CD28 signals the differential control of regulatory T cells and effector T cells

One possible means of driving antigen‐specific immune suppression is to expand or induce antigen‐specific FoxP3‐expressing Treg cells. One way of activating and expanding these specialized cells, both in vitro and in vivo, is by strong costimulation via CD28 with an agonistic anti‐CD28 monoclonal antibody, called anti‐CD28 superagonist (CD28SA). However, CD28SA also strongly activates conventional T (Tconv) cells to secrete proinflammatory cytokines and, under certain conditions, causes serious cytokine release syndrome. In this issue of European Journal of Immunology, Tabares et al. [Eur. J. Immunol. 2014. 44: 1225–1236] address how CD28SA can be used for the differential control of human Treg and Tconv cells to suppress immune responses without serious adverse effects. They show that, depending on the dose of the antibody or by comedication of cortico‐steroid, the selective expansion of Treg cells can be achieved without significantly activating Tconv cells to produce inflammatory cytokines. This difference in CD28 signal sensitivity between the two populations can be exploited for better control of immune responses.     

NBCe1 as a model carrier for understanding the structure–function properties of Na+-coupled SLC4 transporters in health and disease

SLC4 transporters are membrane proteins that in general mediate the coupled transport of bicarbonate (carbonate) and share amino acid sequence homology. These proteins differ as to whether they also transport Na⁺ and/or Cl^?, in addition to their charge transport stoichiometry, membrane targeting, substrate affinities, developmental expression, regulatory motifs, and protein–protein interactions. These differences account in part for the fact that functionally, SLC4 transporters have various physiological roles in mammals including transepithelial bicarbonate transport, intracellular pH regulation, transport of Na⁺ and/or Cl^?, and possibly water. Bicarbonate transport is not unique to the SLC4 family since the structurally unrelated SLC26 family has at least three proteins that mediate anion exchange. The present review focuses on the first of the sodium-dependent SLC4 transporters that was identified whose structure has been most extensively studied: the electrogenic Na⁺-base cotransporter NBCe1. Mutations in NBCe1 cause proximal renal tubular acidosis (pRTA) with neurologic and ophthalmologic extrarenal manifestations. Recent studies have characterized the important structure–function properties of the transporter and how they are perturbed as a result of mutations that cause pRTA. It has become increasingly apparent that the structure of NBCe1 differs in several key features from the SLC4 Cl^?–HCO₃ ^? exchanger AE1 whose structural properties have been well-studied. In this review, the structure–function properties and regulation of NBCe1 will be highlighted, and its role in health and disease will be reviewed in detail.     

Anatomy of hierarchy: Feedforward and feedback pathways in macaque visual cortex

The laminar location of the cell bodies and terminals of interareal connections determines the hierarchical structural organization of the cortex and has been intensively studied. However, we still have only a rudimentary understanding of the connectional principles of feedforward (FF) and feedback (FB) pathways. Quantitative analysis of retrograde tracers was used to extend the notion that the laminar distribution of neurons interconnecting visual areas provides an index of hierarchical distance (percentage of supragranular labeled neurons [SLN]). We show that: 1) SLN values constrain models of cortical hierarchy, revealing previously unsuspected areal relations; 2) SLN reflects the operation of a combinatorial distance rule acting differentially on sets of connections between areas; 3) Supragranular layers contain highly segregated bottom‐up and top‐down streams, both of which exhibit point‐to‐point connectivity. This contrasts with the infragranular layers, which contain diffuse bottom‐up and top‐down streams; 4) Cell filling of the parent neurons of FF and FB pathways provides further evidence of compartmentalization; 5) FF pathways have higher weights, cross fewer hierarchical levels, and are less numerous than FB pathways. Taken together, the present results suggest that cortical hierarchies are built from supra‐ and infragranular counterstreams. This compartmentalized dual counterstream organization allows point‐to‐point connectivity in both bottom‐up and top‐down directions. J. Comp. Neurol. 522:225–259, 2014. © 2013 Wiley Periodicals, Inc.     

Increased nitric oxide production and gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats

The fetal lung is affected by maternal diabetes. Nuclear receptor PPARα regulates nitric oxide (NO) overproduction in different tissues. We aimed to determine whether fetal lung PPARα expression is altered by maternal diabetes, and if there are gender-dependent changes in PPARα regulation of NO production in the fetal lung. Fetal lungs from control and diabetic rats were explanted on day 21 of gestation and evaluated for PPARα expression and NO production. Fetuses were injected with the PPARα ligand LTB(4) on days 19, 20 and 21, and the fetal lung explanted on day 21 to evaluate PPARα and the inducible isoform of NO synthase (iNOS). Besides, pregnant rats were fed with olive oil- and safflower oil-supplemented diets, enriched in PPAR ligands, for evaluation of fetal lung NO production and PPARα expression. We found reduced PPARα concentrations only in the lung from male fetuses from the diabetic group when compared to controls, although maternal diabetes led to NO overproduction in both male and female fetal lungs. Fetal activation of PPARα led to changes in lung PPARα expression only in female fetuses, although this treatment increased iNOS expression in both male and female fetuses in the diabetic group. Diets supplemented with olive oil and not with safflower oil led to a reduction in NO production in male and female fetal lungs. In conclusion, there are gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats, although PPARα activation prevents maternal diabetes-induced lung NO overproduction in both male and female fetuses.     

