A minimal longitudinal dynamic model of a tailless flapping wing robot for control design.

Recently, several insect- and hummingbird-inspired tailless flapping wing robots have been introduced. However, their flight dynamics, which are likely to be similar to that of their biological counterparts, remain yet to be fully understood. We propose a minimal dynamic model that is not only validated with experimental data, but also able to predict the consequences of various important design changes. Specifically, the model captures the flapping-cycle-averaged longitudinal dynamics, considering the main aerodynamic effects. We validated the model with flight data captured with a tailless flapping wing robot, the DelFly Nimble, for air speeds from near-hover flight up to 3.5 m s-1. Moreover, the model succeeds in predicting the effects of changes to the center of mass location, and to the control system gains. Hence, the model is suitable even for the initial control design phase. To demonstrate this, we have used the simulation model to tune the robot's control system for higher speeds. Using the new control parameters on the real robot improved its maximal stable speed from 4 m s-1 to 7 m s-1.

Clinically driven design of multi-scale cancer models: the ContraCancrum project paradigm.

The challenge of modelling cancer presents a major opportunity to improve our ability to reduce mortality from malignant neoplasms, improve treatments and meet the demands associated with the individualization of care needs. This is the central motivation behind the ContraCancrum project. By developing integrated multi-scale cancer models, ContraCancrum is expected to contribute to the advancement of in silico oncology through the optimization of cancer treatment in the patient-individualized context by simulating the response to various therapeutic regimens. The aim of the present paper is to describe a novel paradigm for designing clinically driven multi-scale cancer modelling by bringing together basic science and information technology modules. In addition, the integration of the multi-scale tumour modelling components has led to novel concepts of personalized clinical decision support in the context of predictive oncology, as is also discussed in the paper. Since clinical adaptation is an inelastic prerequisite, a long-term clinical adaptation procedure of the models has been initiated for two tumour types, namely non-small cell lung cancer and glioblastoma multiforme; its current status is briefly summarized.

Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis.

BACKGROUND: The myofibroblast plays a central role in wound contraction and in the pathology of fibrosis. The origin(s) of this important cell type in skin has not been firmly established. METHODS: Human epithelioid dermal microvascular endothelial cells (HDMEC) were isolated from foreskin tissue and maintained in cell culture. The transformation of epithelioid HDMEC into myofibroblasts (EMT) was induced by the inflammatory cytokines interleukin-1beta (IL-1beta) or tumour necrosis factor-alpha (TNF-alpha), and the transformed cells were characterized by electron microscopy, immunohistochemistry and quantitative RT-PCR. RESULTS: After short-term exposure to IL-1beta or TNF-alpha (<3 days), EMT was reversible; after long-term exposure (>10 days), EMT was permanent. The transformed cells were identified as myofibroblasts by cytoplasmic microfilaments with dense bodies and attachment plaques, by the expression of alpha-smooth muscle actin, type I collagen and calponin, and by quantitative RT-PCR gene expression of type I collagen and alpha-smooth muscle actin. CONCLUSIONS: Long-term exposure to TNF-alpha or IL-1beta induced the permanent transformation of HDMEC into myofibroblasts in cell culture. A similar transformation following chronic inflammatory stimulation in vivo may explain one source of myofibroblasts in skin fibrogenesis.

Does melatonin play a role in aging processes?

Increasing number of people in advanced age is one of the most distinctive demographic events of the 21(st) century which raise many social and medical issues. Therefore, there is a search for any therapeutic agent improving the quality of life of the elderly. Melatonin, the hormone of the pineal gland, received recently a great deal of attention because of its suggested role in aging processes and availability as over-the-counter drug or food supplement in some countries, including Poland. In this survey the basic data on the possible role of melatonin in human aging as well as its possible therapeutic significance are reviewed and discussed.

Primary stenting in the treatment of focal atherosclerotic abdominal aortic stenoses.

