Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo.

Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4(+/+) or il4(-/-) eosinophils. Eosinophils controlled CD103(+) dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity.

Pulsatile control of rotary blood pumps: Does the modulation waveform matter?

Mechanical support of a failing heart is typically performed with rotary blood pumps running at constant speed, which results in a limited control on cardiac workload and nonpulsatile hemodynamics. A potential solution to overcome these limitations is to modulate the pump speed to create pulses. This study aims at developing a pulsatile control algorithm for rotary pumps, while investigating its effect on left ventricle unloading and the hemodynamics.

Reply to the editor

We appreciate the comments and concerns expressed by Arakawa and colleagues regarding our article, titled “Pulsatile control of rotary blood pumps: Does the modulation waveform matter?”1 Unfortunately, we have to disagree with Arakawa and colleagues. As is obvious from the title of our article, it investigates the effect of different waveforms on the heart–device interaction. In contrast to the authors' claim, this is the first article in the literature that uses basic waveforms (sine, triangle, saw tooth, and rectangular) with different phase shifts to examines their impact on left ventricular unloading. The previous publications2, 3 and 4 just varied the pump speed during systole and diastole, which was first reported by Bearnson and associates5 in 1996, and studied its effect on aortic pressure, coronary flow, and end-diastolic volume. We should mention that dp/dtmax is a load-sensitive parameter of contractility and not representative for the degree of unloading. Moreover, none of the aforementioned reports has studied mechanical unloading and in particular the stroke work of the left ventricle. Our method is unique because we do not just alternate between high and low speed but have accurate control of the waveform because of the direct drive system of Levitronix Technologies LLC (Waltham, Mass) and a custom-developed pump controller. Without referring, Arakawa and associates state “several previous studies have already reported the coronary flow diminishes as the left ventricular assist device support increases.” It should be noted that all the waveforms used in our study have 2000 rpm average value with 1000 rpm amplitude, which is not an excessive speed for the CentriMag rotary pump (Levitronix) to collapse the ventricle and diminish the coronary flow. We agree with Arakawa and coworkers that there is a need for a heart failure model to come to more relevant results with respect to clinical expectations. However, we have explored many existing models, including species and breeds that have a native proneness to cardiomyopathy, but all of them differ from the genetic presentation in humans. We certainly do not believe that the use of microembolization, in which the coronary circulation is impaired by the injection of microspheres, would form a good model from which to draw conclusions about coronary flow change under different loading conditions. A model would be needed in which either an infarct is created to mimic ischemic heart failure or the coronary circulation remains untouched to simulate, for instance, dilated cardiomyopathy. Furthermore, in discussion we clearly mention that “lack of heart failure is a major limitation of our study.” We also believe that unloading is not the only factor of the cardiac functional recovery, and an excessive unloading of the left ventricle might lead to cardiac tissue atrophy. Therefore, in our article we mention that control of the level of cardiac unloading by assist devices has been suggested as a mechanical tool to promote recovery, and more studies are required to find better strategies for the speed modulation of rotary pumps and to achieve an optimal heart load control to enhance myocardial recovery. Finally, there are many publications about pulsing rotary blood pumps and it was impossible to include them all. We preferred to reference some of the earlier basic works such as an original research by Bearnson and coworkers5 and another article published by our group,6 which is more relevant.

A robust reference signal generator for synchronized ventricular assist devices

Ventricular assist devices (VADs) are blood pumps that offer an option to support the circulation of patients with severe heart failure. Since a failing heart has a remaining pump function, its interaction with the VAD influences the hemodynamics. Ideally, the heart's action is taken into account for actuating the device such that the device is synchronized to the natural cardiac cycle. To realize this in practice, a reliable real-time algorithm for the automatic synchronization of the VAD to the heart rate is required. This paper defines the tasks such an algorithm needs to fulfill: the automatic detection of irregular heart beats and the feedback control of the phase shift between the systolic phases of the heart and the assist device. We demonstrate a possible solution to these problems and analyze its performance in two steps. First, the algorithm is tested using the MIT-BIH arrhythmia database. Second, the algorithm is implemented in a controller for a pulsatile and a continuous-flow VAD. These devices are connected to a hybrid mock circulation where three test scenarios are evaluated. The proposed algorithm ensures a reliable synchronization of the VAD to the heart cycle, while being insensitive to irregularities in the heart rate.

