Hyperthermic isolated limb perfusion increases circulating levels of inflammatory cytokines

Hyperthermic isolated limb perfusion is an established method of treatment for regionally advanced melanoma. Recent studies suggest that exogenously administered cytokines potentiate tumor response in patients with in-transit melanoma. We hypothesized that isolated limb perfusion induces an immunogenic response characterized by increased circulating levels of cytokines in the pump circuit, potentially contributing to the antitumor effect. We obtained blood samples from the perfusion circuit and systemic circulation at various intervals from patients undergoing isolated chemotherapeutic perfusion for melanoma. Samples were analyzed for serum cytokine profiles by enzyme-linked immunosorbent assay. When compared with baseline values, significant increases in serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF) occurred within the perfusion circuit during isolated limb perfusion (P<0.05). In addition, there was a corresponding increase in IL-8 within the systemic circulation at the 60-min interval (P<0.05), suggesting some degree of leakage from the isolated circuit due to the extremely high levels of IL-8 in the perfusion circuit. A transient but insignificant decrease in circulating levels of neutrophils was also observed during the perfusion process, which may be attributed to margination. Increased levels of cytokines IL-6, IL-8, and TNF occurred within the isolated circuit during hyperthermic limb perfusion and may contribute to tumor response seen in patients treated with isolated limb perfusion.Presented at the Annual Meeting of the Society of Surgical Oncology, 17–20 March 1994 Houston, Texas     

Functional analysis of the p40 and p75 proteins from Lactobacillus casei BL23

The genomes of Lactobacillus casei/paracasei and Lactobacillus rhamnosus strains carry two genes encoding homologues of p40 and p75 from L. rhamnosus GG, two secreted proteins which display anti-apoptotic and cell protective effects on human intestinal epithelial cells. p40 and p75 carry cysteine, histidine-dependent aminohydrolase/peptidase (CHAP) and NLPC/P60 domains, respectively, which are characteristic of proteins with cell-wall hydrolase activity. In L. casei BL23 both proteins were secreted to the growth medium and were also located at the bacterial cell surface. The genes coding for both proteins were inactivated in this strain. Inactivation of LCABL_00230 (encoding p40) did not result in a significant difference in phenotype, whereas a mutation in LCABL_02770 (encoding p75) produced cells that formed very long chains. Purified glutathione-S-transferase (GST)-p40 and -p75 fusion proteins were able to hydrolyze the muropeptides from L. casei cell walls. Both fusions bound to mucin, collagen and to intestinal epithelial cells and, similar to L. rhamnosus GG p40, stimulated epidermal growth factor receptor phosphorylation in mouse intestine ex vivo. These results indicate that extracellular proteins belonging to the machinery of cell-wall metabolism in the closely related L. casei/paracasei-L. rhamnosus group are most likely involved in the probiotic effects described for these bacteria.     

Divergent patterns of integration and reduced constraint in the human hip and the origins of bipedalism

When compared to other hominids--great apes including humans--the human pelvis reveals a fundamental reorganization of bony morphology comprised of multiple trait-level changes, many of which are associated with bipedal locomotion. Establishing how patterns of integration--correlations and covariances among traits--within the pelvis have evolved in concert with morphology is essential to explaining this evolutionary transition because integration may facilitate or constrain morphological evolution. Here, we show that the human hip bone has significantly lower levels of integration and constraint overall when compared to other hominids, that the focus of these changes is on traits hypothesized to play major functional roles in bipedalism, and we provide evidence that the human hip was reintegrated in a pattern distinct from other members of this group. Additionally, the evolutionary transition from a nonhuman great ape-like to human hip bone morphology was significantly easier to traverse using the human integration pattern in each comparison, which suggests hominin patterns may have evolved to facilitate this transition. Our results suggest natural selection for bipedalism broke down earlier hominid integration patterns, allowing relevant traits to respond to separate selection pressures to a greater extent than was previously possible, and reintegrated traits in a way that could have facilitated evolution along the vector specifying ancestral hominid and hominin morphological differences.     

Activation of peroxisome proliferator-activated receptor gamma suppresses nuclear factor kappa B-mediated apoptosis induced by Helicobacter pylori in gastric epithelial cells

Helicobacter pylori colonization leads to epithelial cell hyperproliferation within inflamed mucosa, but levels of apoptosis vary, suggesting that imbalances between rates of cell production and loss may contribute to differences in gastric cancer risk among infected populations. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates inflammatory and growth responses of intestinal epithelial cells. We determined whether activation of PPARgamma modified H. pylori-induced apoptosis in gastric epithelial cells. PPARgamma was expressed and functionally active in gastric epithelial cell lines sensitive to H. pylori-induced apoptosis. PPARgamma ligands 15d-PGJ(2) and BRL-49653 significantly attenuated H. pylomicronri-induced apoptosis, effects that could be reversed by co-treatment with a specific PPARgamma antagonist. Cyclopentanone prostaglandins that do not bind and activate PPARgamma had no effects on H. pylori-induced apoptosis. The ability of H. pylori to activate nuclear factor (NF)-kappaB and increase levels of the NF-kappaB target IL-8 was blocked by co-treatment with PPARgamma agonists, and direct inhibition of NF-kappaB also abolished H. pylori-stimulated apoptosis. These results suggest that activation of the PPARgamma pathway attenuates the ability of H. pylori to induce NF-kappaB-mediated apoptosis in gastric epithelial cells. Because PPARgamma regulates a multitude of host responses, activation of this receptor may contribute to varying levels of cellular turnover as well as the diverse pathologic outcomes associated with chronic H. pylori colonization.     

