Preparation of dendritic cells for cancer immunotherapy

Development of new effective method for cancer therapy is one of the most important trends in the modern medicine. Along with surgery, chemotherapy and radiotherapy, induction of an immune response against the tumor cells is a promising approach for therapy of cancer, particularly metastatic, slowly dividing tumors and cancer stem cells. Induction of the antitumor T-cell immune response involves activation of antigen-presenting cells, which can efficiently present the cancer antigens and activate T-lymphocytes. The immune response may be activated by dendritic cells (DC) loaded with tumor antigens, such as tumor-specific proteins, tumor cell lysates, apoptotic or necrotic tumor cells, as well as nucleic acids encoding tumor antigens. Regardless of the selected source of the tumor antigen, preparation of mature DC is a principal step in the development of anticancer vaccines aimed at the induction of the cytotoxic T-cell immune response. Recently, various research groups have proposed several strategies for producing mature DC, differed by the set of agents used. It has been shown that the maturation strategy influences both their phenotype and the ability to induce the immune response. In this review we have analyzed the results of studies on the various strategies of preparation of mature DCs.     

Intraspecific,size-dependent variation in the movement behaviour of a brackish-water isopod: a resource-free laboratory experiment

Intraspecific variability represents an important, yet inadequately investigated factor affecting the movement behaviour and ecology of mobile organisms. Here, the influence of sex, seasonality and body size on the movement behaviour of the brackish isopod Lekanesphaera hookeri were examined under resource-free laboratory conditions. The mean step length, total path length and average speed were determined twice during the year for adult and juvenile isopods encompassing a 10-fold range in body length. The scale-independent fractal dimension D was used to quantify the tortuosity of the movement paths. No relationships were observed between sex or season and all the movement metrics. In contrast, isopods' body size scaled negatively with the fractal dimension D of movement paths with a breakpoint at 2.6 mm, roughly corresponding to the size of morphometric maturation. No other relationships were observed between the body length of isopods and mean step length, total path length and average speed. The results indicate a sex- and season-independent ontogenetic shift in movement behaviour in L. hookeri. This suggests that in sphaeromatid isopods post-embryonic development determines not only continuous variations in size and proportions, but also a discontinuous change in the movement strategy adopted to interact with the surrounding space. Overall, these findings underscore the need to account explicitly for such changes in models predicting the spatial distribution of organisms characterised by wide intra-population size variation.     

Progressing a human embryonic stem-cell-based regenerative medicine therapy towards the clinic

Since the first publication of the derivation of human embryonic stem cells in 1998, there has been hope and expectation that this technology will lead to a wave of regenerative medicine therapies with the potential to revolutionize our approach to managing certain diseases. Despite significant resources in this direction, the path to the clinic for an embryonic stem-cell-based regenerative medicine therapy has not proven straightforward, though in the past few years progress has been made. Here, with a focus upon retinal disease, we discuss the current status of the development of such therapies. We also highlight some of our own experiences of progressing a retinal pigment epithelium cell replacement therapy towards the clinic.     

Advising Patients on the Use of Complementary and Alternative Medicine

Complementary and alternative medicine (CAM) is an area of great public interest and activity, both nationally and worldwide. Many alternative medical practices have existed for hundreds, even thousands of years. Patients and professionals are turning to CAM for a variety of reasons. Most have tried conventional medicine for a particular (usually chronic) medical condition and have found the results inadequate. Some are concerned over the side effects of conventional therapies. Some are seeking out a more “holistic” orientation in health care where they can address body, mind, and spirit. A continuing challenge will be how to address CAM services that are based on time, practitioner–patient interactions, and self-care, using modern standards of evidence, education, licensing, and reimbursement. For most CAM therapies, there is insufficient research to say definitively that it works and CAM research is especially limited in the area of cancer. Given that situation, the questions (but not answers) facing the medical practitioner are clear-cut. Should the practitioner await the definitive results of formal Phase III randomized clinical trials, or should the practitioner rely on limited data, seeking out evidence that makes physiological sense and small trials that seem to offer some benefit to the patient? When and at what point do you discourage, permit, or recommend an available alternative therapy? The answers are not simple. There may be differences of opinion and values among the patient, the practitioner, and the organizations that pay for a therapy. CAM areas should be approached with every patient who enters the office recognizing that there are precautions to consider when patients are using, or plan to use, such therapies. This paper presents a broad survey of what complementary and alternative medicine is from the perspectives of both the public as user and the conventional medical practitioner, as well as provides examples of issues pertinent to understanding and evaluating research in CAM. The past is back and the future will involve integration of modern and ancient ways.     

