Th17 Cell and Inflammatory Infiltrate Interactions in Cutaneous Leishmaniasis: Unraveling Immunopathogenic Mechanisms.

The inflammatory response during cutaneous leishmaniasis (CL) involves immune and non-immune cell cooperation to contain and eliminate Leishmania parasites. The orchestration of these responses is coordinated primarily by CD4+ T cells; however, the disease outcome depends on the Th cell predominant phenotype. Although Th1 and Th2 phenotypes are the most addressed as steers for the resolution or perpetuation of the disease, Th17 cell activities, especially IL-17 release, are recognized to be vital during CL development. Th17 cells perform vital functions during both acute and chronic phases of CL. Overall, Th17 cells induce the migration of phagocytes (neutrophils, macrophages) to the infection site and CD8+ T cells and NK cell activation. They also provoke granzyme and perforin secretion from CD8+ T cells, macrophage differentiation towards an M2 phenotype, and expansion of B and Treg cells. Likewise, immune cells from the inflammatory infiltrate have modulatory activities over Th17 cells involving their differentiation from naive CD4+ T cells and further expansion by generating a microenvironment rich in optimal cytokines such as IL-1ß, TGF-ß, IL-6, and IL-21. Th17 cell activities and synergies are crucial for the resistance of the infection during the early and acute stages; however, if unchecked, Th17 cells might lead to a chronic stage. This review discusses the synergies between Th17 cells and the inflammatory infiltrate and how these interactions might destine the course of CL.

Th17 Cell and Inflammatory Infiltrate Interactions in Cutaneous Leishmaniasis: Unraveling Immunopathogenic Mechanisms

The inflammatory response during cutaneous leishmaniasis (CL) involves immune and nonimmune cell cooperation to contain and eliminate Leishmania parasites. The orchestration of these responses is coordinated primarily by CD4 + T cells; however, the disease outcome depends on the Th cell predominant phenotype. Although Th1 and Th2 phenotypes are the most addressed as steers for the resolution or perpetuation of the disease, Th17 cell activities, especially IL-17 release, are recognized to be vital during CL development. Th17 cells perform vital functions during both acute and chronic phases of CL. Overall, Th17 cells induce the migration of phagocytes (neutrophils, macrophages) to the infection site and CD8 + T cells and NK cell activation. They also provoke granzyme and perforin secretion from CD8 + T cells, macrophage differentiation towards an M2 phenotype, and expansion of B and Treg cells.Likewise, immune cells from the inflammatory infiltrate have modulatory activities over Th17 cells involving their differentiation from naive CD4 + T cells and further expansion by generating a microenvironment rich in optimal cytokines such as IL-1β, TGF-β, IL-6, and IL-21. Th17 cell activities and synergies are crucial for the resistance of the infection during the early and acute stages; however, if unchecked, Th17 cells might lead to a chronic stage. This review discusses the synergies between Th17 cells and the inflammatory infiltrate and how these interactions might destine the course of CL.

Neutrophil extracellular trap-associated molecules: a review on their immunophysiological and inflammatory roles.

Neutrophil extracellular traps (NETs) are a defense mechanism against pathogens. They are composed of DNA and various proteins and have the ability to hinder microbial spreading and survival. However, NETs are not only related to infections but also participate in sterile inflammatory events. In addition to DNA, NETs contain histones, serine proteases, cytoskeletal proteins and antimicrobial peptides, all of which have immunomodulatory properties that can augment or decrease the inflammatory response. Extracellular localization of these molecules alerts the immune system of cellular damage, which is triggered by recognition of damage-associated molecular patterns (DAMPs) through specific pattern recognition receptors. However, not all of these molecules are DAMPs and may have other immunophysiological properties in the extracellular space. The release of NETs can lead to production of pro-inflammatory cytokines (due to TLR2/4/9 and inflammasome activation), the destruction of the extracellular matrix, activation of serine proteases and of matrix metallopeptidases (MMPs), modulation of cellular proliferation, induction of cellular migration and adhesion, promotion of thrombogenesis and angiogenesis and disruption of epithelial and endothelial permeability. Understanding the dynamics of NET-associated molecules, either individually or synergically, will help to unravel their role in inflammatory events and open novel perspectives for potential therapeutic targets. We here review molecules contained within NETS and their immunophysiological roles.

Artificial intelligence based model for optimization of COD removal efficiency of an up-flow anaerobic sludge blanket reactor in the saline wastewater treatment.