AIM: To evaluate the results of primary stent placement in focal atherosclerotic aortic stenoses using balloon expandable stents. MATERIALS AND METHODS: Twenty-six primary balloon expandable stent placements in the abdominal aorta were performed and reviewed. All the aortic stenoses were atherosclerotic. Patients were followed up by ankle/brachial pressure indices (ABPI) and Doppler ultrasound (US) at 24h after procedure and at 12 and 24 months. Follow-up angiograms were performed at 12 months. RESULTS: Twenty-six stents in 26 patients were placed in the infrarenal aorta. All procedures were technically successful and immediate clinical success was obtained. The mean ABPI significantly improved from 0.52+/-0.10 to 0.94+/-0.09 within 24h after procedure, and remained at 0.90+/-0.12 between 12 and 24 months follow-up (mean 18 months). There was full haemodynamic success at hospital discharge and at 12 and 24 months after the procedure. Clinical success at 12 and 24 months (mean 18 months) was defined as an improvement in the Fontaine classification by at least one class compared with the pre-procedure class and was shown to be 100%. CONCLUSION: In summary, we report that primary stenting is a safe and effective alternative to surgery in cases of symptomatic stenosis of the infrarenal abdominal aorta. The excellent intermediate term results suggested that we would recommend primary stenting as the treatment of choice for focal atherosclerotic stenoses of the infrarenal aorta in selected patients.

Melatonin in humans.

Melatonin, the hormone of the pineal gland, received a great deal of attention in the last decade because of its availability as over-the-counter drug or food supplement in some countries and suggested role in many vital physiological processes. Melatonin secretion is not restricted to mammals but is also produced in nonmammalian vertebrates, in some invertebrates, and in many plants, with the same molecular structure. The synthesis of melatonin is strictly controlled by lighting conditions and shows a clear circadian rhythm with low values during the daytime and significant increase at night. In this survey the basic data on melatonin significance in human physiology and in pathological processes as well as its possible therapeutic significance are reviewed and discussed.

Melatonin, human aging, and age-related diseases.

The worldwide prolongation of the mean life expectancy has resulted in a rapid increase of the size of the elderly population (over the age of 60), both in numbers and as a proportion of the whole. As a consequence, increasing the number of potential beneficiaries of health and pension funds, mainly those aged 65 and over raises many social and economic problems since they are supported by a relatively smaller number of potential contributors, i.e. those in the economically active ages between 18 and 64. Therefore, there is a search for any therapeutic agent improving quality of life in the elderly. A role for melatonin as such a compound was recently suggested. In this survey, data on the possible role of melatonin in human aging and age-related diseases are briefly presented. Undoubtedly the aging process is multi-factorial, and no single factor has been identified which satisfactorily explains the phenomenon. Although many theories relating the pineal gland and its secretory product melatonin to aging have been proposed, the role of this agent in the aging process is still unclear. However, for several reasons it seems reasonable to postulate a role for melatonin in this process. Melatonin levels decline gradually over the life-span and may be related to lowered sleep efficacy, very often associated with advancing age, as well as to deterioration of many circadian rhythms. Melatonin exhibits immunomodulatory properties, and a remodeling of immune system function is an integral part of aging. Finally, because melatonin is a potent free radical scavenger, its deficiency may result in reduced antioxidant protection in the elderly which may have significance not only for aging per se but also may contribute to the incidence or severity of some age-related diseases. Presently available data do not allow us to conclude that melatonin may have a role in extending normal longevity. However, although melatonin cannot be recognized as 'rejuvenating' agent, some of its actions may be beneficial for the aging process. Administration of melatonin may improve temporal organization in advanced age. Moreover, it has beneficial effects on sleep as well as age-related diseases. Although recommendations of melatonin supplementation in elderly should be considered, there is a need for extensive studies on the use of melatonin in order to improve the quality of life in advanced age.

Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer.

The effects of melatonin and the thiazolinidinedione derivative CGP 52608 on apoptosis of Colon 38 cancer cells were investigated. Male mice were implanted subcutaneously with a suspension of Colon 38 cells. Ten days after induction of tumors, the animals were treated with melatonin or CGP 52608. Both substances were given in subcutaneous injections in daily doses of 10 or 100 microg in the evening for 6 days. The control group received solvent. The apoptotic cells were visualized in paraffin sections by means of the transferase-mediated dUTPnick end-labeling method. Both treatments increased significantly and to the same degree the number of apoptotic cells in tumors. This finding confirms our earlier observation that melatonin exerts a pro-apoptotic effect on murine colonic cancer cells. Moreover, because CGP 52608 is a ligand of RZR/ROR receptors and the latter are considered by some investigators as nuclear binding sites for melatonin, our data suggest the involvement of these receptors in the pro-apoptotic effect of melatonin.