Predictive diagnostics and personalized medicine for the prevention of chronic degenerative diseases

Progressive increase of mean age and life expectancy in both industrialized and emerging societies parallels an increment of chronic degenerative diseases (CDD) such as cancer, cardiovascular, autoimmune or neurodegenerative diseases among the elderly. CDD are of complex diagnosis, difficult to treat and absorbing an increasing proportion in the health care budgets worldwide. However, recent development in modern medicine especially in genetics, proteomics, and informatics is leading to the discovery of biomarkers associated with different CDD that can be used as indicator of disease's risk in healthy subjects. Therefore, predictive medicine is merging and medical doctors may for the first time anticipate the deleterious effect of CDD and use markers to identify persons with high risk of developing a given CDD before the clinical manifestation of the diseases. This innovative approach may offer substantial advantages, since the promise of personalized medicine is to preserve individual health in people with high risk by starting early treatment or prevention protocols. The pathway is now open, however the road to an effective personalized medicine is still long, several (diagnostic) predictive instruments for different CDD are under development, some ethical issues have to be solved. Operative proposals for the heath care systems are now needed to verify potential benefits of predictive medicine in the clinical practice. In fact, predictive diagnostics, personalized medicine and personalized therapy have the potential of changing classical approaches of modern medicine to CDD.     

Experimental simulation in behavioral ecology: a multimedia approach with the spatial searching simulation RattleSnake?

Searchers in nature often have accurate knowledge of the spatial location of the resource targets they seek, though in many other cases they have none. For example, the spatial distribution of targets such as food patches or potential mates may shift or change unpredictably from season to season. Searchers encountering circumstances of these sorts may be said to be “naive”. This problem is compounded by the fact that spatial distributions of targets may vary statistically as well: they may be distributed randomly, uniformly, or they may be clustered. Accordingly, since we study an animal system in nature that encounters such challenges (i.e., free-ranging rattlesnakes in many parts of their range), we wrote a comprehensive spatial searching program for Macintosh systems that simulates this problem thoroughly, RattleSnake^©. In a large series of experimental simulations using this software, we found that search paths of high vector magnitude (approaching 1.0), or those that approached straight lines, generated large numbers of collisions in large, clustered worlds. No search path was any better than any other in large, randomly or uniformly distributed worlds. Zig-zag paths of low vector magnitude (approaching zero) in small worlds of all types and of all densities were efficacious, due to continuous turning which prevented searchers from moving out of or exiting patches. Thus it appears that there are design rules in nature governing target collision probabilities in some but not all two-dimensional spatial worlds. Search paths of high vector magnitude, or those approaching straight lines, generate high collision frequencies in statistically clustered spatial worlds, for example. RattleSnake^© thus may be useful in programs of basic and/or applied behavioral ecology, including conservation, as well as in laboratory and multimedia classroom education.Electronic supplementary material Electronic supplementary material is available for this article at and accessible for authorised users.     

Control of Heparin Therapy

Heparin therapy in 114 patients was controlled by daily blood tests—the whole blood coagulation time, kaolin-activated partial thromboplastin time of plasma, and plasma heparin assay. Bleeding episodes occurred in 7 out of 92 patients (7·6%) who had normal haemostatic mechanisms before therapy and in 11 out of 22 patients (50%) with defective haemostasis, mostly due to intravascular coagulation or renal failure. The dose of heparin ranged from 20,000 to 60,000 units in each 24-hour period. In some patients bleeding was related to overdosage, but in others the laboratory tests indicated satisfactory or suboptimal dosage at the time of bleeding. Though there were positive correlations between the results of the three tests, these were not close, and no one test was preferable. Hence laboratory control of heparin therapy is unsatisfactory and patients may bleed despite careful control of the dose by all three methods.     

