Background: Our previous studies revealed cyclicity in the incidence rate of skin malignant melanoma (SMM; ICD9, Dx:172) in the Czech Republic (period T=7.50~7.63 years), UK (T=11.00 years) and Bulgaria (T=12.20 years). Incidences compared with the sunspot index Rz (lag-period dT=+2,+4,+6,+10 or +12 years) have indicated that maximal rates are most likely to appear on descending slopes of the 11-year solar cycle, i.e., out of phase. We summarized and explored more deeply these cyclic variations and discussed their possible associations with heliogeophysical activity (HGA) components exhibiting similar cyclicity. Methods: Annual incidences of SMM from 5 countries (Czech Republic, UK, Bulgaria, USA and Canada) over various time spans during the years 1964~1992 were analyzed and their correlations with cyclic Rz (sunspot number) and aa (planetary geomagnetic activity) indices were summarized. Periodogram regression analysis with trigonometric approximation and phase-correlation analysis were applied. Results: Previous findings on SMM for the Czech Republic, UK and Bulgaria have been validated, and cyclic patterns have been revealed for USA (T=8.63 years, P<0.05) and Canada (Ontario, T=9.91 years, P<0.10). Also, various 'hypercycles' were established (T=45.5, 42.0, 48.25, 34.5 and 26.5 years, respectively) describing long-term cyclic incidence patterns. The association of SMM for USA and Canada with Rz (dT=+6 and +7 years, respectively) and aa (dT=-10 and +9 years, respectively) was described. Possible interactions of cyclic non-photic influences (UV irradiation, Schumann resonance signal, low-frequency geomagnetic fluctuations) with brain waves absorbance, neuronal calcium dynamics, neuro-endocrine axis modulation, melatonin/serotonin disbalance and skin neuro-immunity impairment as likely causal pathways in melanoma appearance, were also discussed. Conclusion: The above findings on cyclicity and temporal association of SMM with cyclic environmental factors could not only allow for better forecasting models but also lead to a better understanding of melanoma aetiology.

Background: Our previous studies revealed cyclicity in the incidence rate of skin malignant melanoma (SMM; ICD9, Dx:172) in the Czech Republic (period T=7.50~7.63 years), UK (T=11.00 years) and Bulgaria (T=12.20 years). Incidences compared with the sunspot index Rz (lag-period dT=+2,+4,+6,+10 or +12 years) have indicated that maximal rates are most likely to appear on descending slopes of the 11-year solar cycle, i.e., out of phase. We summarized and explored more deeply these cyclic variations and discussed their possible associations with heliogeophysical activity (HGA) components exhibiting similar cyclicity. Methods: Annual incidences of SMM from 5 countries (Czech Republic, UK, Bulgaria, USA and Canada) over various time spans during the years 1964~1992 were analyzed and their correlations with cyclic Rz (sunspot number) and aa (planetary geomagnetic activity) indices were summarized. Periodogram regression analysis with trigonometric approximation and phase-correlation analysis were applied. Results: Previous findings on SMM for the Czech Republic, UK and Bulgaria have been validated, and cyclic patterns have been revealed for USA (T=8.63 years, P<0.05) and Canada (Ontario, T=9.91 years, P<0.10). Also, various 'hypercycles' were established (T=45.5, 42.0, 48.25, 34.5 and 26.5 years, respectively) describing long-term cyclic incidence patterns. The association of SMM for USA and Canada with Rz (dT=+6 and +7 years, respectively) and aa (dT=-10 and +9 years, respectively) was described. Possible interactions of cyclic non-photic influences (UV irradiation, Schumann resonance signal, low-frequency geomagnetic fluctuations) with brain waves absorbance, neuronal calcium dynamics, neuro-endocrine axis modulation, melatonin/serotonin disbalance and skin neuro-immunity impairment as likely causal pathways in melanoma appearance, were also discussed. Conclusion: The above findings on cyclicity and temporal association of SMM with cyclic environmental factors could not only allow for better forecasting models but also lead to a better understanding of melanoma aetiology.

