STAT3 is required for IL-21-induced secretion of IgE from human naive B cells

The production of immunoglobulin E (IgE) is tightly regulated. This is evidenced by the fact that it comprises less than 0.0001% of serum Ig, and aberrant production causes atopic conditions, including allergy, rhinitis, and anaphylaxis. Interleukin-4 (IL-4) is a well-characterized inducer of IgE by human and murine B cells, whereas interferon-gamma can antagonize this effect. IL-21 has also been recognized for its ability to suppress IL-4-induced IgE production by murine B cells. Here, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human naive B cells. Furthermore, there was a striking synergy between IL-4 and IL-21 on inducing IgE secretion by CD40L-stimulated human B cells, such that the levels detected under these conditions exceeded those induced by IL-4 or IL-21 alone by more than 10-fold. IL-21 induced activation of STAT3 and analysis of B cells from patients with loss-of-function STAT3 mutations revealed that the ability of IL-21 to induce IgE secretion, and augment that driven by IL-4, was STAT3-dependent. These findings highlight a fundamental difference between the regulation of IgE production by human and murine B cells and have implications for the dysregulated production of IgE in conditions characterized by extremely high levels of serum IgE.     

The genetics of ivermectin resistance in Caenorhabditis elegans

The ability of organisms to evolve resistance threatens the effectiveness of every antibiotic drug. We show that in the nematode Caenorhabditis elegans, simultaneous mutation of three genes, avr-14, avr-15, and glc-1, encoding glutamate-gated chloride channel (GluCl) alpha-type subunits confers high-level resistance to the antiparasitic drug ivermectin. In contrast, mutating any two channel genes confers modest or no resistance. We propose a model in which ivermectin sensitivity in C. elegans is mediated by genes affecting parallel genetic pathways defined by the family of GluCl genes. The sensitivity of these pathways is further modulated by unc-7, unc-9, and the Dyf (dye filling defective) genes, which alter the structure of the nervous system. Our results suggest that the evolution of drug resistance can be slowed by targeting antibiotic drugs to several members of a multigene family.     

Is Frailty a Predictor of Outcomes in Elderly Inpatients with Acute Kidney Injury? A Prospective Cohort Study

Background

Frailty and acute kidney injury are independently associated with an increased risk of morbidity and mortality. The degree of frailty can be assessed by the Clinical Frailty Score (CFS). This study assessed whether an individual's CFS was associated with acute kidney injury in acute elderly medical admissions and recorded the short-term outcomes.

In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease

The B-lymphocyte/accessory-cell activation antigen B7 (BB1) has been shown in vitro to stimulate T-lymphocyte proliferation and cytokine production via CD28 present on the latter cells. In this study, benign lymphoid tissues, lymphomas, and extralymphoid inflammatory sites were examined immunohistochemically using anti-B7 and other relevant monoclonal antibodies. B7 was expressed by benign transformed germinal center B cells, as it was by B cells of follicular lymphomas. B7 was also expressed by a subpopulation (a mean of 31% to 65%) of macrophages and dendritic cells in a variety of lymphoid tissues. It was present in abundance on all macrophages constituting sarcoid granulomas in lymph nodes. In extralymphoid inflammation, 17% to 35% of macrophages expressed B7 only weakly. Cases of Hodgkin's disease showed expression of B7 by the majority of Reed-Sternberg cells or malignant mononuclear variants, a phenomenon that potentially contributes to the lymphocytic accumulation that is a feature of this condition. CD28+ T cells were seen in all areas where T cells were present. B7+ and CD28+ cells colocalized in, for example, lymphoid follicles, lymph node paracortex, sarcoid granulomas, and Hodgkin's disease tissue, indicating a potential for cellular interaction via these molecules at these sites.     

Pulmonary surfactant as a vehicle for intratracheal delivery of technetium sulfur colloid and pentamidine in hamster lungs

Tracheal instillation of pentamidine in a surfactant vehicle may be an effective direct method of antibiotic delivery to the lungs. In 10 healthy hamsters, we compared the pulmonary distribution of 99mTc sulfur colloid (TcSC) mixed with pentamidine, using as a vehicle either surfactant (n = 5) or saline (n = 5). Each animal was instilled with 0.25 ml/kg of suspension containing 0.0018 mCi TcSC and pentamidine mixed with either surfactant or saline. After 4 h of spontaneous respiration, the lungs were excised, inflated to TLC, dried, and sliced into 3-mm cross sections from apex to base. Autoradiographs were examined to evaluate 99mTc distribution. The surfactant group had detectable radioactivity in 93% of all slices compared with 72% in the saline group (p = 0.02). Six slices per animal (43% of total) and their corresponding autoradiographs were analyzed for distribution of radioactivity. Lung slice area was determined by planimetry, and autoradiograph area was determined by video densitometry. We calculated the fraction of each lung slice with detectable radioactivity. The surfactant group had 41% of the lung slice areas exposed compared with 21% in the saline group (p = 0.02). The coefficient of variation of radioactive intensities within each slice was used as an index of spatial uniformity. There was a trend towards more uniform distribution in the surfactant group, with a narrower range of variation of intensities (1.51 to 2.56) than the saline group (1.95 to 6.47). We conclude that a surfactant vehicle significantly increases airspace deposition of TcSC and pentamidine instilled intratracheally in normal hamster lungs, and may improve uniformity of spread.     