Diurnal profile of melatonin concentrations in patients with major depression: relationship to the clinical manifestation and antidepressant treatment.

OBJECTIVES: The aim of the study was to establish if there are differences in the 24-hour melatonin secretion profile between patients with major depression (before, and after treatment with clomipramine) compared to those in healthy subjects. Additionally, we determined if there are differences in melatonin concentrations, depending on the severity of depression, and the presence of 24-hour rhythm disturbances. MATERIAL AND METHODS: Twenty patients with major depression and 24-hour rhythm disturbances, and 14 healthy volunteers took part in the study. Before, and after treatment with clomipramine all subjects had blood samples collected at 08:00, 14:00, 20:00, 24:00, 02:00, 04:00, and 08:00 h, for estimation of melatonin concentrations. Before and after treatment, the severity of depression was evaluated using the following scales: the Hamilton Depression Rating Scale (HADRS), Beck Depression Inventory (BDI), and clinical observation, as well as presence, and if so, severity of 24-hour rhythm disturbances were assessed. RESULTS: In individuals with major depression with marked disturbances of their diurnal rhythms, melatonin secretion is also disturbed, shown by the higher melatonin concentrations at night as compared to those in healthy individuals. However, melatonin levels were independent of the severity or the clinical manifestation of depression. Moreover, no correlation between the disturbances in their diurnal rhythms (sleep-watchfulness, diurnal mood shifts) and disturbed melatonin pattern was observed. CONCLUSIONS: Melatonin nocturnal concentrations in patients with major depression were higher than those in healthy individuals. However, the melatonin concentration values do not differentiate the patients in terms of the severity of the depressive symptoms.

Twelve-month follow-up of a controlled trial of intradiscal thermal anuloplasty for back pain due to internal disc disruption.

STUDY DESIGN: Case-control study. OBJECTIVES: To determine the prima facie efficacy of intradiscal electrothermal anuloplasty (IDTA). SUMMARY OF BACKGROUND DATA: Although it is being used increasingly as a putative treatment for internal disc disruption, no studies have been published on the efficacy of IDTA. METHODS: Fifty-three patients with back pain determined by computed tomographic (CT)-discography to be due to internal disc disruption were offered treatment. The outcomes of 35 patients treated with IDTA were compared with those of a convenience sample of 17 patients treated with a physical rehabilitation program, by using a visual analog pain scale, use of analgesics, and return to work as measures. RESULTS: At 3 months, only one control patient obtained any significant degree of relief of pain, compared with 23 in the index group. Relief of pain was sustained at 6 and 12 months and was associated with improvement in disability, reduced drug use, and a return to work rate of 53%. Depending on the stringency of criteria used, the success rate of IDTA may be as low as 23% or as high as 60% with confidence intervals of +/-16%. CONCLUSIONS: In carefully selected cases, IDTA can eliminate or dramatically reduce the pain of internal disc disruption in a substantial proportion of patients and appears to be superior to conventional conservative care for internal disc disruption.

In vitro characteristics of neonatal hemangioma endothelial cells: similarities and differences between normal neonatal and fetal endothelial cells.

BACKGROUND: Increased angiogenesis and eventual involution are major characteristics of neonatal hemangiomas. The mechanism to explain this transition is not completely understood. METHODS: To determine the nature of these changes, endothelial cells were isolated from eight hemangiomas and the growth characteristics and morphology of these cells were compared to cells isolated from normal fetal and neonatal skin. Three cells lines were further characterized by analyzing protein expression with immunohistochemistry and FACS analysis. RESULTS: Hemangioma endothelial cells converted to a spindle-shaped morphology similar to that of fetal endothelial cells whereas neonatal endothelial cells maintained their characteristic epithelioid morphology. While neonatal, hemangioma and fetal endothelial cells continued to express platelet-endothelial cell adhesion molecule-1 (PECAM-1) and von Willebrand factor (vWf), hemangioma and fetal cells expressed both proteins at a lower level and in a distribution distinct from normal neonatal endothelial cells. Neonatal endothelial cells continued to express epithelial specific Type IV collagen, while hemangioma and fetal endothelial cells produced interstitial Type I collagen. CONCLUSIONS: Both cell morphology and protein expression of neonatal hemangioma endothelial cells were more characteristic of embryonic microvascular endothelial cells than that of postembryonic cells demonstrating a similarity in these two cell types and suggesting a dysfunction in the normal growth and maturation of endothelial cells in this tumor.