A novel interface for hybrid mock circulations to evaluate ventricular assist devices

This paper presents a novel mock circulation for the evaluation of ventricular assist devices (VADs), which is based on a hardware-in-the-loop concept. A numerical model of the human blood circulation runs in real time and computes instantaneous pressure, volume, and flow rate values. The VAD to be tested is connected to a numerical-hydraulic interface, which allows the interaction between the VAD and the numerical model of the circulation. The numerical-hydraulic interface consists of two pressure-controlled reservoirs, which apply the computed pressure values from the model to the VAD, and a flow probe to feed the resulting VAD flow rate back to the model. Experimental results are provided to show the proper interaction between a numerical model of the circulation and a mixed-flow blood pump.

A Physiological Controller for Turbodynamic Ventricular Assist Devices Based on a Measurement of the Left Ventricular Volume

The current article presents a novel physiological control algorithm for ventricular assist devices (VADs), which is inspired by the preload recruitable stroke work. This controller adapts the hydraulic power output of the VAD to the end-diastolic volume of the left ventricle. We tested this controller on a hybrid mock circulation where the left ventricular volume (LVV) is known, i.e., the problem of measuring the LVV is not addressed in the current article. Experiments were conducted to compare the response of the controller with the physiological and with the pathological circulation, with and without VAD support. A sensitivity analysis was performed to analyze the influence of the controller parameters and the influence of the quality of the LVV signal on the performance of the control algorithm. The results show that the controller induces a response similar to the physiological circulation and effectively prevents over- and underpumping, i.e., ventricular suction and backflow from the aorta to the left ventricle, respectively. The same results are obtained in the case of a disturbed LVV signal. The results presented in the current article motivate the development of a robust, long-term stable sensor to measure the LVV.

Analysis of Pressure Head-Flow Loops of Pulsatile Rotodynamic Blood Pumps

The clinical importance of pulsatility is a recurring topic of debate in mechanical circulatory support. Lack of pulsatility has been identified as a possible factor responsible for adverse events and has also demonstrated a role in myocardial perfusion and cardiac recovery. A commonly used method for restoring pulsatility with rotodynamic blood pumps (RBPs) is to modulate the speed profile, synchronized to the cardiac cycle. This introduces additional parameters that influence the (un)loading of the heart, including the timing (phase shift) between the native cardiac cycle and the pump pulses, and the amplitude of speed modulation. In this study, the impact of these parameters upon the heart-RBP interaction was examined in terms of the pressure head-flow (HQ) diagram. The measurements were conducted using a rotodynamic Deltastream DP2 pump in a validated hybrid mock circulation with baroreflex function. The pump was operated with a sinusoidal speed profile, synchronized to the native cardiac cycle. The simulated ventriculo-aortic cannulation showed that the level of (un)loading and the shape of the HQ loops strongly depend on the phase shift. The HQ loops displayed characteristic shapes depending on the phase shift. Increased contribution of native contraction (increased ventricular stroke work [WS ]) resulted in a broadening of the loops. It was found that the previously described linear relationship between WS and the area of the HQ loop for constant pump speeds becomes a family of linear relationships, whose slope depends on the phase shift.