The complex non-linear behavior presented in the biological treatment of wastewater requires an accurate model to predict the system performance. This study evaluates the effectiveness of an artificial intelligence (AI) model, based on the combination of artificial neural networks (ANNs) and genetic algorithms (GAs), to find the optimum performance of an up-flow anaerobic sludge blanket reactor (UASB) for saline wastewater treatment. Chemical oxygen demand (COD) removal was predicted using conductivity, organic loading rate (OLR) and temperature as input variables. The ANN model was built from experimental data and performance was assessed through the maximum mean absolute percentage error (= 9.226%) computed from the measured and model predicted values of the COD. Accordingly, the ANN model was used as a fitness function in a GA to find the best operational condition. In the worst case scenario (low energy requirements, high OLR usage and high salinity) this model guaranteed COD removal efficiency values above 70%. This result is consistent and was validated experimentally, confirming that this ANN-GA model can be used as a tool to achieve the best performance of a UASB reactor with the minimum requirement of energy for saline wastewater treatment.

Study of different carbon materials for their use as bioanodes in microbial fuel cells.

Microbial fuel cells (MFCs) are capable of removing the organic matter contained in water while generating a certain amount of electrical power at the same time. One of the most important aspects in the operation of MFCs is the formation of biofilms on the anode. Here, we report the characterization of different carbon electrodes and biofilm using a rapid and easy methodology for the growth of biofilms. The biofilms were developed and generated a voltage in less than 4 days, obtaining a maximum of 0.3 V in the cells. Scanning electron microscopy images revealed that growth of the biofilm was only on the surface of the electrode, and consequently both carbon cloth Electrochem and carbon cloth Roe materials showed a greater quantity of volatile solids on the surface of the anode and power density. The results suggested that the best support was carbon cloth Electrochem because it generated a power density of 13.4 mW/m(2) and required only a few hours for the formation of the biofilm.

Odor is a time cue for circadian behavior.

Many physiological and behavioral processes such as sleep and wakefulness, hormone secretion, and olfactory sensitivity exhibit a 24-h rhythmicity that persists in constant conditions with a period close to (circa) 24 h. These circadian rhythms are driven by a network of endogenous clocks residing in various tissues, including the olfactory system, and are synchronized to the outside world by environmental time cues such as light, temperature, and food. In addition to having these well-known zeitgebers of circadian clocks, most environments consist of a multitude of odors that report, for example, the availability of food or the presence of predators--and often, they do so in a time-of-day-dependent manner. Considering the evolutionary significance of odors for various fitness-related behaviors such as mate choice, predator avoidance, and foraging strategies, we asked whether odors--similar to light, temperature, or food--might act as a circadian time cue able to influence circadian locomotor behavior in mammals. Administering individual air flow, periodically saturated with an artificial odor mix, to running wheel-equipped mouse cages, we found that rhythmic odor administrations significantly lengthened the period of circadian activity rhythms. Additionally, odor cues led to partial reemergence of circadian locomotor rhythmicity in suprachiasmatic nuclei (SCN)-lesioned mice, suggesting that the SCN as the central circadian pacemaker are not immediately required for odor-mediated effects on circadian behavior. However, odor-based modulation of circadian behavior did not occur in clock mutant (cry1(-/-) /cry2(-/-)) mice, indicating an odor-mediated mechanism that involves extra-SCN canonical clocks, such as the olfactory clock itself. Our results indicate not only that odor stimuli can act as a circadian time cue modulating circadian behavior but also that odor effects are even more pronounced in the absence of the SCN but nevertheless require the presence of a functional canonical clock.

Annual change in insulin sensitivity.

The incidence of both type 2 diabetes and cardiac events is reported to be higher during winter, indicating a putative annual periodic change in insulin sensitivity (IS). Annual differences in IS - quantified as HOMA-%S and Matsuda-Sensitivity Index - were analyzed using a cosine wave-fitting algorithm in a cross-sectional study group including 2 385 participants. Additionally, semi-annual differences in IS were compared. We found periodicity for HOMA-%S and Matsuda-Sensitivity Index (p=0.02 or 0.006), which was strengthened after restriction to participants without diabetes (p=0.009 or 0.004). The rhythm amplitude of 0.08 indicated moderate changes in IS throughout the year. IS was significantly higher when participants were enrolled during the second vs. the first half of the year (HOMA-%S 112.0±3.0% vs. 97.4±2.4%, p<0.001). The impact of the half-year on IS, which remained significant after adjustment for confounders, was again moderate and explained only 0.5% of the variation. IS showed a significant moderate annual periodicity, which may affect the interpretation of studies reporting small changes in IS.

Initial demonstration of rhythmic Per gene expression in the hypothalamus of a non-mammalian vertebrate, the house sparrow.

