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Copyright of Journal of Sport & Health Research is the property of Journal of Sport & Health Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Sport & Health Research is the property of Journal of Sport & Health Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Sport & Health Research is the property of Journal of Sport & Health Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The contextualization of chemistry is of great importance to our society as it allows to bring this science to students of secondary education thus facilitating the learning process, so that students can identify and explain the phenomena that occur around. As a way to improve student learning, driven redox processes are contextualized through the process of corrosion of metals, which can place them in real contexts, for which there were two experiences, one on corrosion reactions that occur over an extended time due to constant contact of the coins one hundred Chilean pesos, the old and current human sweat by verifying which of the two alloys are most affected. The other experience is to determine qualitatively the degree of corrosion experienced by coins of the same value mentioned above, through two media, a dry and moist soil, respectively. Both activities were used with chemical reagents readily available..

(1) Background: Society's shift to a tech-focused era and has created a hyper-connected, sedentary lifestyle. The purpose of this study is to address two objectives: firstly, to describe and analyze the effects of an active breaks program associated with the learning of curricular content (CF-AB) on levels of attention, concentration, and academic performance (AP); secondly, to examine the relationship between intense physical activity (PA), attention, concentration, academic self-concept, basic psychological needs, and academic performance in schoolchildren who practice CF-ABs. (2) Method: A randomized controlled trial quasi-experimental pre-test/post-test study with a non-probabilistic sample included 313 secondary school students divided into intervention and control groups. The intervention, a curricular-focused academic break (CF-AB) (8 weeks, 5-10 min/session), is taken in the middle of the class and linked with the subject content. Measuring instruments: Attention Test D2, ad hoc test for the AP, self-concept AF5, Basic Psychological Needs Satisfaction Scale in General (BNSG-S), and the Global PA Questionnaire (GPAC.V2). (3) Results: Attention and concentration improved in both groups, with no significant differences. There were no significant differences in academic self-concept, but the intervention group showed higher scores in basic psychological needs. AP correlated positively with concentration, academic self-concept, and physical activity. A proportion of 20% of the variance of AP in spelling is explained by the regression model. Students who improved the most in AP practiced intense PA outside school, with good self-concept and satisfactory social relationships. Although concentration was related to AP, it did not explain the improvement. (4) Conclusion: CF-ABs may have a positive impact on attention and AP, with socioemotional factors and PA playing an important role in this effect. (5) Limitations and Future Research: The relationship between PA performed in class and AP should be considered with caution due to the multifactorial nature of AP. Future research should consider the number of sessions per week, the prolongation of the same during the school year, the intensity and duration of the activity, and the intervention type of active breaks. In addition, attention should be paid to possible incident factors in AP related to personal and social variables.

Introduction: The liver is the organ responsible for the metabolism of nutrients, some drugs, and the production of coagulation factors. According to the World Health Organization, approximately 23 million people worldwide are diagnosed with liver disease each year. As a result, it is common for dentists to encounter these patients on a daily basis in their practice. The objective of this review is to establish the dental management of patients with liver disease., Material and Methods: A manual literature search was conducted using the indexed articles in PUBMED and EBSCO databases using the keywords "oral surgery," AND "liver disease," AND "hepatic cirrhosis," AND "dental management"., Results: Patients with liver disease present important characteristics for the dentist, which must be recognized in order to perform procedures with the lowest risk of intraoperative and postoperative complications. A patient with poorly controlled underlying liver disease is more prone to infections and bleeding, which implies a high risk of morbidity., Conclusions: Dental care for patients with liver disease should be assessed according to the reason for consultation, control of the disease, the complexity of the procedure to be performed, and both intraoperative and postoperative hemostatic measures. All necessary hemostatic measures should be considered and dose adjustments should be considered in the use of NSAIDs., Competing Interests: Potenciales conflictos de intereses: Los autores declaran no tener ningún conflicto de intereses

Physical activity has benefits for health, but many adolescents are inactive. However, video games such as Immersive Virtual Reality (IVR) have grown in popularity as a leisure activity among young people, allowing them to manipulate objects in virtual environments increasing the practice of physical activity. The evidence indicates that the interest in physical activity through IVR is greater than in traditional methods, and different experiences have been reported. However, few studies indicate the sample evaluated, the effects found, or the IVR instruments used. Due to this, is the aim of this study is to identify the publications referring to IVR and physical activity, characterize them, and present the obtained main findings. For this, the guidelines described in the PRISMA-ScR for scoping reviews were applied. After the use of the inclusion and exclusion criteria, eight articles were included. Results show evidence regarding physiological outcomes, perceptual variables, interest and enjoyment, and psychological effects regarding physical activity through IVR. Additionally, the use of different devices and their prescriptions are explored. It is concluded that there is interest from the scientific community for the practice of physical activity through IVR, as well as for its application for the maintenance of active habits. This is important as it positions IVR as a method that can be a more experiential and effective way to develop and maintain a healthy lifestyle.