Effects of Passive Hydrotherapy WATSU (WaterShiatsu) in the Third Trimester of Pregnancy: Results of a Controlled Pilot Study

Background. WATSU (WaterShiatsu) is a complementary therapeutic treatment method comprising passive stretches and massage techniques administered in 35°C warm water. Pregnant women claim safe methods to reduce pain, stress, and fatigue. Therefore, we conducted a pilot study evaluating the effects of WATSU on pregnancy-related complaints in third trimester pregnant women. Methods. Nine healthy pregnant women at gestational week ≥34 were included in an intervention group (receiving WATSU) and compared to eight women in a passive control group (receiving no treatment). WATSU was performed on days 1 and 4 of the study, accompanied by ultrasound examinations. Outcomes include physiological and psychometric as well as qualitative data. Participants in the control group completed questionnaires only. Results. WATSU was found to significantly lower participants’ levels of stress and pain and to improve their mental health-related quality of life and mood. In comparison to the passive control group, participants in the intervention group reported reduction in perceived stress from day 1 to day 8 (p = 0.036, Cohen’s f = 0.57). Qualitative data indicate that WATSU was appreciated as enjoyable and deeply relaxing. No negative side effects were reported. Conclusion. Our findings support the notion that WATSU yields therapeutic benefits for pregnant women and warrant further research. This study has been registered at ClinicalTrials.gov: NCT01708018.

Increased parietal activity after training of interference control

Recent studies suggest that computerized cognitive training leads to improved performance in related but untrained tasks (i.e. transfer effects). However, most study designs prevent disentangling which of the task components are necessary for transfer. In the current study, we examined whether training on two variants of the adaptive dual n-back task would affect untrained task performance and the corresponding electrophysiological event-related potentials (ERPs). Forty three healthy young adults were trained for three weeks with a high or low interference training variant of the dual n-back task, or they were assigned to a passive control group. While n-back training with high interference led to partial improvements in the Attention Network Test (ANT), we did not find transfer to measures of working memory and fluid intelligence. ERP analysis in the n-back task and the ANT indicated overlapping processes in the P3 time range. Moreover, in the ANT, we detected increased parietal activity for the interference training group alone. In contrast, we did not find electrophysiological differences between the low interference training and the control group. These findings suggest that training on an interference control task leads to higher electrophysiological activity in the parietal cortex, which may be related to improvements in processing speed, attentional control, or both.

Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin's lymphoma: a systematic review

Combined modality treatment (CMT) of chemotherapy followed by localized radiotherapy is standard treatment for patients with early stage Hodgkin's lymphoma. However, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. We thus performed a systematic review with meta-analysis of randomized controlled trials comparing chemotherapy alone with CMT in patients with early stage Hodgkin's lymphoma with respect to response rate, tumor control and overall survival (OS). We searched Medline, EMBASE and the Cochrane Library as well as conference proceedings from January 1980 to February 2009 for randomized controlled trials comparing chemotherapy alone versus the same chemotherapy regimen plus radiotherapy. Progression free survival and similar outcomes were analyzed together as tumor control. Effect measures used were hazard ratios for OS and tumor control as well as relative risks for complete response (CR). Meta-analyses were performed using RevMan5. Five randomized controlled trials involving 1,245 patients were included. The hazard ratio (HR) was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumor control and 0.40 (95% CI 0.27 to 0.59) for OS for patients receiving CMT compared to chemotherapy alone. CR rates were similar between treatment groups. In sensitivity analyses another 6 trials were included that did not fulfill the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. In conclusion, adding radiotherapy to chemotherapy improves tumor control and OS in patients with early stage Hodgkin's lymphoma.

Quantitative mRNA analysis of adrenergic receptor subtypes in the intestines of healthy dairy cows and dairy cows with cecal dilatation-dislocation

