Regulatory T cells--the renaissance of the suppressor T cells

Immune reactions are stringently regulated and balanced by complex interactions of stimulating and suppressing mechanisms. Dysfunctions of this sophisticated immune regulatory network can lead to a variety of diseases such as autoimmunity, allergy, cancer, and pregnancy disorders. The rediscovery of suppressor T cells a decade ago--now designated as T regulatory cells--set off a huge avalanche of research activities leading to a multitude of preclinical and clinical studies. Herein, we give a comprehensive review about this research on T regulatory cells and the relevance of this suppressive T cell population for the development of innovative immune therapeutic strategies.     

Haploidentical Stem Cell Transplantation for Refractory/Relapsed Neuroblastoma

Pediatric patients with refractory or relapsed metastatic neuroblastoma (NBL) have a poor prognosis despite autologous stem cell transplantation (SCT). Allogeneic SCT from a haploidentical donor has a remarkable alloreactive effect in patients with leukemia; thus, we evaluated this approach in children with very high-risk NBL. We analyzed data from 2 prospective phase I/II trials. A total of 26 patients with refractory (n?=?5), metastatic relapsed (n?=?20), or locally relapsed MYCN-positive (n?=?1) NBL received a median of 17?×?10⁶/kg T/B cell-depleted CD34⁺ stem cells with 68?×?10³/kg residual T cells and 107?×?10⁶/kg natural killer cells. The conditioning regimen comprised melphalan, fludarabine, thiotepa, OKT3, and a short course of mycophenolate mofetil post-transplantation. Engraftment occurred in 96% of the patients. Event-free survival and overall survival at 5 years were 19% and 23%, respectively. No transplantation-related mortality was observed, and the single death was due to progression/subsequent relapse. The median duration of follow-up was 8.1 years. Patients in complete remission before SCT had a significantly better prognosis than those with residual tumor load (P?<?.01). All patients with progressive disease before SCT relapsed within 1 year. Grade II and grade III acute graft-versus-host disease (GVHD) occurred in 31% and 12% of the patients, respectively. Chronic limited and extensive GVHD occurred in 28% and 10%, respectively. Our data indicate that haploidentical SCT is a feasible treatment option that can induce long-term remission in some patients with NBL with tolerable side effects, and may enable the development of further post-transplantation therapeutic strategies based on the donor-derived immune system.     

Microbiologic Diagnostic Workup of Acute Respiratory Failure with Pulmonary Infiltrates after Allogeneic Hematopoietic Stem Cell Transplantation: Findings in the Era of Molecular- and Biomarker-Based Assays

Allogeneic hematopoietic stem cell transplantation (HSCT) recipients frequently develop acute respiratory failure (ARF) with pulmonary infiltrates. Molecular- and biomarker-based assays enhance pathogen detection, but data on their yield in this population are scarce. This was a retrospective single-center study of 156 consecutive HSCT recipients admitted to the intensive care unit (ICU) between May 2013 and July 2017. Findings from a microbiologic diagnostic workup using currently available methods on bronchoalveolar lavage (BAL) and blood samples from 66 patients (age, 58 years [range, 45 to 64]; HSCT to ICU, 176 days [range, 85 to 407]) with ARF and pulmonary infiltrates were analyzed. In 47 patients (71%) a causative pathogen was identified (fungal, n?=?28; viral, n?=?26; bacterial, n?=?18). Polymicrobial findings involving several pathogen groups occurred in 20 patients (30%). Culture (12/16, 75%), galactomannan (13/15, 87%), and Aspergillus-PCR (8/9, 89%) from BAL but not serum galactomannan (6/14, 43%) helped to diagnose invasive aspergillosis (n?=?16, 24%). Aspergillus-PCR detected azole resistance in 2 cases. Mucorales was found in 7 patients (11%; BAL culture, n?=?6; Mucorales-PCR, n?=?1). Patients with identified pathogens had higher Simplified Acute Physiology Score II scores (P?=?.049) and inferior ICU survival (6% versus 37%, P?<?.01), which largely related to the presence of an invasive fungal infection. Eight patients (12%) had 1 or more viruses with uncertain lung pathogenicity as the sole microbiologic finding. A diagnostic microbiologic workup incorporating molecular- and biomarker-based assays identified pathogens in most HSCT recipients with ARF and pulmonary infiltrates admitted to the ICU. Implications of polymicrobial infection and pathogen patterns in these patients warrant further investigation.     

Incidence of class 1 and 2 integrases in clinical and commensal bacteria from livestock, companion animals, and exotics

Many pathogenic and commensal organisms are multidrug resistant due to exposure to various antibiotics. Often, this antimicrobial resistance is encoded by integrons that occur on plasmids or that are integrated into the bacterial chromosome. Integrons are commonly associated with bacterial genera in the family Enterobacteriaceae. We determined that class 1 integrases were present in approximately 46% of the isolates from the family Enterobacteriaceae; class 2 integrases were present only among Escherichia coli and Salmonella isolates. Seven percent of veterinary isolates were positive for class 3 integrase by DNA-DNA hybridization but could not be confirmed to be positive by PCR. None of the veterinary isolates possessed the class 4 integrase gene. The distribution of these integrase genes was variable within the members of the family Enterobacteriaceae when some or all integrase classes were absent from a particular genus. There was also considerable variability in the distribution of these integrases within a species, depending on the animal host. Unlike the class 1 integrases, the other integrase class, intI2, appears to be more restricted in its distribution among the members of the family Enterobacteriaceae. There is also considerable variability in the distribution of the class 1 integrases within E. coli strains isolated from different food animals. The class 1 integrases are the most widely disseminated of the four classes among the members of the family Enterobacteriaceae from both the clinical and normal flora of animals. This is the first report to closely examine the distribution of class 2 integrases in members of the family Enterobacteriaceae isolated in the United States.     