Traditional models to train and teach young players in team sports assume that athletes learn as linear systems. However, an actual methodology called Non-Linear Pedagogy (NLP) accounts for the fact that the players and the team are complex dynamic systems. Experiences in handball under this methodology are scarce; due to this, an observational study has been conducted with a follow-up, idiographic and multidimensional design, in which 14 female school handball players belonging to four different local teams in Santiago, Chile (age = 15.55 + 0.51) agreed to participate in three special handball training sessions with the use of the NLP methodology where three different constraints were used. Descriptive analysis with the Chi-squared test showed a total of 252 observations where most of the variables were dependent on the constraints ( p ≤ 0.001). Frequency showed that mainly "Defense in Line of progression" and "Proximal contact" were the most activated variables, followed by "Harassment" and "Deterrence" for all constraints. However, only constraint 2 highly activated two collective motor behaviors, while the rest only did it with individual motor behaviors. It is concluded that the constraints used in training seem to be effective in activating a group of defensive handball motor behaviors, specifically those that are basic for female school handball players.

Handgrip strength is a simple measure of general muscle strength and is related to functionality in people with intellectual disabilities. The objective of this research was to describe the normative values of absolute and relative handgrip strength in children, adolescents and adults according to sex. The sample was made up of 264 schoolchildren (n = 168 men) belonging to five special education schools in Santiago of Chile. The results show higher levels of absolute handgrip strength in males compared to females. The maximum peak of the absolute manual handgrip is reached in females in adolescence with a decrease in adulthood. Relative handgrip strength levels are similar in boys and girls. In females, the relative handgrip strength is similar in childhood and adolescence. Relative handgrip strength declines in both sexes from adolescence to adulthood. The reference values of this study can be used by professionals in the areas of health and education as a guide for interpretation, monitoring and follow-up of Chilean schooled people with intellectual disabilities.

Mini handball is among the sports included as part of school physical education in Chile to improve children's motor skills and to motivate their adherence to a healthy and active lifestyle in response to concerns about this country's high level of childhood obesity. To this end, non-linear pedagogy (NLP) has been used to develop motor skills through mini handball in the school context. However, socioeconomic differences that influence the development of children's motor skills have not been considered to determine whether the methodology applies to everyone. The aim of the present observational study is to describe and compare the effectiveness of the previously applied NLP methodology in two contrasting socioeconomic contexts to determine whether it helps to develop motor skills through mini handball in both school contexts. The Levine test was used to determine the homogeneity of the variances ( p < 0.05), as the distribution of the data was not normal. The Kruskal-Wallis H statistical test was used to analyse within-group data. Additionally, the Mann-Whitney U test was applied for comparisons between groups. The results show significant improvements in the acquisition of the expected motor skills specific to mini handball. Additionally, a shortening of the gap was evidenced between the groups during the training process, with no significant differences at the end of the progression. Therefore, the investigated NLP is equally as effective for schoolchildren in two opposite socioeconomic contexts.

Lockdown due to the COVID-19 pandemic has negatively impacted the social, psychological, and physical well-being of the world population. In the case of people with intellectual disabilities, the impact of lockdown on their physical condition and functionality is not completely clear. This study aimed to determine the effects of COVID-19 lockdown on the anthropometric indicators of cardiometabolic risk, muscle strength, and functionality on schoolchildren with intellectual disabilities. The sample was composed of 132 students of both sexes ( n = 74 pre-lockdown; n = 58 lockdown) belonging to two special education centers from the Metropolitan Region of Santiago, Chile. Our results showed significant reductions ( p ≤ 0.05) in absolute and relative handgrip strength, as well as in functionality, when comparing pre-lockdown and lockdown measurements, with a greater loss in girls than boys. The design and implementation of physical exercise programs centered on strength training are necessary for the physical and functional reconditioning of this population. These programs need to be implemented in special education centers considering the general well-being, quality of life and work needs of people with intellectual disabilities.