In mammals, the major pacemaker controlling circadian rhythmicity is located in the hypothalamic suprachiasmatic nuclei which are characterized by specific molecular features including the expression of three homologues of the Drosophila clock gene period (per). Until now, no comparable structure has been unambiguously described in the brain of any non-mammalian vertebrate. We cloned the PAS-domain of the Per2 gene in the house sparrow (Passer domesticus), a model organism in circadian research. Hypothalamic expression of passerPer2 (pPer2) showed a marked diurnal rhythm in the suprachiasmatic nucleus, a cell group located in the anterior hypothalamus directly above the optic chiasm and adjacent to the third ventricle. Additionally, pPer2 was diurnally expressed in the lateral hypothalamus. This first demonstration of rhythmic clock gene expression in the hypothalamus of a non-mammalian vertebrate provides basic information for future research on the evolution of circadian pacemaking systems.

Predictors of coronary disease in patients with end stage renal disease.

Patients with end stage renal disease have a high prevalence of cardiovascular disease and coronary arteriography is often routinely performed prior to kidney transplantation. However, the value of the conventional risk factors and non-invasive markers of coronary artery disease (CAD) in triaging patients for coronary arteriography has not been fully examined. 116 patients with end stage renal disease were evaluated. Coronary arteriography was performed in all patients either for a suspicion of CAD or as part of a routine pre-transplant evaluation. Lesions causing > or = 50% luminal diameter stenosis in any of the three major coronary artery systems were considered significant. The mean age was 53.3 +/- 9.3 years. Significant CAD was present in 69 patients (60%). Increasing age, family history of premature ischemic heart disease, the presence of angina, abnormal Q waves on the ECG or abnormal ST segment depression and the presence of coronary calcification were significant markers of coronary artery disease. However male gender, diabetes mellitus and obesity did not correlate with coronary disease. Even though hypertension, hypercholesterolemia and smoking were also not useful predictors these could have been modified by the renal failure. In conclusion increasing age, a family history of premature ischemic heart disease and some non-invasive markers were useful predictors of coronary disease.

Photoperiodic information acquired and stored in vivo is retained in vitro by a circadian oscillator, the avian pineal gland.

Endogenous circadian rhythms have been described in a wide range of organisms from prokaryotes to man. Although basic circadian mechanisms at the molecular level are genetically fixed, certain properties of circadian rhythms at the organismic level can be modified by environmental conditions and subsequently retained for some time, even in organisms shielded from 24-hr environmental variations. To investigate the capacity of animals to acquire and store photoperiodic information, we examined activity and melatonin rhythms in house sparrows during synchronization to two different photoperiods and during subsequent prolonged darkness. Under constant environmental conditions, intact animals continued to have long feeding activity times when previously exposed to long days and short feeding activity times when previously exposed to short days. Correspondingly, significantly different durations of elevated melatonin in the plasma directly reflected the differences in night length during synchronization as well as during prolonged darkness. Additionally, we found a significant difference in the amplitude of the nocturnal melatonin signal, which also was conserved in prolonged darkness. To investigate whether the photoperiodic experience of an intact animal can be "memorized" by an isolated component of its circadian pacemaking system, we have investigated in vitro melatonin release during continuous darkness from explanted pineal glands of house sparrows after in vivo synchronization to two distinct photoperiods. Differences in the durations of elevated melatonin occurred during the first two cycles in culture and a difference in melatonin amplitude was detectable during the first night in culture. Our data indicate that photoperiodic patterns imposed on sparrows during in vivo synchronization can be maintained as an internal representation of time within the isolated pineal gland. Hence, the pineal gland, as one of the most significant components of the songbird circadian pacemaker, not only has the capacity to autonomously produce circadian rhythms of melatonin release but also is capable of storing biologically meaningful information experienced during previous cycles.

Exogenous melatonin reduces the resynchronization time after phase shifts of a nonphotic zeitgeber in the house sparrow (Passer domesticus).

Continuous melatonin administration via silastic implants accelerates the resynchronization of the circadian locomotor activity rhythm in house sparrows (Passer domesticus) after exposure to phase shifts of a weak light-dark cycle. Constant melatonin might induce this effect either by increasing the sensitivity of the visual system to a light zeitgeber or by reducing the degree of self-sustainment of the circadian pacemaker. To distinguish between these two possible mechanisms, two groups of house sparrows, one carrying melatonin implants and the other empty implants, were kept in constant dim light and subjected to advance and delay shifts of a 12-h feeding phase. The resynchronization times of their circadian feeding rhythm following the phase shifts were significantly shorter when the birds carried melatonin implants than when they carried empty implants. In a second experiment, melatonin-implanted and control birds were released into food ad libitum conditions 2 days after either a delay or an advance phase shift. The number of hours by which the activity rhythms had been shifted on the second day in food ad libitum conditions was assessed. Melatonin-implanted house sparrows had significantly larger phase shifts in their circadian feeding rhythm than control birds. This is in accordance with the first experiment since a larger phase shift at a given time reflects accelerated resynchronization. Additionally, the second experiment also excludes any possible masking effects of the nonphotic zeitgeber. In conclusion, constant melatonin accelerates resynchronization even after phase shifts of a nonphotic zeitgeber, indicating that constant high levels of melatonin can reduce the degree of self-sustainment of the circadian pacemaker independent of any effects on the photoreceptive system.

