Effect of pembrolizumab on CD4+ CD25+ , CD4+ LAP+ and CD4+ TIM-3+ T cell subsets.

Tumor immune evasion involves the expansion of avidly proliferating immunosuppressive cells and inhibition of effector T cell proliferation. Immune checkpoints (IC) block the activation pathways of tumor-reactive T cells. IC pathways are often exploited by tumor cells to evade immune destruction, and blocking these pathways through IC inhibitors (ICI) has shown promising results in multiple malignancies. In this study, we investigated the effects of an ICI, pembrolizumab, on various T cell subsets in vitro. We compared the suppressive activity of CD4+ CD25+ regulatory T cells (conventional Treg ) with T cells expressing T cell immunoglobulin-3+ (TIM-3+ ) and latency-associated peptide (LAP)+ T cells. We found that LAP-expressing T cells were more suppressive than conventional Treg , but TIM-3-expressing T cells were not suppressive. Our results show that pembrolizumab does not modulate functions of Treg and mediates its immunostimulatory effects via the release of effector T cells from suppression. These findings may assist in the development of agents designed to intervene in IC pathways to overcome Treg resistance to ICI.

Effect of team sports and resistance training on physical function, quality of life, and motivation in older adults.

The aim of this study was to investigate the effect of team sports and resistance training on physical function, psychological health, quality of life, and motivation in older untrained adults. Twenty-five untrained men and forty-seven untrained women aged 80 (range: 67-93) years were recruited. Fifty-one were assigned to a training group (TRG) of which twenty-five performed team training (TG) and twenty-six resistance training (RG). The remaining twenty-one were allocated to a control group (CG). TRG trained for 1 hour twice a week for 12 weeks. Compared with CG, TRG improved the number of arm curls within 30 seconds (P<.05) and 30-seconds chair stand (P<.05) during the intervention. In TRG, participation in training led to higher (P<.05) scores in the subscales psychological well-being, general quality of life, and health-related quality of life, as well as decreased anxiety and depression levels. No differences between changes in TG and RG were found over the intervention period, neither in physical function tests nor psychological questionnaires. Both TG and RG were highly motivated for training, but TG expressed a higher degree of enjoyment and intrinsic motivation mainly due to social interaction during the activity, whereas RG was more motivated by extrinsic factors like health and fitness benefits. In conclusion, both team training and resistance training improved physical function, psychological well-being, and quality of life. However, team sport training motivated the participants more by intrinsic factors than resistance training.

Effect modification of the association between fine particulate air pollution during a wildfire event and respiratory health by area-level measures of socio-economic status, race/ethnicity, and smoking prevalence.

Fine particulate air pollution (PM2.5) is decreasing in most areas of the United States, except for areas most affected by wildfires, where increasing trends in PM2.5 can be attributed to wildfire smoke. The frequency and duration of large wildfires and the length of the wildfire season have all increased in recent decades, partially due to climate change, and wildfire risk is projected to increase further in many regions including the western United States. Increasingly, empirical evidence suggests differential health effects from air pollution by class and race; however, few studies have investigated such differential health impacts from air pollution during a wildfire event. We investigated differential risk of respiratory health impacts during the 2008 northern California wildfires by a comprehensive list of socio-economic status (SES), race/ethnicity, and smoking prevalence variables. Regardless of SES level across nine measures of SES, we found significant associations between PM2.5 and asthma hospitalizations and emergency department (ED) visits during these wildfires. Differential respiratory health risk was found by SES for ED visits for chronic obstructive pulmonary disease where the highest risks were in ZIP codes with the lowest SES levels. Findings for differential effects by race/ethnicity were less consistent across health outcomes. We found that ZIP codes with higher prevalence of smokers had greater risk of ED visits for asthma and pneumonia. Our study suggests that public health efforts to decrease exposures to high levels of air pollution during wildfires should focus on lower SES communities.

Wartime upper-extremity injuries in the Sahelian strip: Experience from a French Forward Surgical Team deployed in Mali.