Diet-induced obesity in rats leads to a decrease in sperm motility

Background  

Obesity is rapidly becoming a worldwide epidemic that affects children and adults. Some studies have shown a relationship between obesity and infertility, but until now it remains controversial. Thus, the aim of the present study was to investigate the effect of high-fat diet-induced obesity on male reproductive parameters.     

A system dynamics model of clinical decision thresholds for the detection of developmental-behavioral disorders

Background

Clinical decision-making has been conceptualized as a sequence of two separate processes: assessment of patients’ functioning and application of a decision threshold to determine whether the evidence is sufficient to justify a given decision. A range of factors, including use of evidence-based screening instruments, has the potential to influence either or both processes. However, implementation studies seldom specify or assess the mechanism by which screening is hypothesized to influence clinical decision-making, thus limiting their ability to address unexpected findings regarding clinicians’ behavior. Building on prior theory and empirical evidence, we created a system dynamics (SD) model of how physicians’ clinical decisions are influenced by their assessments of patients and by factors that may influence decision thresholds, such as knowledge of past patient outcomes. Using developmental-behavioral disorders as a case example, we then explore how referral decisions may be influenced by changes in context. Specifically, we compare predictions from the SD model to published implementation trials of evidence-based screening to understand physicians’ management of positive screening results and changes in referral rates. We also conduct virtual experiments regarding the influence of a variety of interventions that may influence physicians’ thresholds, including improved access to co-located mental health care and improved feedback systems regarding patient outcomes.

Results

Results of the SD model were consistent with recent implementation trials. For example, the SD model suggests that if screening improves physicians’ accuracy of assessment without also influencing decision thresholds, then a significant proportion of children with positive screens will not be referred and the effect of screening implementation on referral rates will be modest—results that are consistent with a large proportion of published screening trials. Consistent with prior theory, virtual experiments suggest that physicians’ decision thresholds can be influenced and detection of disabilities improved by increasing access to referral sources and enhancing feedback regarding false negative cases.

Conclusions

The SD model of clinical decision-making offers a theoretically based framework to improve understanding of physicians’ behavior and the results of screening implementation trials. The SD model is also useful for initial testing of hypothesized strategies to increase detection of under-identified medical conditions.

     

Forelimb and hindlimb forces in walking and galloping primates

One trait that distinguishes the walking gaits of most primates from those of most mammalian nonprimates is the distribution of weight between the forelimbs and hindlimbs. Nonprimate mammals generally experience higher vertical peak substrate reaction forces on the forelimb than on the hindlimb. Primates, in contrast, generally experience higher vertical peak substrate reaction forces on the hindlimb than on the forelimb. It is currently unclear whether this unusual pattern of force distribution characterizes other primate gaits as well. The available kinetic data for galloping primates are limited and present an ambiguous picture about peak-force distribution among the limbs. The present study investigates whether the pattern of forelimb-to-hindlimb force distribution seen during walking in primates is also displayed during galloping. Six species of primates were video-recorded during walking and galloping across a runway or horizontal pole instrumented with a force-plate. The results show that while the force differences between forelimb and hindlimb are not significantly different from zero during galloping, the pattern of force distribution is generally the same during walking and galloping for most primate species. These patterns and statistical results are similar to data collected during walking on the ground. The pattern of limb differentiation exhibited by primates during walking and galloping stands in contrast to the pattern seen in most nonprimate mammals, in which forelimb forces are significantly higher. The data reported here and by Demes et al. ([1994] J. Hum. Evol. 26:353-374) suggest that a relative reduction of forelimb vertical peak forces is part of an overall difference in locomotor mechanics between most primates and most nonprimate mammals during both walking and galloping.     

Body size and joint posture in primates

Body mass has been shown in experimental and comparative morphological studies to have a significant effect on joint posture in major limb joints. The generalizability of experimental studies is limited by their use of small sample sizes and limited size ranges. In contrast, while comparative morphological studies often have increased sample sizes, the connection between joint posture and morphological variables is often indirect. The current study infers joint postures for a large sample of primates using an experimentally validated method, and tests whether larger primates use more extended joint postures than smaller species. Postures are inferred through the analysis of patterns of subchondral bone apparent density on the medial femoral condyle. Femora from 94 adult wild‐shot individuals of 28 species were included. Apparent density measurements were obtained from CT scans using AMIRA software, and the angular position of the anterior‐most extent of the region of maximum apparent density on the medial femoral condyle was recorded. In general, the hypothesis that larger‐bodied primates use more extended knee posture was supported, but it should be noted that considerable variation exists, particularly at small body sizes. This indicates that smaller species are less constrained by their body size, and their patterns of apparent density are consistent with a wide range of knee postures. The size‐related increase in inferred joint posture was observed in most major groups of primates, and this observation attests to the generalizability of Biewener's model that relates body size and joint posture. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.