OBJECTIVE: To investigate the distribution of mRNA coding for 9 adrenoceptor subtypes in the intestines of healthy dairy cows and cows with cecal dilatationdislocation (CDD). SAMPLE POPULATION: Full-thickness specimens of the intestinal wall were obtained from the ileum, cecum, proximal loop of the ascending colon (PLAC), and external loop of the spiral colon (ELSC) of 15 cows with CDD (group 1) and 15 healthy (control) cows (group 2, specimens collected during laparotomy; group 3, specimens collected after slaughter). PROCEDURES: Concentrations of mRNA for 9 adrenoceptor subtypes (alpha(1A), alpha(1B), alpha(1D), alpha(2AD), alpha(2B), alpha(2C), beta(1), beta(2), and beta(3)) were measured by quantitative real-time reverse transcriptase-PCR assay. Results were expressed relative to mRNA expression of a housekeeping gene. RESULTS: Expression of mRNA for alpha(1B)-, alpha(2AD)-, alpha(2B)-, beta(1)-, and beta(2)-adrenoceptors was significantly lower in cows with CDD than in control cows. In the ileum, these receptors all had lower mRNA expression in cows with CDD than in control cows. The same effect was detected in the ELSC for mRNA for alpha(2AD)-, alpha(2B)-, beta(1)-, and beta(2)-adrenoceptors, and in the cecum and PLAC for alpha(2B)- and beta(2)-adrenoceptors. Groups did not differ significantly for alpha(1A)-adrenoceptors. The mRNA expression for alpha(1D)-, alpha(2C)-, and beta(3)-adrenoceptors was extremely low in all groups. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in expression of mRNA coding for adrenoceptors, most pronounced in the ileum and spiral colon, between cows with CDD and control cows support the hypothesis of an implication of adrenergic mechanisms in the pathogenesis of CDD in dairy cows.

Insular and caudate lesions release abnormal yawning in stroke patients.

Abnormal yawning is an underappreciated phenomenon in patients with ischemic stroke. We aimed at identifying frequently affected core regions in the supratentorial brain of stroke patients with abnormal yawning and contributing to the anatomical network concept of yawning control. Ten patients with acute anterior circulation stroke and ≥3 yawns/15 min without obvious cause were analyzed. The NIH stroke scale (NIHSS), Glasgow Coma Scale (GCS), symptom onset, period with abnormal yawning, blood oxygen saturation, glucose, body temperature, blood pressure, heart rate, and modified Rankin scale (mRS) were assessed for all patients. MRI lesion maps were segmented on diffusion-weighted images, spatially normalized, and the extent of overlap between the different stroke patterns was determined. Correlations between the period with abnormal yawning and the apparent diffusion coefficient (ADC) in the overlapping regions, total stroke volume, NIHSS and mRS were performed. Periods in which patients presented with episodes of abnormal yawning lasted on average for 58 h. Average GCS, NIHSS, and mRS scores were 12.6, 11.6, and 3.5, respectively. Clinical parameters were within normal limits. Ischemic brain lesions overlapped in nine out of ten patients: in seven patients in the insula and in seven in the caudate nucleus. The decrease of the ADC within the lesions correlated with the period with abnormal yawing (r = -0.76, Bonferroni-corrected p = 0.02). The stroke lesion intensity of the common overlapping regions in the insula and the caudate nucleus correlates with the period with abnormal yawning. The insula might be the long sought-after brain region for serotonin-mediated yawning.

Clinically relevant quality measures for risk factor control in primary care: a retrospective cohort study

BACKGROUND Assessment of the proportion of patients with well controlled cardiovascular risk factors underestimates the proportion of patients receiving high quality of care. Evaluating whether physicians respond appropriately to poor risk factor control gives a different picture of quality of care. We assessed physician response to control cardiovascular risk factors, as well as markers of potential overtreatment in Switzerland, a country with universal healthcare coverage but without systematic quality monitoring, annual report cards on quality of care or financial incentives to improve quality. METHODS We performed a retrospective cohort study of 1002 randomly selected patients aged 50-80 years from four university primary care settings in Switzerland. For hypertension, dyslipidemia and diabetes mellitus, we first measured proportions in control, then assessed therapy modifications among those in poor control. "Appropriate clinical action" was defined as a therapy modification or return to control without therapy modification within 12 months among patients with baseline poor control. Potential overtreatment of these conditions was defined as intensive treatment among low-risk patients with optimal target values. RESULTS 20% of patients with hypertension, 41% with dyslipidemia and 36% with diabetes mellitus were in control at baseline. When appropriate clinical action in response to poor control was integrated into measuring quality of care, 52 to 55% had appropriate quality of care. Over 12 months, therapy of 61% of patients with baseline poor control was modified for hypertension, 33% for dyslipidemia, and 85% for diabetes mellitus. Increases in number of drug classes (28-51%) and in drug doses (10-61%) were the most common therapy modifications. Patients with target organ damage and higher baseline values were more likely to have appropriate clinical action. We found low rates of potential overtreatment with 2% for hypertension, 3% for diabetes mellitus and 3-6% for dyslipidemia. CONCLUSIONS In primary care, evaluating whether physicians respond appropriately to poor risk factor control, in addition to assessing proportions in control, provide a broader view of the quality of care than relying solely on measures of proportions in control. Such measures could be more clinically relevant and acceptable to physicians than simply reporting levels of control.