This study aimed to analyze upper-extremity combat-related injuries (CRIs) and non-combat-related injuries (NCRIs) treated in the French Forward Surgical Team currently deployed in Gao, Mali. A retrospective study was conducted using the French Military Health Service OpEX surgical database from February 2013 to March 2020. All patients operated on for upper-extremity injury were included: 224 patients, with a mean age of 28.15 years, for 249 upper-extremity injuries. Seventy-six (33.9%) sustained CRIs and 148 (66.1%) NCRIs. Multiple upper-extremity injuries and associated injuries were significantly more common in the CRI group. The majority of NCRIs involved the hand. Debridement and wound care was the most common procedure in both groups. External fixation and fasciotomy were significantly more frequent in the CRI group, and internal fracture fixation in the NCRI group. The overall number of procedures was significantly higher in the CRI group. Due to the high frequency of upper-extremity injury in current theaters of operations, deployed orthopedic surgeons should be trained in basic hand surgery so as to optimally manage both CRIs and NCRIs.

[Retinal damage by perfluorocarbon liquids - a question of specific gravity? Intraocular pressure peaks and shearing forces]. / Retinale Schäden durch flüssige Perfluorkarbone - eine Frage des spezifischen Gewichts? Intraokulare Druckspitzen und Scherkräfte.

BACKGROUND: Perfluorocarbon liquids (PFCL) cause retinal damage when used as long-term ocular endotamponades. Whether these changes are related to the mechanical or to the chemical properties of PFCL is unclear. The purpose of this study was to evaluate pressure spikes or shearing forces during endotamponade with PFCL and standardised eye movements. MATERIAL AND METHODS: Part 1: In an eye model the resulting pressure forces of 6 PFCL were measured at four different sites during standardised eye movements. Part 2: Shearing forces were determined in a plexiglass eye model and the resulting tangential forces at the PFCL-retina interface were calculated. Part 3: Rabbit eyes were vitrectomised and filled with light and heavy fluorocarbons for 6 weeks. Subsequently, the retina were examined histologically and by immunohistochemistry. RESULTS: With increasing filling of the eye model, the maximum of the pressure peaks moved from the inferior wall of the eye model to the lateral eye walls. For perfluorodecalin (PFD) the highest pressure peak was 407 Pa with a 75 % filling of the vitreous cavity. The lowest pressure peak was 314 Pa with a 50 % filling of hexafluoropropene oxide. Shearing forces for standardised accelerations were dependent on viscosity and ranged between 0.87 mN/m(2) (perfluorohexyloctane) and 8055 mN/m(2) (hexafluoropropene oxide). Part 3: Histological and immunohistochemical analyses did not reveal pressure-related damage or any difference between the effects of the different tamponades in vivo. CONCLUSION: In comparison with physiological dynamic and static pressure peaks, the measured mechanical forces induced by intraocular PFCL tamponades are low. Specific gravity and mechanical damage by intraocular PFCL as a cause of retinal damage seem unlikely. Animal studies underline these findings.

Metacarpal bone reconstruction by a cementless induced membrane technique.

Gunshot wounds to the hand often produce complex injuries and large segmental bone defects. Bone reconstruction remains a challenge in this context. The induced membrane technique is a simple and effective procedure for reconstruction of segmental bone defects. The technique is straightforward but must be performed rigorously. Usually polymethylmethacrylate (PMMA) cement is required for the first stage of the surgery. We describe four cases of metacarpal bone reconstruction after gunshot wounds in a limited-resource setting. Two patients were treated using the induced membrane technique with a polypropylene syringe body instead of PMMA cement, which was unavailable in this situation. A thick membrane was observed 6 weeks after spacer implantation. Bone union was achieved in all cases.

Onset of wavy vortices in Taylor-Couette flow with imperfect reflection symmetry.

We reveal experimentally a mechanism that alters the critical behavior of a Hopf bifurcation substantially due to the presence of imperfections of the reflection symmetry in a hydrodynamic system. The onset of rotating waves in Taylor vortex flow, which is widely considered as a "classical" example for a Hopf bifurcation in hydrodynamics, is investigated primarily by transient response experiments. While wavy vortex flow is not influenced by such (unavoidable) experimental imperfections, the critical behavior of the axially subharmonic rotating wave with wavy outflow boundaries, also called the small-jet mode, is qualitatively altered. Experimental evidence is provided that the modified critical behavior at the Hopf bifurcation is associated with imperfections of the reflection symmetry of the Taylor-Couette setup. The experimental results on Hopf bifurcation are discussed in the context of a cusp-Hopf bifurcation model recently proposed by Harlim and Langford [Int. J. Bifurcation Chaos Appl. Sci. Eng. 17, 2547 (2007)] and compared to experimental results on imperfect pitchfork bifurcation in small-aspect ratio Taylor-Couette flow.

