: Participants in this prospective study were women, age 30-85 years, with newly diagnosed breast carcinoma who underwent BCS (n = 103), mastectomy alone (n = 55), or mastectomy with reconstruction (n = 40). Quality of life was assessed after diagnosis (baseline) and at 1, 3, 6, 12, 18, and 24 months after baseline by using the Mischel Uncertainty in Illness Scale, Profile of Mood States, and Functional Assessment of Cancer Therapy for Breast Cancer. RESULTS: In multivariate regression analyses controlling for the QOL score obtained at baseline, age, and type of nonsurgical treatment, women who underwent mastectomy with reconstruction had greater mood disturbance (P = 0.002) and poorer well-being (P = 0.002) after baseline than women who had mastectomy alone; these differences remained 18 months after surgery. Although similar analyses also showed that women who underwent BCS had more mood disturbance than women who had mastectomy alone, this difference was significant only at 12 months after baseline. The BCS and mastectomy-only group did not differ significantly regarding well-being. CONCLUSIONS: Aspects of QOL other than body image are not better in women who undergo BCS or mastectomy with reconstruction than in women who have mastectomy alone. In fact, mastectomy with reconstruction is associated with greater mood disturbance and poorer well-being.

Catalytic C-F activation of polyfluorinated pyridines by nickel-mediated cross-coupling reactions.

The cross-coupling reaction of pentafluoropyridine with tributyl(vinyl)tin affording 2-vinyltetrafluoropyridine by activation of a carbon-fluorine bond is catalysed by [NiF(2-C5NF4)(PEt3)2]; a similar reaction is observed with 2,3,5,6-tetrafluoropyridine.

Educating patients on sentinel lymph node dissection for breast cancer.

PURPOSE: This article reviews the current literature on lymphatic mapping and sentinel lymph node dissection (SLND) for breast cancer and presents educational information for patients who are considering undergoing this procedure. OVERVIEW: Lymphatic mapping with SLND has been tested widely in patients with breast cancer, primarily in the context of clinical trials. Research studies have found a high degree of accuracy, with the sentinel lymph node (SLN) predicting the status of the axillary node basin. The ability of the surgeon to identify the SLN and the accuracy of the technique correlate with the number of procedures conducted. With the increase in the number of patients having lymphatic mapping and SLND for breast cancer who may not be part of a clinical trial, there is a need for educational materials to help clinicians teach patients about the procedure. CLINICAL IMPLICATIONS: Because of the complexity of the information, patients need both written and verbal information to decide whether to undergo an SLND. In the setting of a clinical trial, patient education materials add to the informed consent document. As the use of SLND for breast cancer becomes more common, the need for clear, concise, informative patient education materials is even more imperative.

Effects of advanced nursing care on quality of life and cost outcomes of women diagnosed with breast cancer.

PURPOSE/OBJECTIVES: To evaluate quality of life (QOL) and cost outcomes of advanced practice nurses' (APNs') interventions with women diagnosed with breast cancer. DESIGN: Randomized clinical trial. SETTING: Integrated healthcare system in a midwestern suburban community. SAMPLE: 210 women with newly diagnosed breast cancer with an age range of 30-85 years. METHODS: The control group (n = 104) received standard medical care. The intervention group (n = 106) received standard care plus APN interventions based on Brooten's cost-quality model and the Oncology Nursing Society's standards of advanced practice in oncology nursing QOL was measured using the Functional Assessment of Cancer Therapy, Mishel Uncertainty in Illness Scale and Profile of Mood States at seven intervals over two years. Information about costs (charges and reimbursement) was collected through billing systems. MAIN RESEARCH VARIABLES: Uncertainty, mood states, well-being, charges, and reimbursement. FINDINGS: Uncertainty decreased significantly more from baseline in the intervention versus control group at one, three, and six months after diagnosis (p = 0.001, 0.026, and 0.011, respectively), with the strongest effect on subscales of complexity, inconsistency, and unpredictability. Unmarried women and women with no family history of breast cancer benefited from nurse interventions in mood states and well-being. No significant cost differences were found. CONCLUSIONS: APN interventions improved some QOL indicators but did not raise or lower costs. IMPLICATIONS FOR NURSING PRACTICE: The first six months after breast cancer diagnosis is a critical time during which APN interventions can improve QOL outcomes. More research is necessary to define cost-effective interventions.

A critical pathway for patients undergoing one-day breast cancer surgery.

As the trend of surgical procedures shifting from inpatient to outpatient settings continues, outpatient-focused standardized care processes will become more of a necessity. A multidisciplinary critical pathway (CP) for breast cancer surgery can assist care providers in meeting patients' educational and psychosocial needs. The CP document discussed in this article takes into account the expedient nature of outpatient surgery and spans the continuum of care from the surgical clinic to the postoperative homecare visit. Integrating homecare nursing improves the quality and consistency of care.