Cellular immune response, stress resistance and competitiveness in nestling great tits in relation to maternally transmitted carotenoids

1. Egg yolks contain carotenoids that protect biological molecules against free-radical damage and promote maturation of the immune system. Availability of carotenoids to birds is often limited. Trade-offs can thus arise in the allocation of carotenoids to different physiological functions, and mothers may influence the immunocompetence of nestlings by modulating the transfer of carotenoid to the yolk.;2. In the great tit Parus major, we experimentally manipulated the dietary supply of carotenoid to mothers, and partially cross-fostered hatchlings to investigate the effect of an increased availability of carotenoids during egg laying on immunocompetence of nestlings.;3. In addition, we infested half of the nests with hen fleas Ceratophyllus gallinae to investigate the relationship between carotenoid availability, resistance to ectoparasites and immunocompetence.;4. We found that the procedure of cross-fostering can reduce the immune response of nestlings, but this effect can be compensated by the maternally transferred carotenoids. Cross-fostered nestlings of carotenoid-supplemented females show a similar immune response to non-cross-fostered nestlings, while cross-fostered nestlings of control females mounted a weaker cell-mediated immune response. This suggests that yolk carotenoids may help nestlings to cope with stress, for example the one generated by cross-fostering and/or they may enhance nestling competitiveness.;5. There was no statistically significant interaction between parasite and carotenoid treatments, as would be expected if carotenoids helped nestlings to fight parasites. Under parasite pressure, however, lighter nestlings raised a lower immune response, while the immune response was only weakly correlated with body mass in uninfested nests.

Water-use efficiency and transpiration across European forests during the Anthropocene

The Earth’s carbon and hydrologic cycles are intimately coupled by gas exchange through plant stomata1, 2, 3. However, uncertainties in the magnitude4, 5, 6 and consequences7, 8 of the physiological responses9, 10 of plants to elevated CO2 in natural environments hinders modelling of terrestrial water cycling and carbon storage11. Here we use annually resolved long-term δ13C tree-ring measurements across a European forest network to reconstruct the physiologically driven response of intercellular CO2 (Ci) caused by atmospheric CO2 (Ca) trends. When removing meteorological signals from the δ13C measurements, we find that trees across Europe regulated gas exchange so that for one ppmv atmospheric CO2 increase, Ci increased by ~0.76 ppmv, most consistent with moderate control towards a constant Ci/Ca ratio. This response corresponds to twentieth-century intrinsic water-use efficiency (iWUE) increases of 14 ± 10 and 22 ± 6% at broadleaf and coniferous sites, respectively. An ensemble of process-based global vegetation models shows similar CO2 effects on iWUE trends. Yet, when operating these models with climate drivers reintroduced, despite decreased stomatal opening, 5% increases in European forest transpiration are calculated over the twentieth century. This counterintuitive result arises from lengthened growing seasons, enhanced evaporative demand in a warming climate, and increased leaf area, which together oppose effects of CO2-induced stomatal closure. Our study questions changes to the hydrological cycle, such as reductions in transpiration and air humidity, hypothesized to result from plant responses to anthropogenic emissions.