Localized spirals in Taylor-Couette flow.

We present a type of spiral vortex state that appears from a supercritical Hopf bifurcation below the linear instability of circular Couette flow in a Taylor-Couette system with rigid end plates. These spirals have been found experimentally as well as numerically as "pure" states but also coexist with "classical" spirals (or axially standing waves for smaller systems) which typically appear from linear instability in counterrotating Taylor-Couette flow. These spiral states have an axial distribution of the strongly localized amplitude in the vicinity of the rigid end plates that confine the system in the axial direction. Furthermore, they show significantly different oscillation frequencies compared to the critical spiral frequencies. Despite the localization of the amplitude near the ends, the states appear as global states with spirals that propagate either toward the middle from each end of the system or vice versa. In contrast to classical spirals, these states exhibit a spatial or a spatiotemporal reflection symmetry.

"Snapping triceps": A rare and misleading condition - a clinical case report.

Snapping triceps corresponds to subluxation of the medial head of the triceps brachii over the medial epicondyle during active elbow flexion. It is a rare and misleading condition that is often associated with ulnar nerve instability. The latter can result in the snapping triceps being missed. Diagnosis requires a detailed clinical examination. Surgical treatment consists of anterior translocation of the nerve with an adipose flap to stabilize it and transfer of the distal attachment of the medial head of triceps brachii.

Exacerbated vein graft arteriosclerosis in protein kinase Cdelta-null mice.

Smooth muscle cell (SMC) accumulation is a key event in the development of atherosclerosis, including vein bypass graft arteriosclerosis. Because members of the protein kinase C (PKC) family signal cells to undergo proliferation, differentiation, or apoptosis, we generated PKCdelta knockout mice and performed vein bypass grafts on these animals. PKCdelta(-/-) mice developed normally and were fertile. Vein segments from PKCdelta(-/-) mice isografted to carotid arteries of recipient mice of either genotype led to a more severe arteriosclerosis than was seen with PKCdelta(+/+) vein grafts. Arteriosclerotic lesions in PKCdelta(-/-) mice showed a significantly higher number of SMCs than were found in wild-type animals; this was correlated with decreased SMC death in lesions of PKCdelta(-/-) mice. SMCs derived from PKCdelta(-/-) aortae were resistant to cell death induced by any of several stimuli, but they were similar to wild-type SMCs with respect to mitogen-stimulated cell proliferation in vitro. Furthermore, pro-apoptotic treatments led to diminished caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and cytochrome c release in PKCdelta(-/-) relative to wild-type SMCs, suggesting that their apoptotic resistance involves the loss of free radical generation and mitochondrial dysfunction in response to stress stimuli. Our data indicate that PKCdelta maintains SMC homeostasis and that its function in the vessel wall per se is crucial in the development of vein graft arteriosclerosis.

Imperfect Hopf bifurcation in spiral Poiseuille flow.

We present the results of an experimental study on the transition to spiral vortices in flow between concentric counter-rotating cylinders in the presence of an axial through-flow, i.e., in spiral Poiseuille flow. The experiments were performed in an apparatus having an aspect ratio Gamma=L/d=22.8 ( L axial length, d gap width between cylinders) and end plates enabling an in and outflow of mass. As a result of an applied axial through-flow the "classical" Hopf bifurcation to spiral vortices (SPI) splits up and a primary and secondary branch of down and upstream propagating SPI, respectively, as well as a transient quasiperiodic flow appear. Downstream propagating SPI resulting from the primary supercritical Hopf bifurcation are either convectively or absolutely unstable. The bifurcation structure observed in this open flow experiment is in qualitative agreement with predictions from theory of Hopf bifurcation with broken reflection symmetry [J. D. Crawford and E. Knobloch, Nonlinearity 1, 617 (1988)] and also in quantitative agreement with results from recent numerical calculations [A. Pinter, M. Lücke, and C. Hoffmann, Phys. Rev. E 67, 026318 (2003); C. Hoffmann, M. Lücke, and A. Pinter, Phys. Rev. E 69, 056309 (2004)].