Chronic exposure to 25-80-microT, 200-Hz magnetic field does not influence serum melatonin concentrations in patients with low back pain.

There is substantial evidence that magnetic field (MF) exposure influences melatonin secretion in animals. However, data on its influence on human melatonin levels are scarce, and seemingly contradictory. Because of its many beneficial effects, very low-frequency MF exposure is used in physiotherapy of some neurological diseases and overloading syndromes of the locomotor system. In previous studies, we observed a decrease in human serum melatonin nocturnal concentrations after exposure to MF (2.9 mT, 40 Hz), and we suggested that differences among various studies may depend on different characteristics of the applied MF. Therefore, in the present study, we examined whether or not MF of different parameters exerts the same effect. The study was performed in seven men (mean age: 36.7 +/- 3.8 years; range: 32-42) suffering from low back pain. Patients were exposed to a pulsating MF (induction: 25 80 microT; frequency: 200 Hz, modulated, automatically programmed; complex saw-like impulse shape; bipolar) generated by a Quatronic MRS 2000 apparatus ("magnetic bed") for 3 wk (5 days/wk, twice a day at 08:00 and 13:00 hr for 8 min each), applied to the whole body in patients laying in a horizontal position. The study was performed in spring. Diurnal serum melatonin profiles were estimated 1 day before exposure to MF (baseline), and 1 day and 1 month after the last exposure. No changes in melatonin concentrations were observed either after 1 day or after 1 month following the exposure in comparison to baseline.

Serial transplants of DMBA-induced mammary tumors in fischer rats as model system for human breast cancer: V. Myoepithelial-mesenchymal conversion during passaging as possible cause for modulation of pineal-tumor interaction.

An elevation of melatonin secretion parallel to an enhanced production of macrophage-derived biopterin was observed in female F344 Fischer rats bearing passage 2 serial transplants derived from a malignant mammary tumor induced by 7,12-dimethylbenz[a]anthracene (DMBA). As opposed to that both parameters were depressed at passage 12. These results indicate the presence of divergent immunoneuroendocrine interactions during different phases of tumor growth. Since these biochemical events must have their common origin in changes taking place within these tumor transplants the current histopathological study was initiated. The primary tumor used for serial transplantation was a moderately differentiated adenocarcinoma of the mammary gland showing cytokeratin-positive epithelial components located in the inner epithelial tubule layer. In addition, bland-looking round or elongated actin-positive myoepithelial cells were detected which apart from epithelial cells are known to constitute the main cellular components of the mammary ductal system which resemble smooth muscle cells both morphologically and functionally. The tumor of passage 1 showed glandular tubules, lined by an inner epithelial layer, and many nests of clear, bland-looking actin-positive myoepithelial cells lying around tubules as well as in the stroma between actin-negative epithelial elements. The tumor of passage 2 used for transplantation consisted of a chaotic mixture of epithelial carcinomatous cells, forming a few irregular small tubules or solid nests, and, predominantly, of elongated plump or spindle-shaped, "myoid" atypical myoepithelial cells with a strong actin-positive reaction and some of these cells showed a focal vimentin expression. The tumor was characterized as a carcinosarcoma. At passage 12 epithelial cells were not identified. The tumor displayed features of a pleomorphic sarcoma consisting mainly of giant cells with bizarre nuclei being cytokeratin- and desmin-negative, weakly vimentin-positive but strongly actin-positive. These results indicate that DMBA-induced mammary tumor cells in female F344 Fischer rats undergo dramatic morphological changes during serial transplantation characterized by a total loss of malignant epithelial (carcinomatous) cells and the emergence and subsequent predominance of malignant (sarcomatous) mesenchymal cells. It appears that these sarcomatous cells develop out of myoepithelial cells since atypical myoepithelial cells with a strong actin-positive reaction showed a focal vimentin expression at passage 2 indicating myofibroblastic differentiation as part of mesenchymal transition. The loss of epithelial cell elements as well as a parallel transition of myoepithelial to mesenchymal cell elements during passaging could lead to a lack of immunological recognition of these tumor transplants and to depression of melatonin. Possible mechanisms involved in these phenomena as well as the relevance of these findings for a better understanding of the role of melatonin in human mammary cancer are discussed.

