Evaluation of circuit-training intensity for firefighters

Firefighters are required to perform a variety of strenuous occupational tasks that require high levels of both aerobic and anaerobic fitness. Thus, it is critical that firefighters train at an appropriate intensity to develop adequate levels of aerobic and anaerobic fitness. Circuit training is a unique training method that stresses both energy systems and therefore may be a viable training method to enhance firefighter preparedness. Thus, the purpose of this study was to compare the aerobic and anaerobic intensities of a circuit-based workout to physiological data previously reported on firefighters performing fire suppression and rescue tasks. Twenty career firefighters performed a workout that included 2 rotations of 12 exercises that stressed all major muscle groups. Heart rate was recorded at the completion of each exercise. Blood lactate was measured before and approximately 5 minutes after the workout. The workout heart rate and post-workout blood lactate responses were statistically compared to data reported on firefighters performing fire suppression and rescue tasks. The mean circuit-training heart rate was similar to previously reported heart rate responses from firefighters performing simulated smoke-diving tasks (79 ± 5 vs. 79 ± 6% maximum heart rate [HRmax], p = 0.741), but lower than previously reported heart rate responses from firefighters performing fire suppression tasks (79 ± 5 vs. 88 ± 6% HRmax, p < 0.001). The workout produced a similar peak blood lactate compared to that when performing firefighting tasks (12 ± 3 vs. 13 ± 3 mmol·L(-1), p = 0.084). In general, the circuit-based workout produced a lower cardiovascular stress but a similar anaerobic stress as compared to performing firefighting tasks. Therefore, firefighters should supplement low-intensity circuit-training programs with high-intensity cardiovascular and resistance training (e.g., ≥85% 1-repetition maximum) exercises to adequately prepare for the variable physical demands of firefighting.     

IL-12Rβ1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey

Background and Objectives

In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common.

Methods and Principal Findings

We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease.

Significance

This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.     

Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo

Tumor cells exhibit an altered metabolism characterized by elevated aerobic glycolysis and lactate secretion which is supported by an increase in glucose transport and consumption. We hypothesized that reducing or eliminating the expression of the most prominently expressed glucose transporter(s) would decrease the amount of glucose available to breast cancer cells thereby decreasing their metabolic capacity and proliferative potential.Of the 12 GLUT family glucose transporters expressed in mice, GLUT1 was the most abundantly expressed at the RNA level in the mouse mammary tumors from MMTV-c-ErbB2 mice and cell lines examined. Reducing GLUT1 expression in mouse mammary tumor cell lines using shRNA or Cre/Lox technology reduced glucose transport, glucose consumption, lactate secretion and lipid synthesis in vitro without altering the concentration of ATP, as well as reduced growth on plastic and in soft agar. The growth of tumor cells with reduced GLUT1 expression was impaired when transplanted into the mammary fat pad of athymic nude mice in vivo. Overexpression of GLUT1 in a cell line with low levels of endogenous GLUT1 increased glucose transport in vitro and enhanced growth in nude mice in vivo as compared to the control cells with very low levels of GLUT1.These studies demonstrate that GLUT1 is the major glucose transporter in mouse mammary carcinoma models overexpressing ErbB2 or PyVMT and that modulation of the level of GLUT1 has an effect upon the growth of mouse mammary tumor cell lines in vivo.     

Nanotube action between human mesothelial cells reveals novel aspects of inflammatory responses

A well-known role of human peritoneal mesothelial cells (HPMCs), the resident cells of the peritoneal cavity, is the generation of an immune response during peritonitis by activation of T-cells via antigen presentation. Recent findings have shown that intercellular nanotubes (NTs) mediate functional connectivity between various cell types including immune cells - such as T-cells, natural killer (NK) cells or macrophages - by facilitating a spectrum of long range cell-cell interactions. Although of medical interest, the relevance of NT-related findings for human medical conditions and treatment, e.g. in relation to inflammatory processes, remains elusive, particularly due to a lack of appropriate in vivo data. Here, we show for the first time that primary cultures of patient derived HPMCs are functionally connected via membranous nanotubes. NT formation appears to be actin cytoskeleton dependent, mediated by the action of filopodia. Importantly, significant variances in NT numbers between different donors as a consequence of pathophysiological alterations were observable. Furthermore, we show that TNF-α induces nanotube formation and demonstrate a strong correlation of NT connectivity in accordance with the cellular cholesterol level and distribution, pointing to a complex involvement of NTs in inflammatory processes with potential impact for clinical treatment.     