Using observations and source specific model tracers to characterize pollutant transport during FRAPPÉ and DISCOVER-AQ.

Transport is a key parameter in air quality research and plays a dominant role in the Colorado Northern Front Range Metropolitan Area (NFRMA), where terrain induced flows and recirculation patterns can lead to vigorous mixing of different emission sources. To assess different transport processes and their connection to air quality in the NFRMA during the FRAPPÉ and DISCOVER-AQ campaigns in summer 2014, we use the Weather Research and Forecasting Model with inert tracers. Overall, the model represents well the measured winds and the inert tracers are in good agreement with observations of comparable trace gas concentrations. The model tracers support the analysis of surface wind and ozone measurements and allow for the analysis of transport patterns and interactions of emissions. A main focus of this study is on characterizing pollution transport from the NFRMA to the mountains by mountain-valley flows and the potential for recirculating pollution back into the NFRMA. One such event on 12 August 2014 was well captured by the aircraft and is studied in more detail. The model represents the flow conditions and demonstrates that during upslope events, frequently there is a separation of air masses that are heavily influenced by oil and gas emissions to the North and dominated by urban emissions to the South. This case study provides evidence that NFRMA pollution not only can impact the nearby Foothills and mountain areas to the East of the Continental Divide, but that pollution can "spill over" into the valleys to the West of the Continental Divide.

Metabolic stabilization of p27 in senescent fibroblasts correlates with reduced expression of the F-box protein Skp2.

When mortal human cells reach their finite lifespan, they enter an irreversible G1 growth arrest status referred to as senescence. Growth suppression of senescent cells can be explained by the accumulation of several growth-suppressive proteins, acting on mitogenic signal transduction and cell cycle regulation, respectively. We show here that the cdk inhibitor p27(KIP1), which is involved in several forms of G1 checkpoint control, accumulates in senescent cells. Whereas, the rate of p27 synthesis is reduced, accumulation of p27 is accompanied by an increase of the metabolic stability in senescent cells. p27 is a substrate for ubiquitin-mediated proteolysis, and its stabilization in senescent cells correlates with a deregulation of the p27-specific E3 ubiquitin ligase referred to as the SCF complex. Whereas, the Skp1 component of the SCF complex is overexpressed in senescent fibroblasts, the abundance of the F-box protein Skp2 is strongly reduced. In contrast to our findings with p27, the synthesis of the cell cycle regulators p21 and cyclin D1 is increased in senescent cells; however, both proteins are also highly unstable in these cells.

An unusual member of the human growth hormone/placental lactogen (GH/PL) family, the testicular alternative splicing variant hPL-A2: recombinant expression revealed a membrane-associated growth factor molecule.

The human growth hormone/placental lactogen (GH/PL) gene cluster consists of five highly-related genes (GH-N, GH-V, PL-L, PL-A, PL-B). This evolutionarily young gene cluster codes for an array of mRNAs and proteins, such as the major 22 k forms (hGH-N/V, identical PL-A and B), 20 k and 17.5 k hGH-N and the recently described 25 k hGH-Delta4, a presumably chimeric molecule. In addition, two longer alternatively spliced, (intron D retaining) mRNAs isoforms, termed PL-A2 and GH-V2, have been described in placenta and testis. To elucidate the role of hPL-A2 in male reproduction and pregnancy, testicular PL-A2 cDNA was cloned in a complementary overlapping 2-way RT-PCR approach to analyze translation, localization and structure/function of this unusual member of the GH/PL growth factor family. Analysis of insect mRNA revealed that intron D-retaining PL-A2 cDNA was expressed without splicing in the baculovirus expression system. Thus, PL-A2 mRNA does not represent a nuclear intermediate splicing product simply co-isolated with the mature RNA, but is a stable mRNA isoform generated by placental/testis-specific splicing factors. Recombinant protein was present in whole cell extracts, and no secreted protein was detected in the supernatant. Immunologically, the N-terminus of the 230 amino acid protein is similar to 22 k hPL-A/B, as determined by hPL-specific monoclonal antibodies. In contrast, the C-terminus shares a hydrophobic region presumably responsible for membrane insertion. By the use of confocal microscopy recombinant hPL-A2 was localized in the cell membrane. Thus, hPL-A2 might exert its function by modulating GH/PL actions or act as an independent growth-regulatory molecule itself and its functions in male reproduction and embryonic development remain to be investigated.