Several resistance training programs using conventional methodologies have been implemented with the purpose of improving the ability to perform power actions in handball, especially during the competitive season. In contrast, methodologies based on a contemporary perspective, which considers the human being as a self-regulating biological entity, and designed specifically for female college players, are scarce. The aim of this research was to investigate the effects of an eight-week resistance training program, in which the athletes were able to control the loads according to their self-perceived effort and rest on their repeated shuttle sprint and jump ability. The sample was composed of 16 female players of a handball team from the faculty of physics and mathematics sciences of a Chilean university. The RSSJA test was used to evaluate players' conditions pre- and post-training program, and the self-perceived effort scale called OMNI-RES was used for the prediction and control of loads. Results indicated that, after the application of an eight-week resistance training program, significant improvements p ≤ 0.05 on the jump height (pre: 1836.4 W; average post: 2088.9 W) and running speed (average pre: 3.2 m/s; average post: 4.0 m/s) were obtained, as well as a significant reduction in the loss of power and speed between each set of the applied test.

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo , validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states., (©2020 American Association for Cancer Research.)

The mitochondrial free radical theory of aging suggests that accumulating oxidative damage to mitochondria and mitochondrial DNA (mtDNA) plays a central role in aging. Circulating cell-free mtDNA (ccf-mtDNA) isolated from blood may be a biomarker of disease. Extracellular vesicles (EVs) are small (30-400 nm), lipid-bound vesicles capable of shuttling proteins, nucleic acids, and lipids as part of intercellular communication systems. Here, we report that a portion of ccf-mtDNA in plasma is encapsulated in EVs. To address whether EV mtDNA levels change with human age, we analyzed mtDNA in EVs from individuals aged 30-64 years cross-sectionally and longitudinally. EV mtDNA levels decreased with age. Furthermore, the maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors. Our results suggest that plasma mtDNA is present in EVs, that the level of EV-derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age-dependent manner., (Published 2020. This article is a US Government work and is in the public domain in the USA.)

The aim of the present study was to define and contrast a explicative model of the relationship between the variables of quality of life that make up the KIDSCREEN-52 questionnaire., Methods: A total of 1641 Colombian university students aged between 17 and 18 years (17.69 + 0.490) participated in this research (61.2% males and 38.8% females) analyzing the dimensions of the KIDSCREEN-52 quality of life questionnaire. A model of structural equation was made and adjusted (χ 2 = 118.021; DF = 6; p < 0.001; CFI = 0.953; NFI = 0.951; IFI = 0.954; RMSEA = 0.076)., Results: The analyzed dimensions of quality of life were related in a positive and direct way, except for the Parent Relationship and Family Life (Family L.) with Social Acceptance (Social A.), which were associated in a negative and indirect manner., Conclusions: The main conclusion of this investigation is that all dimensions of quality of life associate in a positive manner with the exception of Parent Relationship and Family Life (Family L.) which associated with Social Acceptance (Social A.). The qualities improve together, highlighting the idea that working on any of the areas that comprise quality of life will cause development of the remaining areas.

PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-domiciliated intrusive triatomine vectors are responsible for a low but significant transmission of Trypanosoma cruzi to humans. Their control is a challenge as insecticide spraying is of limited usefulness, and alternative strategies need to be developed for a sustainable control. We performed a non-randomized controlled trial of an Ecohealth intervention based on window insect screens and community participation to reduce house infestation by Triatoma dimidiata in two rural villages in Yucatan, Mexico. Efficacy of the intervention was measured over a three years follow-up period and entomological indicators showed that the proportion of triatomines found inside houses was significantly reduced in houses with insect screens, which effectively kept more bugs on the outside of houses. Using a previously developed model linking entomological data to the prevalence of infection in human, we predicted that the intervention would lead to a 32% reduction in yearly incidence and in the prevalence of T. cruzi infection. The cost for the coverage of all the windows of a house was of comparable magnitude to what families currently spend on various domestic insecticide, and most screens were still in good conditions after three years. In conclusion, the Ecohealth approach proposed here is effective for the long-term and sustainable control of intrusive T. dimidiata vectors in the Yucatan peninsula, Mexico. This strategy may also be easily adapted to other intrusive triatomine species as well as other regions/countries with comparable eco-epidemiological settings, and would be an excellent component of a larger integrated program for the control of a variety of other vector-borne diseases, bringing additional benefits to the communities. Our results should encourage a further scaling-up of our implementation strategy in additional villages in the region., Competing Interests: The authors have declared that no competing interests exist.