Prolonged hypoxemia enhances and acute hypoxemia attenuates laryngeal reflex apnea in young lambs.

To determine the influence of an altered carotid body function on the laryngeal chemoreflex (LCR) response, reflex apnea was induced by laryngeal water stimulation during normoxia or acute hypoxia in unanesthetized awake lambs in which the ventilatory response to acute hypoxia was attenuated by prolonged postnatal hypoxemia. Prolonged hypoxemia (H) was induced in seven lambs for 12 d after birth through exposure to 0.10 fraction of inspired oxygen. Five control lambs were kept in 0.21 fraction of inspired oxygen. Studies were performed repeatedly during the first 7 wk after birth. The ventilatory response to LCR stimulation, expressed as a percent decrease in minute ventilation, was tested in 0.21, 0.14, and 0.10 fraction of inspired oxygen. H after birth resulted in a markedly increased inhibition of ventilation in response to LCR stimulation and postponed the age-related decrease in LCR response. A potential failure to recover from apnea occurred only in the H lambs, and in these lambs there was a significantly greater requirement for mechanical ventilation after LCR stimulation. Acute hypoxemia preceding LCR stimulation significantly attenuated the ventilatory response in both control and H lambs, with a stronger effect in the H lambs. There was no difference between the two groups in heart rate response to LCR stimulation. Acute hypoxemia significantly augmented reflex bradycardia in the H lambs. These results show that there is a relationship between H immediately after birth--which is known to delay resetting of carotid chemoreceptors--and augmented ventilatory inhibition in response to LCR stimulation. They do not confirm the theory that acute hypoxia reinforces reflex apnea.

Long-lasting effect of prolonged hypoxemia after birth on the immediate ventilatory response to changes in arterial partial pressure of oxygen in young lambs.

The effect of prolonged hypoxemia (H) after birth on the evolution of the ventilatory response to changes in arterial partial pressure of O2 was determined in unanesthetized, awake lambs. H was induced for 12 d after birth in seven lambs through exposure to 0.10 fraction of inspired O2 (FiO2). Five control (C) lambs were kept in 0.21 FiO2. The ventilatory response (percent increase from baseline) to acute hypoxia was tested with 0.14 FiO2 and 0.10 FiO2. The tonic activity of the peripheral chemoreceptors was assessed by the transient pure oxygen inhalation test (Dejours' test). The occlusion technique was used to measure the baseline neuromuscular drive of breathing. A markedly decreased early ventilatory response to acute hypoxia persisted in the H lambs for at least 5 wk after termination of H compared with the C group. The second phase of the response was significantly lower only at 12 d (the end of H) and was thereafter comparable to that in the C lambs. The ventilatory response to hyperoxia was significantly lower in the H lambs only at the end of hypoxemia at 12 d and rapidly normalized after return to normoxia. H did not significantly affect resting neuromuscular drive. These results show that postnatal maturation of the ventilatory response to changes in arterial partial pressure of O2 can be delayed by prolonged postnatal hypoxemia. The effect on the response to hyperoxia is transient, whereas the response to acute hypoxia is affected for an extended time. This study illustrates the importance of an adequate postnatal arterial partial pressure of O2 for the development of the ventilatory response to acute hypoxia.

Surfactant improves gas mixing and alveolar ventilation in preterm lambs.

Prophylactic treatment with ovine surfactant was evaluated in preterm lambs at risk for development of hyaline membrane disease. Eight mechanically ventilated newborn lambs were treated before delivery and 10 served as controls (gestational age 129-131 d). Lung mechanics, functional residual capacity, alveolar ventilation, efficiency of ventilation, and distribution of ventilation were tested using pressure, flow, and nitrogen elimination (nitrogen washout during 100% oxygen breathing) measurements in the endotracheal tube. The surfactant-treated animals showed significantly improved gas mixing efficiency in the lung with improved alveolar ventilation. Single exponential washout pattern dominated in both groups. Adequate functional residual capacity was established earlier after birth in the treated lambs than in the control animals. Lung mechanics in the treated group showed significant improvement in dynamic lung compliance. Surfactant treatment also improved gas exchange and reduced respirator pressure requirement. We speculate that the main functional effect of surfactant treatment in preterm lambs at risk to develop hyaline membrane disease is to maintain the patency of the peripheral airways in the lung, which improves diffusive gas mixing, alveolar ventilation, and gas exchange. The techniques used in this study should also be useful to evaluate lung function in preterm human infants after specific adaptation of the equipment size.

[Initial experience with cryopreservation of human embryos]. / První zkusenosti s kryokonzervací lidských embryí.

We present our first experience with human embryo cryopreservation. In our hands the best results were obtained with cryopreservation of pronuclear-staged embryos using propanediol as cryoprotectant. In this group 3 embryos out of 4 continued their development after thawing. The advantages of embryo cryopreservation in IVF programs are discussed.