Abstract Quantitative data on melatonin in stroke patients are scarce. Gender- and age-matched cross-sectional case-control study in 33 patients with ischaemic stroke (IS) was performed and associations between nocturnal melatonin and other factors (e.g., cortisol) evaluated. Clinical and laboratory (e.g., melatonin and cortisol) measurements (3 and 8 a.m.) with statistical techniques [e.g., multifactorial regressions, receiver operating characteristics (ROC) curve and curvilinear estimations] were used. We identified mean value and 95% confidence interval (69.70 pg/ml, 95% CI 53.86-85.54) for control levels of nocturnal melatonin in healthy subjects. The patients with stroke had lower melatonin (48.1+/-35.9 pg/ml) and higher cortisol (297.3+/-157.8 nmol/l) at 3 a.m.(p<0.05) but not at 8 a.m.(p>0.05). The stroke was the strongest factor of disturbed nocturnal cortisol (p<0.001) while decreased melatonin depended on the stroke (p=0.010) and gender (p=0.018). In the same time, vice versa, only nocturnal measures were associated with increased probability of presence of stroke (accuracy>75%, p-model<0.001). Thus, a hypothesis that a decrease of melatonin with 1.0 pg/ml might be associated with >2% increase in the probability of presence of stroke [adjusted odds ratio = 1.020 (95%CI 1.002-1.037)] was also suggested. ROC curve (0.67, p=0.0119) and optimisation techniques indicated that a novel best cut-off<51.5 pg/ml for decreased nocturnal melatonin in the view of the presence of stroke (odds ratio = 3.12, p=0.0463) might exist. The classification performance of such cut-off might be confirmed by existing nocturnal melatonin and cortisol differences between the sub-groups; potential differences in diurnal melatonin were also suggested. In conclusion, a novel melatonin cut-off of 51.5 pg/ml may be associated with the presence of ischaemic stroke. As a single marker (84% sensitivity, 74% specificity), its hypothesised modelling performance was independent of age, gender and cortisol. These new results, including the suggested hypothesis, might be further tested in follow-up (cohort), longitudinal studies and be applied to further explore melatonin disturbances as targets in high-risk pre-stroke and post-stroke patients.

Background/Aims: Risk of ischaemic stroke (IS) was associated with total homocysteine (tHCY). On the other hand, serum selenium (Se) exhibited anti-aging and cardiopreventive effects. Se and tHCY showed relationships in animals but these were contradictory or inconclusive in humans; therefore, we searched for such associations in acute IS. Methods: Ninety-four participants aged around 47 years were identified and 39 patients versus 46 healthy controls were analysed. Clinical, laboratory (blinded) and risk factor questionnaire methods were used. Comparison, correlation and multifactorial regression analyses were applied. Results: IS patients were similar to controls concerning age and gender. IS was prevalent in the carotid system (76.9%); 82.1% had a subacute onset. IS patients expressed higher tHCY (14.65 +/- 9.79 mumol/l) and lower Se levels (1.3 +/- 0.5 mumol/l). Twice as many IS patients (23%) had optimal Se levels of <1.01 mumol/l. Subjects with hyperhomocysteinaemia (tHCY >/=15 mumol/l) showed lower Se levels during IS; Se accounted for 15.4% of tHCY variations (R =-0.393; p = 0.015) with unit change increasing tHCY by 8.25 units. Se remained predictive of tHCY levels after adjustments (vitamin B(6), fibrinogen, triglycerides). Conclusions: Lower Se was observed during acute IS, being inversely associated with and predicting increased tHCY levels. Of note, there were more IS patients with suboptimal Se than controls.

Background: Only few follow-up studies have compared the long-term risk of such major vascular events (MVE) as myocardial infarction (MI) and/or stroke following transient ischaemic attack (TIA) or minor ischaemic stroke (MIS). Estimates of relative risk and cumulative long-term occurrence of MVE may provide better information and contribute to the optimization of treatment decisions. Methods: In the current post hoc modelling study with unique data from Bulgaria, we analysed 183 consecutive patients with TIA (n = 89) or MIS (n = 94), aged >40 years, who were prospectively followed over 36 months for non-fatal or fatal MVE. The cumulative survival, hazard and risks (with 95% confidence intervals) for MVE (combined or by stratification) were calculated by Kaplan-Meier analysis and adjusted (age, sex) by multivariate Cox proportional hazard models. A set of regression models was then applied to MVE incidence (per 100 patients; 4-month intervals). Results: Median follow-up was 36 months (interquartile range 30.8-36.0); no differences by age or sex were found (p > 0.05). The risk of non-fatal or fatal MVE was approximately 28%(stroke 19.7%, MI 8.2%). The adjusted cumulative risk of stroke was 0.21 versus 0.10 for MI. The odds ratio of TIA versus MIS was 0.75 (95% CI 0.43-1.32), i.e. lower for stroke (0.63, 0.31-1.25) than for MI (1.12, 0.40-3.14). The risk of non-fatal MVE was higher in MIS than in TIA (p(Breslow)= 0.0497), especially for non-fatal stroke (p = 0.0325). Time series regression models provided best estimates of the different outcome dynamics in TIA versus MIS (R(2)(TIA)= 0.969 with b(power)= 1.04 vs. R(2)(MIS)= 0.989 with b(linear)= 0.84; p(1-tailed)= 0.04) over the study period. Conclusions: The age- and sex-adjusted cumulative 36-month hazard of MVE is higher after MIS than after TIA, but MVE fatality was higher after TIA than after MIS. Although stroke incidence was higher (up to 3 times that of MI), with the highest difference between months 8 and 18, MI fatality was always higher in absolute, relative or adjusted terms. The above alarming patterns and increasing, diverging tendencies for MVE indicate a higher long-term cumulative risk after MIS compared with TIA. These results confirm our hypothesis of a differential risk of TIA versus MIS and, at least, point toward equal importance of therapies aimed at preventing MVE in both types of preceding conditions (TIA or MIS) and the increased fatality after MI, in particular in patients with TIA. Copyright (c) 2008 S. Karger AG, Basel.