Expression levels of heat shock protein 60 in human endothelial cells in vitro are unaffected by exposure to 50 Hz magnetic fields.

Magnetic fields (MFs) from domestic power sources have been implicated as being a potential risk to human health. A number of epidemiological studies have found a significant link between exposure to MFs and increased rates of cancers. There have also been a number of in vivo and in vitro studies reporting effects of MFs in animal disease models and on the expression or activity of a range of proteins. In the past decade, our group proposed that atherosclerosis may have an autoimmune component, with heat shock protein 60 (Hsp60) expressed in endothelial cells as the dominant autoantigen. A number of stressors have been shown to induce the expression of Hsp60, including the classical risk factors for atherosclerosis. We were interested to see if the exposure of endothelial cells to an MF elicited increased expression of Hsp60, as has been reported previously for Hsp70. The present work describes the exposure of endothelial cells to domestic power supply (50 Hz) MFs at an intensity of 700 microT. The results from our system indicate that cultured endothelial cells exposed to a high intensity of MF either alone or in combination with classical heat stress show no effects on the expression of Hsp60 at either the messenger ribonucleic acid or the protein level. As such, there is no evidence that exposure to extremely low-frequency MF would be expected to increase the expression of Hsp60 and therefore the initiation or progression of atherosclerosis.

Clozapine-induced agranulocytosis in a Native American: HLA typing and further support for an immune-mediated mechanism.

BACKGROUND: Approximately 30% of schizophrenic patients defined as treatment refractory significantly improve with clozapine. However, clozapine produces agranulocytosis in approximately 1% to 2% of patients in the United States. The mechanism of clozapine-induced agranulocytosis has not been established, but evidence suggests an immune-mediated mechanism. METHOD: Human leukocyte antigen (HLA) typing was performed in a native American with clozapine-induced agranulocytosis. RESULTS: Our findings support previous observations of a role of the HLA-B16, DR4, DQw3 haplotype in predicting susceptibility to agranulocytosis in clozapine-treated patients. CONCLUSION: We suggest that HLA typing of clozapine candidates may be useful for predicting the risk for clozapine-induced agranulocytosis.

Delay estimation for cortico-peripheral relations.

In neurophysiology, time delays between concurrently measured time series are usually estimated from the slope of a straight line fitted to the phase spectrum. We point out that this estimate is valid only in the case in which, one signal is a mere time-delayed copy of the other one. We present a procedure for delay estimation that applies to a much wider class of systems with nontrivial phase spectrum like for example lowpass filters. The procedure is based on the Hilbert transform relation between the phase of a linear system and its log gain. The Hilbert transform relation is nonlocal in frequency space, a fact that limits its applicability to experimental data. We explore these limits, and demonstrate that the method is applicable to neurophysiological time series. We present the successful application of the Hilbert transform behavior method to concurrently recorded epicortical brain activity and peripheral tremor. We point out and explain physiologically unreasonable delay estimates given by the traditional method. Finally, we discuss the assumptions underlying the applicability of the Hilbert transform method in the neuroscience context.

Superior hydrodynamics of a modified cavopulmonary connection for the Norwood operation.

BACKGROUND: In the Fontan circulation, energy consumption at the cavopulmonary connection is crucial. Our hypothesis was that a modification of the standard Norwood variant of cavopulmonary connection with an extended anastomosis would improve hydrodynamics. METHODS: The in vitro hydrodynamics of two different Perspex glass models resembling the Norwood variant of cavopulmonary connection (model I) and the modification (model II) were analyzed in a mock circulation at nonpulsatile flows of 2 to 5 L/min to simulate rest and exercise. The pulmonary flow split was varied to imitate varying lung resistances. Inferior-to-superior caval flow ratio and size of models were increased to simulate growth. RESULTS: The pulmonary flow was preferentially directed to the left lung in model I and was better balanced in model II. Power losses increased exponentially with total flow in both models and were markedly higher in model I. These differences were attenuated in the larger models. Anastomotic turbulences were larger in model I. Power losses in both models were relatively insensitive to changes in pulmonary flow split. CONCLUSIONS: The proposed modification of the Norwood variant of cavopulmonary connection seems to be hydrodynamically advantageous and warrants further evaluation.