Diastolic dysfunction: can it be diagnosed by Doppler echocardiography?

Heart failure with a normal ejection fraction (HFNEF) predominantly afflicts older, female individuals and is considered to be a consequence of diastolic dysfunction. Doppler echocardiography has become the standard method for identifying and characterizing diastolic function. However, the important distinction between Doppler measures of filling dynamics and true indexes of intrinsic ventricular diastolic chamber properties is not widely appreciated. Herein, we delineate physiologic measures of intrinsic ventricular diastolic function, as determined by pressure volume analysis, and compare and contrast these measures with those derived from Doppler echocardiography. Doppler-derived indexes of ventricular filling do not provide specific information on intrinsic passive diastolic properties, and thus, abnormal filling dynamics do not necessarily equate with intrinsic myocardial diastolic dysfunction. This raises a fundamental question as to whether delayed relaxation and/or stiffened passive properties are the unifying pathophysiologic mechanisms in all patients who present with HFNEF.     

Social cognition and social problem solving abilities in individuals with alcohol use disorder

Background: Up to now, little is known about higher order cognitive abilities like social cognition and social problem solving abilities in alcohol-dependent patients. However, impairments in these domains lead to an increased probability for relapse and are thus highly relevant in treatment contexts. Method: This cross-sectional study assessed distinct aspects of social cognition and social problem solving in 31 hospitalized patients with alcohol use disorder (AUD) and 30 matched healthy controls (HC). Three ecologically valid scenario-based tests were used to gauge the ability to infer the mental state of story characters in complicated interpersonal situations, the capacity to select the best problem solving strategy among other less optimal alternatives, and the ability to freely generate appropriate strategies to handle difficult interpersonal conflicts. Standardized tests were used to assess executive function, attention, trait empathy, and memory, and correlations were computed between measures of executive function, attention, trait empathy, and tests of social problem solving. Results: AUD patients generated significantly fewer socially sensitive and practically effective solutions for problematic interpersonal situations than the HC group. Furthermore, patients performed significantly worse when asked to select the best alternative among a list of presented alternatives for scenarios containing sarcastic remarks and had significantly more problems to interpret sarcastic remarks in difficult interpersonal situations.

Conclusions: These specific patterns of impairments should be considered in treatment programs addressing impaired social skills in individuals with AUD.     

Contribution of the Cerebellum in Cue-Dependent Force Changes During an Isometric Precision Grip Task

The “raspberry task” represents a precision grip task that requires continuous adjustment of grip forces and pull forces. During this task, subjects use a specialised grip rod and have to increase the pull force linearly while the rod is locked. The positions of the fingers are unrestrained and freely selectable. From the finger positions and the geometry of the grip rod, a physical lever was derived which is a comprehensive measurement of the subject’s grip behaviour. In this study, the involvement of the cerebellum in establishing cued force changes (CFC) was examined. The auditory stimulus was associated with a motor behaviour that has to be readjusted during an ongoing movement that already started. Moreover, cerebellar involvement on grip behaviour was examined. The results show that patients presenting with degenerating cerebellar disease (CBL) were able to elicit CFC and were additionally able to optimise grip behaviour by minimising the lever. Comparison of the results of CBL with a control group of healthy subjects showed, however, that the CFC incidence was significantly lower and the reduction of the lever was less in CBL. Hence, the cerebellum is involved not only in the classical conditioning of reflexes but also in the association of sensory stimuli with complex changes in motor behaviour. Furthermore, the cerebellum is involved in the optimisation of grip behaviour during ongoing movements. Recent studies lead to the assumption that the cerebello-reticulo-spinal pathway might be important for the reduced optimisation of grip behaviour in CBL.     

Searching Choices: Quantifying Decision‐Making Processes Using Search Engine Data

When making a decision, humans consider two types of information: information they have acquired through their prior experience of the world, and further information they gather to support the decision in question. Here, we present evidence that data from search engines such as Google can help us model both sources of information. We show that statistics from search engines on the frequency of content on the Internet can help us estimate the statistical structure of prior experience; and, specifically, we outline how such statistics can inform psychological theories concerning the valuation of human lives, or choices involving delayed outcomes. Turning to information gathering, we show that search query data might help measure human information gathering, and it may predict subsequent decisions. Such data enable us to compare information gathered across nations, where analyses suggest, for example, a greater focus on the future in countries with a higher per capita GDP. We conclude that search engine data constitute a valuable new resource for cognitive scientists, offering a fascinating new tool for understanding the human decision‐making process.