BACKGROUND & PURPOSE: Hyperhomocysteinaemia has been postulated to participate in pathogenesis of ischaemic stroke (IS). However, especially in young adults, there is possibility of significantly increased IS risk due to increased normal homocysteinaemia, i.e., hidden (pathologically dormant) prevalence within a healthy, normally-defined range. We performed a post-hoc modelling investigation on plasma total homocysteinaemia (THCY) in gender- and age-matched young patients in the acute IS phase. We evaluated relationships between THCY and prevalence of other potential risk factors in 41 patients vs. 41 healthy controls. METHOD: We used clinical methods, instrumental and neuroimmaging procedures, risk factors examination, total plasma homocysteine measurements and other laboratory and statistical modelling techniques. RESULTS: IS patients and healthy controls were similar not only for matching variables, but also for smoking, main vitamin status, serum creatinine and lipid profile. Patients with IS, however, had lower vitamin B6 levels and higher THCY, fibrinogen and triglycerides (TGL). At multivariate stepwise logistic regression only increased THCY and TGL were significantly and independently associated with the risk for stroke (72% model accuracy, p model=0.001). An increase of THCY with 1.0 micromol/L was associated with 22% higher risk of ischaemic stroke [adjusted OR=1.22 (95%CI 1.03?1.44)]. In this way, novel lower cut-off value for HCY of 11.58 micromol/L in younger patients has been revealed (ROC AUC= 0.67, 95CI% 0.55-0.78, p=0.009). CONCLUSION: The new THCY cut-off clearly discriminated between absence and presence of IS (sensitivity>63%, specificity>68%) irrespectively of age and gender and may be applied to better evaluate and more precisely define, as earlier as possible, the young patients at increased IS risk.

Background Women with cystic fibrosis are at increased risk for mucoid conversion of Pseudomonas aeruginosa, which contributes to a sexual dichotomy in disease severity. Methods We evaluated the effects of estradiol and its metabolite estriol on P. aeruginosa in vitro and in vivo and determined the effect of estradiol on disease exacerbations in women with cystic fibrosis. Results Estradiol and estriol induced alginate production in P. aeruginosa strain 01 and in clinical isolates obtained from patients with and those without cystic fibrosis. After prolonged exposure to estradiol, P. aeruginosa adopted early mucoid morphology, whereas short-term exposure inhibited bacterial catalase activity and increased levels of hydrogen peroxide, which is potentially damaging to DNA. Consequently, a frameshift mutation was identified in mucA, a key regulator of alginate biosynthesis in P. aeruginosa. In vivo levels of estradiol correlated with infective exacerbations in women with cystic fibrosis, with the majority occurring during the follicular phase (P<0.05). A review of the Cystic Fibrosis Registry of Ireland revealed that the use of oral contraceptives was associated with a decreased need for antibiotics. Predominantly nonmucoid P. aeruginosa was isolated from sputum during exacerbations in the luteal phase (low estradiol). Increased proportions of mucoid bacteria were isolated during exacerbations occurring in the follicular phase (high estradiol), with a variable P. aeruginosa phenotype evident in vivo during the course of the menstrual cycle corresponding to fluctuating estradiol levels. Conclusions Estradiol and estriol induced mucoid conversion of P. aeruginosa in women with cystic fibrosis through a mutation of mucA in vitro and were associated with selectivity for mucoid isolation, increased exacerbations, and mucoid conversion in vivo.(Funded by the Molecular Medicine Ireland Clinician-Scientist Fellowship Programme.).

Allergies are generally thought to be a detrimental outcome of a mistargeted immune response that evolved to provide immunity to macroparasites. Here we present arguments to suggest that allergic immunity has an important role in host defence against noxious environmental substances, including venoms, haematophagous fluids, environmental xenobiotics and irritants. We argue that appropriately targeted allergic reactions are beneficial, although they can become detrimental when excessive. Furthermore, we suggest that allergic hypersensitivity evolved to elicit anticipatory responses and to promote avoidance of suboptimal environments.

