Targeted immune interventions for type 1 diabetes: not as easy as it looks!

PURPOSE OF REVIEW: Although insulin is lifesaving and sustaining for those with type 1 diabetes (T1D), curing the disease will be much more complex than simple replacement of this hormone. T1D is an autoimmune disease orchestrated by T cells, and includes many arms of the immune response. Tremendous effort has gone into understanding its underlying immune, genetic, and environmental causes, and this progress has led to immunologically based clinical trials in T1D. This review will focus primarily on the clinical trials of the past decade that have attempted to translate these fundamental findings. RECENT FINDINGS: It is known that powerful, nonspecific immune suppressants can temporarily slow the course of newly diagnosed T1D, yet are too toxic for long-term use, especially in children. Recent clinical trials to reverse T1D have used newly developed therapies that target specific components of the immune process believed to be involved with T1D. Although well justified and designed, no recent approach has resulted in clinical remission and few have had any effect on disease course. SUMMARY: Advances in our fundamental understanding of how the human diabetes immune response is activated and regulated coupled with lessons that have been learnt from the most recent era of completed trials are guiding us toward the development of more effective, multipronged therapies to ablate diabetes autoimmunity, restore immune tolerance, preserve β cells, and, ultimately, improve the lives of patients with T1D

Propofol-Based Procedural Sedation with or without Low-Dose Ketamine in Children

Objective Examine comparative dosing, efficacy, and safety of propofol alone or with an initial, subdissociative dose of ketamine approach for deep sedation. Background Propofol is a sedative-hypnotic agent used increasingly in children for deep sedation. As a nonanalgesic agent, use in procedures (e.g., bone marrow biopsies/aspirations, renal biopsies) is debated. Our intensivist procedural sedation team sedates using one of two protocols: propofol-only (P-O) approach or age-adjusted dose of 0.25 or 0.5 mg/kg intravenous ketamine (K + P) prior to propofol. With either approach, an initial induction dose of 1 mg/kg propofol is recommended and then intermittent dosing throughout the procedure to achieve adequate sedation to safely and effectively perform the procedure. Approach: Retrospective evaluation of 754 patients receiving either the P-O or K + P approach to sedation. Results A total of 372 P-O group patients and 382 K + P group. Mean age (7.3 ± 5.5 years for P-O; 7.3 ± 5.4 years for K + P) and weight (30.09 ± 23.18 kg for P-O; 30.14 ± 24.45 kg for K + P) were similar in both groups (p = NS). All patients successfully completed procedures with a 16% combined incidence of hypoxia (SPO2 < 90%). Procedure time was 3 minutes longer for K + P group than P-O group (18.68 ± 15.13 minutes for K + P; 15.11 ± 12.77 minutes for P-O; p < 0.01), yet recovery times were 5 minutes shorter (17.04 ± 9.36 minutes for K + P; 22.17 ± 12.84 minutes for P-O; p < 0.01). Mean total dose of propofol was significantly greater in P-O than in K + P group (0.28 ± 0.20 mg/kg/min for K + P; 0.40 ± 0.26 mg/kg/min for P-O; p < 0.0001), and might explain the shorter recovery time. Conclusion Both sedation approaches proved to be well tolerated and equally effective. Addition of ketamine was associated with reduction in the recovery time, probably explained by the statistically significant decrease in the propofol dose

Factors associated with survival during high frequency oscillatory ventilation in children

Our aim is to determine indicators of survival in children with severe hypoxic respiratory failure (HRF) after transition to high-frequency oscillatory ventilation (HFOV). Single-center retrospective examination of children with HRF transitioned to HFOV. Blood gases and ventilator settings 24 hours prior to and 48 hours after HFOV in survivors and nonsurvivors were evaluated. Sixty-two children with mean age of 7 years and mean weight of 26 kg were included with an observed mortality of 29%. Mean airway pressures (Paw), oxygenation index (OI), arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) (P/F) ratio, pH, bicarbonate, and arterial carbon dioxide partial pressure were similar prior to HFOV in survivors and nonsurvivors. During HFOV, mean OI and P/F ratio improved in both groups with an average Paw increase of ∼10 cm H2O. Survivors had lower OI than nonsurvivors (21 ± 0.9 vs. 26.5 ± 2.2; p 200. Survivors had higher pH than nonsurvivors at 36 hours (7.40 ± 0.01 vs. 7.32 ± 0.02; p < 0.05), higher bicarbonate levels (27.1 ± 0.7 vs. 23.9 ± 1.3 mEq/L), and similar arterial carbon dioxide partial pressure with less oscillatory support (i.e., hertz and amplitude). Inhaled nitric oxide was used in 53% of patients with improvements in oxygenation but with no effect on mortality. HFOV improves oxygenation in children with severe HRF. Nonsurvivors can be distinguished from survivors at 24 to 36 hours during HFOV by higher OI, metabolic acidosis, and higher oscillatory support. These data may assist in prognostication or timing of initiating alternative therapies, such as extracorporeal membrane oxygenation

A magnified view of star formation at redshift 0.9 from two lensed galaxies

We present new narrow-band H alpha imaging from the Hubble Space Telescope of two redshift 0.91 galaxies that have been lensed by foreground galaxy cluster Abell 2390. These data probe spatial scales as small as 0.3 kpc, providing a magnified look at the morphology of star formation at an epoch when the global star formation rate was high. However, dust attenuates our spatially resolved star formation rate (SFR) indicators, the H alpha and rest-UV emission, and we lack a direct measurement of extinction. Other studies have found that ionized gas in galaxies tends to be roughly 50 percent more obscured than stars; however, given an unextincted measurement of the SFR we can quantify the relative stellar to nebular extinction and the extinction in H{\alpha}. We infer SFRs from Spitzer and Herschel mid- to far-infrared observations and compare these to integrated H alpha and rest-UV SFRs; this yields stellar to nebular extinction ratios consistent with previous studies. We take advantage of high spatial resolution and contextualize these results in terms of the source-plane morphologies, comparing the distribution of H alpha to that of the rest-frame UV and optical light. In one galaxy, we measure separate SFRs in visually distinct clumps, but can set only a lower limit on the extinction and thus the star formation. Consequently, the data are also consistent with there being an equal amount of extinction along the lines of sight to the ionized gas as to the stars. Future observations in the far-infrared could settle this by mapping out the dust directly.Comment: Published as 2014, The Astronomical Journal, 148, 6

The Carnegie Hubble Program: The Distance and Structure of the SMC as Revealed by Mid-infrared Observations of Cepheids

Using Spitzer observations of classical Cepheids we have measured the true average distance modulus of the SMC to be $18.96 \pm 0.01_{stat} \pm 0.03_{sys}$ mag (corresponding to $62 \pm 0.3$ kpc), which is $0.48 \pm 0.01$ mag more distant than the LMC. This is in agreement with previous results from Cepheid observations, as well as with measurements from other indicators such as RR Lyrae stars and the tip of the red giant branch. Utilizing the properties of the mid--infrared Leavitt Law we measured precise distances to individual Cepheids in the SMC, and have confirmed that the galaxy is tilted and elongated such that its eastern side is up to 20 kpc closer than its western side. This is in agreement with the results from red clump stars and dynamical simulations of the Magellanic Clouds and Stream.Comment: Accepted for publication in ApJ. 38 Pages, 11 figures. Figure 9 is interactive. Spitzer photometry for all Cepheids available as online tabl