The study of CD8 positive cells in peripheral blood has become an essential part of research in the field of cancer immunotherapies, vaccine development, inflammation, autoimmune disease, etc. In this study, an 8-color flow cytometry panel, containing lineage and functional markers, was developed for the identification of CD8+ cytotoxic T cells in previously cryopreserved peripheral blood mononuclear cells from healthy human donors. By studying functional markers in naïve and CD3/CD28 activated T cells we demonstrate that the panel is capable of detecting protein markers corresponding to different T cell activation statuses. Data generated by flow cytometry were corroborated by different antibody based assay technologies to detect soluble cytokines. Our findings suggest that there is an inter donor variability in both baseline and activation responses. We have also successfully developed an antibody panel for flow cytometry that could be used to study cytotoxic function of CD8 T cells in clinical immunology research areas.

Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3-ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI). Up to now, the activity of the multi-targeted FLT3 inhibitor, midostaurin, against cells expressing activated SYK has not been explored in the context of leukemia, although SYK has been identified as a target of midostaurin in systemic mastocytosis. We compared the ability of midostaurin to inhibit activated SYK in mutant FLT3-positive AML cells with that of inhibitors displaying dual SYK/FLT3 inhibition, targeted SYK inhibition, and targeted FLT3 inhibition. Our findings suggest that dual FLT3/SYK inhibitors and FLT3-targeted drugs potently kill oncogenic FLT3-transformed cells, while SYK-targeted small molecule inhibition displays minimal activity. However, midostaurin and other dual FLT3/SYK inhibitors display superior anti-proliferative activity when compared to targeted FLT3 inhibitors, such as crenolanib and quizartinib, against cells co-expressing FLT3-ITD and constitutively activated SYK-TEL. Interestingly, additional SYK suppression potentiated the effects of dual FLT3/SYK inhibitors and targeted FLT3 inhibitors against FLT3-ITD-driven leukemia, both in the absence and presence of activated SYK. Taken together, our findings have important implications for the design of drug combination studies in mutant FLT3-positive patients and for the design of future generations of FLT3 inhibitors., Competing Interests: CONFLICTs OF INTEREST P.W.M. is an employee of Novartis Pharma AG. J.D.G. and P.M. have a financial interest with Novartis Pharma AG.

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C + subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease., (Copyright © 2017, American Association for the Advancement of Science.)

Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

Interleukin 2 (IL-2) administered at low doses for prolonged periods can markedly expand the number of CD56(+) natural killer (NK) cells in patients with metastatic cancer. The cytotoxic capacity of NK cells obtained from patients receiving IL-2 in vivo can be dramatically augmented by additional exposure to IL-2 in vitro. These observations formed the basis of a clinical trial in which patients with metastatic cancer were treated with low-dose continuous daily infusions of IL-2 to increase the number of their NK cells in conjunction with intermittent boluses of additional IL-2 to stimulate this expanded pool of cytotoxic cells. Twenty-three patients were registered to receive IL-2 at 4.5 x 10(5) units/m2/day for 8 weeks by continuous i.v. infusion. After 4 weeks of "priming" with low-dose continuous infusion IL-2, cohorts of three to five patients received 5 weekly 2-h boluses of IL-2 at doses ranging from 2.5 x 10(5) units/m2 to 1.0 x 10(6) units/m2. Low-dose continuous infusion IL-2 was usually well tolerated; 2-h bolus infusions of IL-2 were often associated with high fevers and constitutional symptoms that resolved after several hours. Low-dose continuous infusion IL-2 resulted in the progressive expansion of circulating CD56(+)CD3(-) NK cells. In contrast, each bolus infusion of IL-2 resulted in an immediate dramatic decrease in both the number of NK cells and activated T lymphocytes with recovery noted within 24 h. Bolus doses of IL-2 as low as 2.5 x 10(5) units/m2 were capable of producing these effects. Cytolytic activity against NK-sensitive and -resistant targets correlated with the presence of circulating activated NK cells. Our results demonstrate that NK cells expanded by low-dose continuous infusions of IL-2 can be further activated in vivo by exposure to very low doses of IL-2 as a 2-h i.v. bolus. This capacity to manipulate human NK cells in vivo through varying the dose and schedule of IL-2 administration may help in defining the therapeutic potential of these cytotoxic effectors in the treatment of both neoplastic and infectious diseases.