Homosexual Mating Displays in Penguins

More than 50 yr ago, field studies recorded the same‐sex pairs (and trios) of penguins displaying to each other during the mating season, using behavior patterns typical of heterosexual mating displays. Such observations led to a hypothesis that due to a lack of sex recognition pairing occurs at random with respect to sex, an idea countered by the argument that sex recognition is highly accurate. No quantification of same‐sex mating displays has tested the frequency of such displays in penguins or tested the hypothesis of random display partners with respect to sex. During their mating season, we studied displaying and paired king penguins, Apenodytes patagonicus, at Kerguelen Island and sexed them using a DNA marker, to quantify any occurrence of this behavior. Indeed, same‐sex courtship displays were common (28.3% of 53 displaying pairs), the great majority of which were between males. Some homosexually displaying males eventually paired with females, but such males were significantly slower in heterosexual pairing than males that did not display homosexually. In two extraordinary cases, same‐sex pairs learned each other’s calls, an essential step in the pairing process. The frequency of such pairs was much lower than among displaying couples, significantly so for males. Finally, the frequency of homosexually displaying pairs was significantly lower than expected from random assortment of displaying birds, for both males and females. We examined possible explanations for same‐sex display and its biological significance. A population sex‐ratio bias in favor of males and high concentration of male sex hormones may help to explain non‐reproductive homosexually displaying pairs.     

Transplantation and its biology: from fantasy to routine.

The replacement of diseased organs and tissues by the healthy ones of others has been a unique milestone in modern medicine. For centuries, transplantation remained a theme of fantasy in literature and the arts. Within the past five decades, however, it has developed from a few isolated attempts to salvage occasional individuals with end-stage organ failure to a routine treatment for many patients. In parallel with the progressive improvements in clinical results has come an explosion in immunology, transplantation biology, immunogenetics, cell and molecular biology, pharmacology, and other relevant biosciences, with knowledge burgeoning at a rate not dreamed of by the original pioneers. Indeed, there have been few other instances in modern medicine in which so many scientific disciplines have contributed in concert toward understanding and treating such a complex clinical problem as the failure of vital organs. The field has been a dramatic example of evolution from an imagined process to an accepted form of therapy.     

Precision medicine in human heart modeling

Precision medicine is a new frontier in healthcare that uses scientific methods to customize medical treatment to the individual genes, anatomy, physiology, and lifestyle of each person. In cardiovascular health, precision medicine has emerged as a promising paradigm to enable cost-effective solutions that improve quality of life and reduce mortality rates. However, the exact role in precision medicine for human heart modeling has not yet been fully explored. Here, we discuss the challenges and opportunities for personalized human heart simulations, from diagnosis to device design, treatment planning, and prognosis. With a view toward personalization, we map out the history of anatomic, physical, and constitutive human heart models throughout the past three decades. We illustrate recent human heart modeling in electrophysiology, cardiac mechanics, and fluid dynamics and highlight clinically relevant applications of these models for drug development, pacing lead failure, heart failure, ventricular assist devices, edge-to-edge repair, and annuloplasty. With a view toward translational medicine, we provide a clinical perspective on virtual imaging trials and a regulatory perspective on medical device innovation. We show that precision medicine in human heart modeling does not necessarily require a fully personalized, high-resolution whole heart model with an entire personalized medical history. Instead, we advocate for creating personalized models out of population-based libraries with geometric, biological, physical, and clinical information by morphing between clinical data and medical histories from cohorts of patients using machine learning. We anticipate that this perspective will shape the path toward introducing human heart simulations into precision medicine with the ultimate goals to facilitate clinical decision making, guide treatment planning, and accelerate device design.

     

The contribution of traditional healers' clinics to public health care system in Addis Ababa, Ethiopia: a cross-sectional study

Background

In practically every human culture, the use of arthropods as medicinal resources has been reported. In Mexico, the Mayan people mainly use plants but occasionally also animals and minerals in their medicine. This article is the first to report the traditional use of the tarantula Brachypelma vagans by medicine men in the Chol community, an ancient indigenous group that inhabits the southeastern part of Mexico. We also describe the utility of such arachnids in traditional medicine.

Methods

This study was carried out in different Chol communities in the states of Chiapas and Campeche (southeastern Mexico) from 2003 until 2007. We interviewed the local medicine men, patients and non-Chol people in each village visited to collect information about the rituals involved and the effectiveness of this traditional medicine and also their opinion of this traditional medicine.