Vital Signs: Estimated Effects of a Coordinated Approach for Action to Reduce Antibiotic-Resistant Infections in Health Care Facilities — United States

BackgroundTreatments for health care–associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversing the increasing incidence of these infections than independent facility-based program efforts.MethodsData from CDC’s National Healthcare Safety Network and Emerging Infections Program were analyzed to project the number of health care–associated infections from antibiotic-resistant bacteria or C. difficile both with and without a large scale national intervention that would include interrupting transmission and improved antibiotic stewardship. As an example, the impact of reducing transmission of one antibiotic-resistant infection (carbapenem-resistant Enterobacteriaceae [CRE]) on cumulative prevalence and number of HAI transmission events within interconnected groups of health care facilities was modeled using two distinct approaches, a large scale and a smaller scale health care network.ResultsImmediate nationwide infection control and antibiotic stewardship interventions, over 5 years, could avert an estimated 619,000 HAIs resulting from CRE, multidrug-resistant Pseudomonas aeruginosa, invasive methicillin-resistant Staphylococcus aureus (MRSA), or C. difficile. Compared with independent efforts, a coordinated response to prevent CRE spread across a group of inter-connected health care facilities resulted in a cumulative 74% reduction in acquisitions over 5 years in a 10-facility network model, and 55% reduction over 15 years in a 102-facility network model.ConclusionsWith effective action now, more than half a million antibiotic-resistant health care–associated infections could be prevented over 5 years. Models representing both large and small groups of interconnected health care facilities illustrate that a coordinated approach to interrupting transmission is more effective than historical independent facility-based efforts.Implications for Public HealthPublic health–led coordinated prevention approaches have the potential to more completely address the emergence and dissemination of these antibiotic-resistant organisms and C. difficile than independent facility–based efforts.     

A robust estimate of the number and characteristics of persons released from prison in Australia

Objective: To estimate the number and characteristics of adults released from prison in Australia. Method: We calculated ratios, stratified by age, sex and Indigenous status, by comparing the number of persons released from prison in New South Wales (NSW), with the number in NSW prisons on 30 June of the corresponding year. These stratified ratios were applied to Australia‐wide prison data to estimate the number and characteristics of persons released annually. Results: We estimated that in 2013, 38,576 persons were released from prison in Australia ? 25.3% more than the daily prison population. Young people, Indigenous people and women were over‐represented among those released. We estimated that 3.69 Indigenous women aged 18–24 were released annually for each equivalent person in prison; and 2.75 non‐Indigenous women aged 18–24 were released annually for each equivalent person in prison. Conclusions: The annual ‘flow’ through Australia's prisons is well in excess of the daily number, but information on those moving through prison systems is not yet publicly available. The characteristics of those released from prison differ meaningfully from those of people in prison. Routine, national reporting of prison separations is critical to informing upscaling and targeting of Throughcare services for this profoundly vulnerable population.     

Lowering dietary protein to U.S. Recommended dietary allowance levels reduces urinary calcium excretion and bone resorption in young women

High-protein diets increase calciuria. No previous studies have examined the ad libitum U.S. diet's effect on calciuria or bone resorption.Thirty-nine healthy, premenopausal women consuming ad libitum diets [mean, 1.1 g/kg protein, 819 mg (20.5 mmol) Ca, 1152 mg (37 mmol) P, 129 mmol Na] were switched to isocaloric diets containing the U.S. recommended dietary allowance (RDA) of protein (0.8 g/kg) and similar amounts of calcium, phosphorus, and sodium. Bone resorption and related endpoints were assessed before and 1 wk after the switch.As dietary protein changed from ad libitum to RDA levels, mean urine nitrogen decreased 26% (2.4 g/d; P < 0.001) and mean blood urea nitrogen decreased 15% (1.9 mg/dl; P < 0.001). Mean urine pH increased from 6.3 to 6.8 (P < 0.001), and net renal acid excretion (NRAE = urine ammonium plus titratable acids minus bicarbonate) decreased 68% (21.4 mEq/d; P < 0.001). Mean urinary calcium decreased 32% [42 mg (1 mmol)/d; P < 0.001], and bone resorption urine N-telopeptides) decreased 17% (74 micromol bovine collagen equivalents/d; P < 0.001). Mean serum calcium, PTH, and 1,25 dihydroxy vitamin D remained unchanged.In this 2-wk study, decreasing dietary protein from ad libitum to RDA levels decreased NRAE, calciuria and estimates of bone resorption, suggesting that decreased U.S. protein consumption might reduce bone loss. Inasmuch as other dietary modifications, such as increasing vegetable and fruit intake, can result in sustained reductions in NRAE without reducing protein intake, the advisability of reducing protein intake for skeletal protection from acid attack requires further investigation.     

Mediator-Directed Therapy in Pancreatitis and Trauma

Both acute pancreatitis and severe trauma induce a systemic sterile inflammatory process which leads to a high incidence of remote organ dysfunction and death. Several attributes of these two entities make them ideal for evaluation of the effects of mediator-directed therapy. The rationale and evidence for mediator-directed therapy in pancreatitis and trauma are reviewed. In pancreatitis, organ dysfunction and death are best prevented using strategies designed to limit the inflammatory response, particularly IL-1a and IL-10. By contrast, the sequelae of a post-traumatic systemic inflammatory response are best mitigated using strategies designed to limit neutrophil adhesion.