The action of anti-inflammatory and anti-allergic drugs that act on the eicosanoid system is briefly reviewed. In addition to the aspirin-like drugs, which directly inhibit the cyclo-oxygenase enzymes, other drugs such as the glucocorticoids and the cromones also inhibit the formation of eicosanoids. In the latter cases this is bought about through the release of a protein factor that acts through formyl peptide receptors on the target cell surface. Of growing interest, is the observation that this receptor is also a target for other eicosanoids, such as lipoxins and resolvin that modulate host defence systems.

Three main subtypes of gliomas with distinct molecular pathologies have been modeled in animals to better understand their biology. Genetically engineered mouse models that take advantage of genetic abnormalities observed in human gliomas have been instrumental in this process. These models better recapitulate signaling transduction pathways and the microenvironment that play crucial roles in glioma formation than in vitro systems or transplantation models. An increasing amount of data supports the existence of cells functionally defined by their self-renewal ability and tumor-initiating potential upon serial transplantation. As the issue of these cells with stem cell character in gliomagenesis becomes more illusive, animal models that provide an accurate experimental system where the stem cell character can be manipulated and studied are urgently needed. This review provides an overview of the current state of the literature with respect to animal models used in the study of gliomas and cells with stem cell character in their native environment.

The destruction of pluripotent stem cell-derived grafts by the host immune system presents a significant barrier to clinical translation of cell therapies. Pearl et al.(2011) report in this issue of Cell Stem Cell that a brief, nontoxic immunosuppressive regimen, achieved by blockade of leucocyte costimulatory pathways, may overcome this problem.

Molecular gradients play an important role in diverse physiological and pathological phenomena such as immune response, wound healing, development and cancer metastasis. In the past 10 years, engineering tools have been increasingly used to develop experimental platforms that capture important aspects of cellular microenvironments to allow quantitative and reproducible characterization of cellular response to gradients. This review discusses the emergence of microfluidics-based gradient generators and their applications in enhancing our understanding of fundamental biological processes such as chemotaxis and morphogenesis. The principles and applications of microfluidic gradient generation in both 2D and 3D cellular microenvironments are discussed with emphasis on approaches to manipulate spatial and temporal distribution of signaling molecules.

Mesenchymal stem cells (MSCs) have huge potential to be used in cell therapies because of their pluripotency and immunoregulatory attributes. To harness and maximize the therapeutic potential of MSCs, a thorough understanding of their differentiation pathways and their responses to the microenvironment is needed. The matrix that the cells reside on is an important microenvironmental cue, not only for its chemical components but also for its physical properties. The rigidity and topography of the matrix are two physical factors that are crucial in directing cell behavior. In this chapter, we describe the isolation, culture, and characterization of MSCs. Then we illustrate the procedure of creating different matrix rigidities using acrylamide gels for MSC differentiation study. Finally, we describe how to create MSC-seeded vascular grafts using scaffolds with nano topographical features.

Dendritic cells (DCs) are key antigen-presenting cells that induce primary and memory immune response. Patients with chronic infections or cancer often display DC dysfunctions. Modification of DCs or DC progenitors in vitro may overcome the problems with defective DCs in vivo. Lentiviral vector is highly efficient in transducing hematopoietic cells including DCs. Examples of lentiviral modification of DCs with immune modulatory genes and analysis of antigen-specific T cells to demonstrate enhanced immune effector functions of DCs will be introduced.

Current evidence regarding potentially different host response mechanisms in sepsis according to the type of initiating infection is sporadic. It is possible that alterations in cell populations, variations in effector molecules, and the degree of apoptosis differ between sepsis caused by ventilator-associated pneumonia (VAP) and non-VAP sepsis. VAP is one of the most common infections and leading causes of sepsis in the intensive care unit, and mortality remains high. A better understanding of the unique pathophysiologic features of VAP is needed in order to develop interventions that target those specific pathways.

A complex and multilayered immune defence system protects the host against harmful agents and maintains tissue homeostasis. Cigarette smoke ex posure markedly impacts the immune system, compromising the host's ability to mount appropriate immune and inflammatory responses and contributing to smoking-related pathologies. These adverse effects on the immune system not only occur in active smokers, but also in those exposed to smoke passively in contaminated environments, and may persist for decades after exposure has ended.

The hypothesis of an autovaccine for HIV is borne out by:(1) the present lack of a valid vaccine;(2) by a remarkable improvement of the HAART, which however does not prevent HIV mutagenicity and a consequent valid immunological response and (3) the persistence of a hidden infection ready to thrive again. The preparation of the autovaccine is described as well as the administration schedule but only a clinical study will define its validity.