Results

In all independent villages, the people who present an illness called 'aire de tarantula' or tarantula wind with symptoms including chest pain, coughing and asthma, were treated by the medicine man (called 'hierbatero') with a tarantula-based beverage. From village to village, the beverage has a similar base composition but some variations occur in additional ingredients depending on the individual medicine man. Like in all traditional Mayan medicine, the ritual of the ceremony consists of drinking the tarantula-based beverage and this is principally accompanied by chants and burning of incense.

Conclusions

The recipe of the tarantula-based beverage and the procedure of this ritual ceremony were fairly constant in all the villages visited. Our work shows that despite the tarantula's bad image in several cultures, in others positive use is made of these spiders, as in modern medicine.     

Addressing the influence of instrument surface heat exchange on the measurements of CO2 flux from open-path gas analyzers

There is a growing concern in the flux community that using the eddy covariance method with open‐path CO₂ analyzers often leads to measurements of an apparent ecosystem CO₂ uptake during off‐season periods, especially in cold climates. Such uptake has not been observed when measurements were made with closed‐path analyzers, chambers, or profile methods, suggesting it is an artifact due in some way to the use of open‐path analyzers. In this study, a series of laboratory tests and field experiments were conducted to determine the magnitude of the instrument surface heat exchange in the open path and its relationship with the measured CO₂ flux. Results showed that (1) the surface of an open‐path instrument became substantially warmer than ambient due to electronics and radiation load during daytime, while at night, radiative cooling moderated temperature increases in the path; (2) high‐frequency temperature measurements inside the path were correlated with vertical wind speed producing sensible heat flux inside the instrument path exceeding the ambient heat flux by up to 14%; (3) enclosing the open‐path instrument eliminated the sensible heat flux in the path, and caused measured CO₂ flux to match a closed‐path reference; (4) using sensible heat flux measured directly inside the open path in the WPL term instead of the ambient sensible heat flux also led to a match in CO₂ flux between open‐path instrument and closed‐path reference; and (5) correcting previously collected open‐path CO₂ flux data was possible by estimating the instrument heating effect with a semi‐empirical model using standard weather variables. Results showed that all proposed techniques led to a significant reduction in apparent CO₂ uptake during off‐season periods and to a reduction of the underestimation of CO₂ release in other periods. Close agreement between the open‐path measurements and closed‐path references was achieved in all cases.     

Settlement Dynamics of the Encrusting Epibenthic Macrofauna in Two Creeks of the Caeté Mangrove Estuary (North Brazil)

The epibenthic encrusting fauna of 2 creeks of the Caeté mangrove estuary, northern Brazil, was studied over a 13 month period using collectors fixed at 2.5 and 3.5 m above the creek bottom and in which upper and lower sides of ceramic and wooden panels were used as settlement substrates. The number of individuals of the most abundant organisms (barnacles, oysters and mussels) settling per panel was determined each month, for each substrate type, panel orientation and height above creek bottom. The barnacle, Fistulobalanus citerosum has a peak settlement period during the wet season whereas both peaks in the numbers of settlers of the oyster Crassostrea rhizophorae were recorded during the dry season and such discrete temporal patterns in settlement have also been observed for barnacles and oysters in other mangroves and estuaries. In contrast to other studies, settlement of the mussel Mytella falcata was generally low during the study period and may be related to over-exploitation of stocks in the region. Overall, settler density was usually greater on the underside of ceramic panels close to the creek bottom, similar to results of other studies of epibenthic settlement in diverse habitats.     

Sequence-dependent DNA structure: a database of octamer structural parameters

We have constructed the potential energy surfaces for all unique tetramers, hexamers and octamers in double helical DNA, as a function of the two principal degrees of freedom, slide and shift at the central step. From these potential energy maps, we have calculated a database of structural and flexibility properties for each of these sequences. These properties include: the values of each of the six step parameters (twist roll, tilt, rise, slide and shift), for each step of the sequence; flexibility measures for both decrease and increase in each property value from the minimum energy conformation for the central step; and the deviation from the path of a hypothetical straight octamer. In an analysis of structural change as a function of sequence length, we observe that almost all DNA tends to B-DNA and becomes less flexible. A more detailed analysis of octamer properties has allowed us to determine the structural preferences of particular sequence elements. GGC and GCC sequences tend to confer bistability, low stability and a predisposition to A-form DNA, whereas AA steps strongly prefer B-DNA and inhibit A-structures. There is no correlation between flexibility and intrinsic curvature, but bent DNA is less stable than straight. The most difficult deformation is undertwisting. The TA step stands out as the most flexible sequence element with respect to decreasing twist and increasing roll. However, as with the structural properties, this behavior is highly context-dependent and some TA steps are very straight.     