Validation of the tetracycline regulatable gene expression system for the study of the pathogenesis of infectious disease

Understanding the pathogenesis of infectious disease requires the examination and successful integration of parameters related to both microbial virulence and host responses. As a practical and powerful method to control microbial gene expression, including in vivo, the tetracycline-regulatable system has recently gained the favor of many investigative groups. However, some immunomodulatory effects of the tetracyclines, including doxycycline, could potentially limit its use to evaluate host responses during infection. Here we have used a well-established murine model of disseminated candidiasis, which is highly dependent on both the virulence displayed by the fungal cells and on the host immune status, to validate the use of this system. We demonstrate that the pathogenesis of the wild type C. albicans CAF2-1 strain, which does not contain any tet-regulatable element, is not affected by the presence of doxycycline. Moreover levels of key cytokines, chemokines and many other biomarkers, as determined by multi-analyte profiling, remain essentially unaltered by the presence of the antibiotic during infection. Our results indicate that the levels of doxycycline needed to control the tetracycline regulatable promoter gene expression system have no detectable effect on global host responses during candidiasis. Because tet-regulatable systems are now being increasingly used in a variety of pathogenic microorganisms, these observations have wide implications in the field of infectious diseases.     

Toward an early marker of metabolic dysfunction: omentin-1 in prepubertal children

Omentin-1 is a recently recognized adipokine primarily originating in visceral adipose tissue. We posited that circulating omentin-1 could be an early marker of metabolic dysfunction. To this end, we examined the associations between circulating omentin-1, body fat (bioelectric impedance), an endocrine-metabolic profile (homeostasis model assessment for insulin resistance (HOMA(IR)), serum lipids, high-molecular-weight (HMW) adiponectin and blood pressure (BP)) and family history of obesity and diabetes in asymptomatic prepubertal children (n = 161; 77 boys and 84 girls; age 7 ± 1 year) with a normal distribution of height and weight. Increased circulating omentin-1 was associated with a poorer metabolic profile, with relatively higher HOMA(IR), fasting triacylglycerol, BP and familial prevalence of diabetes (all P < 0.005 to P < 0.0001), and relatively lower fraction of HMW adiponectin (P < 0.005), whereas no relationship was found with body weight or fat or with family history of obesity. All these associations were independent of age, gender and fat mass. In conclusion, circulating omentin-1 may become a marker of metabolic dysfunction integrating insulin sensitivity, markers of adipose-tissue metabolism and BP as early as in prepubertal childhood.     

Implications of Advancing Paternal Age: Does It Affect Offspring School Performance?

Average paternal age is increasing in many high income countries, but the implications of this demographic shift for child health and welfare are poorly understood. There is equivocal evidence that children of older fathers are at increased risk of neurodevelopmental disorders and reduced IQ. We therefore report here on the relationship between paternal age and a composite indicator of scholastic achievement during adolescence, i.e. compulsory school leaving grades, among recent birth cohorts in Stockholm County where delayed paternity is notably common. We performed a record-linkage study comprising all individuals in Stockholm County who finished 9 years of compulsory school from 2000 through 2007 (n = 155,875). Data on school leaving grades and parental characteristics were retrieved from administrative and health service registers and analyzed using multiple linear regression. Advancing paternal age at birth was not associated with a decrease in school leaving grades in adolescent offspring. After adjustment for year of graduation, maternal age and parental education, country of birth and parental mental health service use, offspring of fathers aged 50 years or older had on average 0.3 (95% CI −3.8, 4.4) points higher grades than those of fathers aged 30–34 years. In conclusion, advancing paternal age is not associated with poorer school performance in adolescence. Adverse effects of delayed paternity on offspring cognitive function, if any, may be counterbalanced by other potential advantages for children born to older fathers.