Comparative molecular similarity index analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries.

Comparative molecular field analysis has been applied to a data set of thermolysin inhibitors. Fields expressed in terms of molecular similarity indices (CoMSIA) have been used instead of the usually applied Lennard-Jones- and Coulomb-type potentials (CoMFA). Five different properties, assumed to cover the major contributions responsible for ligand binding, have been considered: steric, electrostatic, hydrophobic, and hydrogen-bond donor or acceptor properties. The statistical evaluation of the field properties by PLS analysis reveals a similar predictive potential to CoMFA. However, significantly improved and easily interpretable contour maps are obtained. The features in these maps intuitively suggest where to modify a molecular structure in terms of physicochemical properties and functional groups in order to improve its binding affinity. They can also be interpreted with respect to the known structural protein environment of thermolysin. Most of the highlighted regions in the maps are mirrored by features in the surrounding environment required for binding. Using the derived correlation model, different members of a combinatorial library designed for thermolysin inhibition have been scored for affinity. The results obtained demonstrate the prediction power of the CoMSIA method.

Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity.

An alternative approach is reported to compute property fields based on similarity indices of drug molecules that have been brought into a common alignment. The fields of different physicochemical properties use a Gaussian-type distance dependence, and no singularities occur at the atomic positions. Accordingly, no arbitrary definitions of cutoff limits and deficiencies due to different slopes of the fields are encountered. The fields are evaluated by a PLS analysis similar to the CoMFA formalism. Two data sets of steroids binding to the corticosteroid-binding-globulin and thermolysin inhibitors were analyzed in terms of the conventional CoMFA method (Lennard-Jones and Coulomb potential fields) and the new comparative molecular similarity indices analysis (CoMSIA). Models of comparative statistical significance were obtained. Field contribution maps were produced for the different models. Due to cutoff settings in the CoMFA fields and the steepness of the potentials close to the molecular surface, the CoMFA maps are often rather fragmentary and not contiguously connected. This makes their interpretation difficult. The maps obtained by the new CoMSIA approach are superior and easier to interpret. Whereas the CoMFA maps denote regions apart from the molecules where interactions with a putative environment are to be expected, the CoMSIA maps highlight those regions within the area occupied by the ligand skeletons that require a particular physicochemical property important for activity. This is a more significant guide to trace the features that really matter especially with respect to the design of novel compounds.

On the prediction of binding properties of drug molecules by comparative molecular field analysis.

Comparative molecular field analysis (CoMFA) has been applied to three different data sets of drug molecules binding to human rhinovirus 14 (HRV14), thermolysin and renin, respectively. Different structural alignments have been tested to predict binding properties. An alignment based on crystallographically determined coordinates of the inhibitors bound to the proteins has been compared with alignments obtained from multiple-fit and field-fit procedures. These methods are commonly used for systems where no reference to protein structural data is available. For HRV14, two different models, one based on experimental evidence and one based on a hypothetical alignment reveal moderate predictions of the binding constant of comparable quality. For thermolysin, hypothetical alignments allow a substantially better prediction than an alignment based on experimental evidence. The prediction of binding properties (expressed as delta G, delta H, and delta S) of renin inhibitors, which were aligned on the basis of crystallographic data from related inhibitors bound to the aspartyl protease endothiapepsin, gives evidence that only enthalpies (delta H) and not free enthalpies (delta G) or binding constants can be properly predicted by comparative molecular field analysis.

[Results of nuclear medical, electroencephalographic, and angiographic examinations after brain tumor operations]. / Ergebnisse nuklearmedizinischer, elektroenzephalographischer und angiographischer Untersuchungen nach Hirntumoroperationen

The methods of nuclear medicine and electro-encephalography allow, in combination, in almost every case the answer to the question of the cerebral tumour relapse. Our evaluation confirms the discovery of the greater sensitivity of the isotopic methods with relapses of glioblastomas, while relapses of meningiomas, astrocytomas, oligodendrogliomas and spongioblastomas can be recognized more frequently only by electro-encephalographic methods. The value of angiography is limited in cases of cerebral tumour relapses without pathological vascularisation, since the swelling can spread in the resection cavity without retroaction on the surrounding areas. For this reason vascular displacement (an only be observed very late on. Clinical judgement is furthermore complicated by the fact that after the removal of the primary tumour, often no reposition of the arteries ensues. After our exainations, a negative angiographic condition can be rule out a diagnosis of a relapse which has been established by electro-encephaolographic and isotopic methods.