Despite the importance of natural killer (NK) cells in the immune response, the regulation of human NK cell growth has not been well characterized. We have hypothesized that, similar to the proliferation of T and B lymphocytes, optimal proliferation of NK cells requires costimulatory signals as well as a primary mitogenic stimulus. Evidence for costimulation by both soluble cytokines and cell contact-dependent factors is presented. Soluble IL-1 and TNF were found to augment NK cell proliferation in response to primary mitogenic cytokines, including IL-2, IL-4, IL-7, and IL-12. The costimulatory effect of IL-1 and TNF is strongly enhanced by the calcium ionophore ionomycin. Coculture of NK cells with irradiated K562 cells can largely substitute for the costimulatory signal provided by ionomycin. Costimulation by K562 requires intimate cell contact and is not reconstituted by cell-free supernatants. Activated T lymphocytes can also mediate contact-dependent costimulation of NK cells; resting PBMC, several NK-sensitive cell lines, and all NK-resistant cell lines tested were not found to be costimulatory. Engagement of CD16 did not augment NK cell proliferation. Thus, triggering of natural killing or antibody-dependent cell-mediated cytotoxicity (ADCC) does not consistently provide a costimulatory signal for NK cell proliferation. Cell contact-dependent costimulation of NK cells does not appear to involve known receptors that can costimulate T cells, including CD2, CD27, CD28, CD29, or LFA-1. The molecular nature of the putative NK cell costimulatory receptor remains to be elucidated. Nevertheless, human NK cells could be expanded in vitro using leukocyte-conditioned medium (LCM) as a source of IL-2 and accessory cytokines and ionomycin to bypass the putative receptor for cell contact-dependent costimulation. NK cells expanded in LCM and ionomycin express typical NK cell antigens and mediate natural killing and ADCC. Further characterization of the costimulatory signals for NK cell proliferation may elucidate the physiologic regulation of NK cell growth and may ultimately allow more effective manipulation of these lymphocytes in the immunotherapy of human diseases.

Background: Despite improvements in supportive care and pharmacologic therapies, sepsis and related disorders such as systemic inflammatory response syndrome (SIRS) continue to be a leading cause of death in the intensive care unit. We hypothesized that immune dysfunction in this setting may in part be mediated at the level of early signal transduction in monocytes and neutrophils as manifested by changes in intracellular free Ca2+., Methods: Monocytes and neutrophils were isolated from patients in the intensive care unit who met the criteria for SIRS and from normal volunteers. Cells were loaded with the Ca(2+)-sensitive fluorescent dye Indo-1 and stimulated with the chemotactic peptide f-Met-Leu-Phe (fMLP). Changes in intracellular calcium ion concentration were measured by flow cytometry., Results: Patient monocytes exhibited a decreased Ca2+ flux (43% +/- 3.1%) as compared with normal monocytes (63% +/- 2.5%) (p < 0.05). Patient neutrophils also exhibited a decreased Ca2+ flux in response to fMLP of 58% +/- 3.7% versus 69.3% +/- 3.1% for normal neutrophils (p < 0.05). Incubation of patient cells in normal plasma reversed this dysfunction and showed an improved Ca2+ flux to 60% +/- 2.7% for monocytes and 71% +/- 3.7% for neutrophils (p < 0.05). Conversely, calcium flux was decreased in both normal monocytes (42.3% +/- 3.1%) and normal neutrophils (55.4% +/- 3.8%) after incubation in SIRS patient plasma (p < 0.05). Incubation of normal monocytes and neutrophils in interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor, or lipopolysaccharide did not show a statistically significant alteration in calcium flux in response to fMLP., Conclusions: Patients with SIRS exhibit alterations in early signal transduction after stimulation with fMLP in monocytes and neutrophils. This effect appears to be mediated by a soluble factor because the defect in SIRS patient cells can be reversed by incubation in normal plasma and normal cells appear to acquire this defect after incubation in patient plasma. Further studies are underway to identify the factor or factors responsible for this functional defect.