园艺疗法探讨

起源于 1 7世纪末的园艺疗法 ,经过欧美 ,日本等国相关科技人员的研究 ,证实它对残疾人 ,精神病患者 ,智力低下者 ,高龄老人等患者均有不同的疗效 ,是对现代医学的补充和完善。在分析国外园艺疗法的研究进展和国内实施园艺疗法的优劣势基础上 ,提出了我国建立园艺疗法的几点建议。     

Seasonal variation in association patterns of wild spider monkeys (<Emphasis Type="Italic">Ateles belzebuth belzebuth</Emphasis>) at La Macarena,Colombia

Spider monkeys exhibit a fission–fusion type of social organization. I studied party size and party composition in wild long-haired spider monkeys (Ateles belzebuth belzebuth) in three study periods at La Macarena, Colombia and found that overall party size was larger in the fruit-abundant season. Mean party size in which males were observed was relatively stable across seasons. In contrast, the mean party size of females varied. Females were observed in larger parties in the fruit-abundant season than in the fruit-scarce season. Moreover, whereas males associated with each other at an almost equal frequency across seasons, females associated with each other more frequently in the fruit-abundant season. Females with infants or small juveniles were more often in association with other individuals than were cycling females. The intensity of individual relationships varied according to season, such that even mothers and sons were not always strongly associated. In a large party, females with infants may gain from predation avoidance but they are at a disadvantage in terms of scramble competition. The balance between these factors may change with fruit availability and may influence party size in different periods. For males, party formation may facilitate the defense of resources from neighboring groups more than provide predation avoidance. Electronic Publication     

Self-Expandable Metal Stents for Persisting Esophageal Variceal Bleeding after Band Ligation or Injection-Therapy: A Retrospective Study

Background and Study Aims

Despite a pronounced reduction of lethality rates due to upper gastrointestinal bleeding, esophageal variceal bleeding remains a challenge for the endoscopist and still accounts for a mortality rate of up to 40% within the first 6 weeks. A relevant proportion of patients with esophageal variceal bleeding remains refractory to standard therapy, thus making a call for additional tools to achieve hemostasis. Self-expandable metal stents (SEMS) incorporate such a tool.

Methods

We evaluated a total number of 582 patients admitted to our endoscopy unit with the diagnosis “gastrointestinal bleeding” according to our documentation software between 2011 and 2014. 82 patients suffered from esophageal variceal bleeding, out of which 11 cases were refractory to standard therapy leading to SEMS application. Patients with esophageal malignancy, fistula, or stricture and a non-esophageal variceal bleeding source were excluded from the analysis. A retrospective analysis reporting a series of clinically relevant parameters in combination with bleeding control rates and adverse events was performed.

Results

The initial bleeding control rate after SEMS application was 100%. Despite this success, we observed a 27% mortality rate within the first 42 days. All of these patients died due to non-directly hemorrhage-associated reasons. The majority of patients exhibited an extensive demand of medical care with prolonged hospital stay. Common complications were hepatic decompensation, pulmonary infection and decline of renal function. Interestingly, we found in 7 out of 11 patients (63.6%) stent dislocation at time of control endoscopy 24 h after hemostasis or at time of stent removal. The presence of hiatal hernia did not affect obviously stent dislocation rates. Refractory patients had significantly longer hospitalization times compared to non-refractory patients.

Conclusions

Self-expandable metal stents for esophageal variceal bleeding seem to be safe and efficient after failed standard therapy. Stent migration appeared to be a common incident that did not lead to reactivation of bleeding in any of our patients. SEMS should be considered a reasonable treatment option for refractory esophageal variceal bleeding after treatment failure of ligature and sclerotherapy and non-availability of or contraindication for other measures (e.g. TIPS).     