Divergent effects of extracellular oxygen on the growth, morphology, and function of human skin microvascular endothelial cells.

Partial pressure of extracellular oxygen influences a number of major cellular functions. The purpose of this study was to determine if the proliferation, morphology, and synthesis of proteins important in the function of skin microvascular endothelial cells were significantly altered by an extracellular oxygen tension used to culture endothelial cells. Microvascular endothelial cells were isolated from the dermis of neonatal foreskins and were studied at a venous capillary oxygen level (5% O(2), 38 mm Hg) and at an atmospheric oxygen level (20.8% O(2,) 158 mm Hg). At all time points studied and at all passage numbers, a significant inhibition of proliferation was observed at 20.8% O(2) compared to identical cultures grown and subcultured at 5% O(2). Two morphologically distinct endothelial cell populations were observed at 5% O(2). When mediators of angiogenesis and inflammation-such as basic fibroblast growth factor (bFGF), phorbol myristate acetate (PMA), and interleukin-1beta (IL-1beta)-were studied, additional differences in proliferation were observed. Atmospheric O(2) inhibited the synthesis of a major basement membrane protein (Type IV collagen), a major surface protein (PECAM-1), and increased the synthesis of von Willebrand factor (vWf). The rate of vascular channel formation induced by collagen gels was decreased at 5% O(2). These results demonstrate that an increase in extracellular oxygen tension from 5 to 20.8% can significantly alter the cellular physiology of human skin microvascular endothelial cells.

Progress in our understanding of the biology of psoriasis.

This review describes the progress made in our understanding of the basic biology of psoriasis and how newer, safer clinical approaches to control the disease may result from these developments. It reveals how epidermal hyperproliferation can be permanently induced using transgenic mouse models, how the discovery of methods to generate humanized mouse monoclonal antibodies may be used to control the synthesis of autocrine and paracrine growth factors, how programmed cell death (apoptosis) is regulated in the epidermis, and how the abnormal synthesis of superantigens, cytokines, and chemokines can result in immune dysfunction and generate increased angiogenesis, inflammation, and epidermal hyperproliferation.

Antiproliferative effects of melatonin and CGP 52608.

The antiproliferative effects of melatonin and CGP 52608, an exogenous ligand for RZR/ROR receptors, are compared in the present paper. Both compounds exerted similar inhibitory effects on the proliferation of neoplastic cells in mouse colonic adenocarcinoma, DU 145 human prostate cancer, MCF-7 human breast carcinoma, and rat diethylstilbestrol-induced prolactinoma. Although it has been suggested that melatonin may influence the proliferation of tumor cells via RZR/ROR receptors, it cannot be excluded that the antiproliferative effects of melatonin and CGP 52608 are unrelated and mediated by different intracellular mechanisms.

Chronic exposure to 2.9 mT, 40 Hz magnetic field reduces melatonin concentrations in humans.

Diurnal rhythm of serum melatonin concentrations was estimated in 12 men with low back pain syndrome before and after exposure to a very low-frequency magnetic field (2.9 mT, 40 Hz, square wave, bipolar). Patients were exposed to the magnetic field for 3 weeks (20 min per day, 5 days per week) either in the morning (at 10:00 hr) or in the late afternoon (at 18:00 hr). Significant depression in nocturnal melatonin rise was observed regardless of the time of exposure. This phenomenon was characteristic for all the subjects, although the percent of inhibition of melatonin secretion varied among the studied individuals.