Biofilm Formation within the Interface of Bovine Root Dentin Treated with Conjugated Chitosan and Sealer Containing Chitosan Nanoparticles

IntroductionThe purpose of this study was to assess biofilm formation within sealer-dentin interfaces of root segments filled with gutta-percha and sealer incorporated with chitosan (CS) nanoparticles with and without canal surface treatment with different formulations of CS.MethodsStandardized canals of 4-mm bovine root segments (N = 35) were filled with gutta-percha and pulp canal sealer incorporated with CS nanoparticles without surface treatment (group CS) or after surface treatment with phosphorylated CS (group PHCS), CS-conjugated rose bengal and photodynamic irradiation (group CSRB), or a combination of both PHCS and CSRB (group RBPH). The control group was filled with gutta-percha and an unmodified sealer. After 7 days of setting, specimens were aged in buffered solution at 37°C for 1 or 4 weeks. Monospecies biofilms of Enterococcus faecalis were grown on specimens for 7 days in a chemostat-based biofilm fermentor. Biofilm formation within the sealer-dentin interface was assessed with confocal laser scanning microscopy.ResultsIn the 4-week–aged specimens only, the mean biofilm areas were significantly smaller than in the control for the CS (P = .008), PHCS (P = .012), and RBPH (P = .034) groups. The percentage of the biofilm-covered interface also was significantly lower than in the control for the CS (P = .024) and PHCS (P = .003) groups. The CS, PHCS, and RBPH groups did not differ significantly.ConclusionsIncorporating CS nanoparticles into the zinc oxide–eugenol sealer inhibited biofilm formation within the sealer-dentin interface. This effect was maintained when canals were treated with phosphorylated CS, and it was moderated by canal treatment with CS-conjugated rose bengal and irradiation.     

Foster Care History and HIV Infection among Drug-Using African American Female Sex Workers

Foster care has been associated with increased HIV risk behaviors among youth, yet long-term association with HIV infection has not been examined. This study explored the associations between foster placement, victimization, mental health, onset of sex work and HIV infection among highly vulnerable female sex workers. 562 drug-involved African American women were enrolled into an intervention study to increase health services utilization and reduce HIV risk. Seventeen percent reported a history of foster placement. Foster history was associated with significantly lower educational attainment, higher victimization, and more severe mental health problems. Women with foster histories reported significantly earlier entry into paid sex work, with some 62% active in the sex trade before age 18. Multivariate analyses found that foster care was independently associated with HIV seropositivity, and that early sex work partially mediated this association. The potential long-term health vulnerabilities associated with foster placement are understudied and warrant additional research.     

Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review

Hypercortisolism due to an ACTH-secreting pituitary adenoma (Cushing’s disease) is a chronic condition associated with high morbidity and mortality if inadequately managed. Pasireotide is a multireceptor-targeted somatostatin analogue and is the only approved medical therapy for Cushing’s disease that treats the underlying cause of the disorder. This paper reviews the available literature for medical-therapy-induced adenoma volume reduction in patients with Cushing’s disease and reports the experience of a 53-year-old surgically, radiologically and medically naïve (de novo) female with a pituitary macroadenoma who declined surgery. This patient was treated with pasireotide as first-line therapy as part of the largest randomized Phase III study evaluating a medical therapy in patients with Cushing’s disease (SOM230B2305 trial). Subcutaneous pasireotide significantly decreased tumor volume, suppressed cortisol secretion, and improved clinical signs and symptoms of Cushing’s disease in this patient. Based on this experience, first-line pasireotide has the potential to achieve substantial tumor volume reduction in addition to significant improvements in cortisol levels and signs and symptoms in patients with Cushing’s disease for whom surgery is not an option.     

Alternative bearings in total knee arthroplasty: risk of early revision compared to traditional bearings: An analysis of 62,177 primary cases

Background and purpose There is no substantial clinical evidence for the superiority of alternative bearings in total knee arthroplasty (TKA). We compared the short-term revision risk in alternative surface bearing knees (oxidized zirconium (OZ) femoral implants or highly crosslinked polyethylene (HXLPE) inserts) with that for traditional bearings (cobalt-chromium (CoCR) on conventional polyethelene (CPE)). The risk of revision with commercially available HXLPE inserts was also evaluated.

Methods All 62,177 primary TKA cases registered in a Total Joint Replacement Registry between April 2001 and December 2010 were retrospectively analyzed. The endpoints for the analysis were all-cause revisions, septic revisions, or aseptic revisions. Bearing surfaces were categorized as OZ-CPE, CoCr-HXLPE, or CoCr-CPE. HXLPE inserts were stratified according to brand name. Confounding was addressed using propensity score weights. Marginal Cox-regression models adjusting for surgeon clustering were used.

Results The proportion of females was 62%. Average age was 68 (SD 9.3) years, and median follow-up time was 2.8 (IQR 1.2–4.9) years. After adjustments, the risks of all-cause, aseptic, and septic revision with CoCr-HXLPE and OZ-CPE bearings were not statistically significantly higher than with traditional CoCr-CPE bearings. No specific brand of HXLPE insert was associated with a higher risk of all-cause, aseptic, or septic revision compared to CoCr-CPE.

Interpretation At least in the short term, none of the alternative knee bearings evaluated (CoCr-HXLPE or OZ-CPE) had a greater risk of all-cause, aseptic, and septic revision than traditional CoCr-CPE bearings.