Management of externally manufactured cell therapy products: the Mayo Clinic approach

BackgroundThe rise of investigative and commercially available cell therapy products adds a new dynamic to academic medical centers; that is, the management of patient-specific cell products. The scope of cell therapy has rapidly expanded beyond in-house collection and infusion of cell products such as bone marrow and peripheral blood transplant. The complexities and volumes of cell therapies are likely to continue to become more demanding. As patient-specific “living drugs,” cell therapy products typically require material collection, product provenance, transportation and maintenance of critical quality attributes, including temperature and expiration dates. These requirements are complicated by variations in product-specific attributes, reporting requirements and interactions with industry not required of typical pharmaceuticals.MethodsTo manage these requirements, the authors set out to establish a framework within the Immune, Progenitor and Cell Therapeutics Lab, the Current Good Manufacturing Practice facility responsible for cell manufacturing at Mayo Clinic Rochester housed within the Division of Transfusion Medicine. The authors created a work unit (biopharmaceutical unit) dedicated to addressing the specialized procedures required to properly handle these living drugs from collection to delivery and housing the necessary processes to more easily integrate externally manufactured cell therapies into clinical practice.ResultsThe result is a clear set of expectations defined for each step of the process, with logical documentation of critical steps that are concise and easy to follow.ConclusionsThe authors believe this system is scalable for addressing the promised growth of cell therapy products well into the future. Here the authors describe this system and provide a framework that could be used by other centers to manage these important new therapies.     

Triple Antithrombotic Therapy after Percutaneous Coronary Intervention (PCI) in Patients with Indication for Oral Anticoagulation: Data from a Single Center Registry

Antithrombotic therapy consisting of a dual anti-platelet therapy (DAPT) and oral anti-coagulation (OAC) with a vitamin k antagonist is often referred to as triple therapy. This combined anticoagulation is applied in patients undergoing coronary artery stent implantation while also having an indication for OAC. Triple therapy increases the risk for bleeding events compared to either DAPT or OAC alone and thereby might be associated with adverse outcomes. Clinical data on the frequency of bleeding events in patients on triple therapy from clinical trials derives from pre-selected patients and may differ from the real world patients. We report data on patient characteristics and bleeding incidence of patients dismissed on triple therapy from a single university hospital. Within the time span from January 2000 to December 2012, we identified a total of 213 patients undergoing PCI who were prescribed a triple therapy for at least 4 weeks (representing 0.86% of all patients treated). The usage of triple therapy significantly increased over the observed time period. The average CHA₂DS₂-VASc Score was 3.1 ± 1.1 with an average HAS-BLED score of 2.5 ± 0.86 representing a high-risk group for thromboembolic events as well as considerable risk for bleeding events. An on-treatment bleeding incidence of 9.4% was detected, with gastrointestinal and airway bleeding being the most frequent (5.1% and 1.4%, respectively). This is consistent with data from clinical trials and confirms the high risk of bleeding in patients on DAPT plus OAC. 29.0% of all patients receiving triple therapy had an indication for OAC other than non-valvular atrial fibrillation. This substantial patient group is underrepresented by clinical trials and needs further attention.     

Species composition and dynamics of larval and juvenile fishes in the surf zone of Mauritius

The importance of the surf zone as a nursery ground for larval and juvenile fishes has been widely recognized, however the zone has yet to be studied in Mauritius. Recently, the coastal area of the island has been increasingly affected by human activities, especially by tourism. We collected fish samples with a hand pulled seine net during the period of August 2001 to March 2003 to clarify the fish fauna and the dynamics of fishes in the surf zone. Two sampling sites adjacent to river mouth areas and one sampling site adjacent to a mangrove area were selected for comparison of fish fauna in relation to environmental conditions. A total of 9,429 fish larvae and juveniles, representing at least 112 species from 48 families were collected. The abundant species were hardyhead silverside, Atherinomorus lacunosus, bluespot mullet, Valamugil seheli, and Ambassis spp., each contributing 16.2, 12.4, and 11.8% of the total number of individuals, respectively. Estuarine species dominated in the surf zone adjacent to the river mouth areas. Species composition and diversity changed seasonally. The number of fish increased during the rainy season. Species diversity increased at the turn of the seasons from the dry season to the rainy season. We conclude that species composition in each site was affected by environmental factors, such as the scale of the flux from the rivers, which is related to the precipitation. The results indicated that freshwater from the river is a trigger to aggregate larvae and juveniles in the surf zone.