Hand transplantation: can we balance the risks and benefits?

Asking ‘can we balance the risks and benefits?’ implies that a quantification of both risk and benefit in hand transplantation (here the terms hand transplant and hand transplantation refer to allotransplantation of the human hand or hand and part or all of the upper limb or limbs) is possible. Despite all we have learned in recent years about hand transplantation, much remains unknown. Even if reliable methods for quantification of risk and benefit were available, fundamental issues relating to effective communication across the gulf of lived experience between the (presumably) handed surgeon and the handless patient remain. Inherent complexities mean some consider hand transplantation an unsolved problem, but we believe the medical and technical considerations fall within the ambit of a competent multidisciplinary team, and that psychosocial and ethical challenges are open to management through robust frameworks for assessment and decision making, underpinned by an extended period of assessment and dialogue, with candid acknowledgement where uncertainty remains. This respects the patient’s autonomy while addressing the need for a prolonged period of informing consent

Reversible pressure-controlled depolymerization of a copper(II)-containing coordination polymer

A unique pressure-induced Cu-N bond breaking/bond forming reaction is reported. The variation of pressure on a single crystal of a one-dimensional copper- (II)-containing coordination polymer (Cu2 L2 (1-methylpiperazine)2 ]n , where H2 L is 1,1'-(1,3-phenylene)-bis(4,4-dimethylpentane-1,3-dione)), was monitored using single crystal X-ray diffraction with the aid of a diamond anvil cell. At a very low elevated pressure (≈0.05 GPa) a remarkable reversible phase change was observed. The phase change results in the depolymerization of the material through the cleavage and formation of axial Cu-N bonds as well as "ring flips" of individual axially coordinated 1-methylpiperazine ligands. Overall, the pressure-induced phase change is associated with a surprising (and non-intuitive) shift in structure-from a 1-dimensional coordination polymer to a discrete dinuclear complex

Spectroscopic study of the O-type runaway supergiant HD 195592

The scope of this paper is to perform a detailed spectroscopic study of the northern O-type supergiant HD 195592. We use a large sample of high quality spectra in order to investigate its multiplicity, and to probe the line profile variability. Our analysis reveals a clear spectroscopic binary signature in the profile of the He {\sc i} $\lambda$ 6678 line, pointing to a probable O + B system. We report on low amplitude radial velocity variations in every strong absorption line in the blue spectrum of HD 195592. These variations are ruled by two time-scales respectively of 5.063 and about 20 days. The former is firmly established, whilst the latter is poorly constrained. We report also on a very significant line profile variability of the H $\beta$ line, with time scales strongly related to those of the radial velocities. Our results provide significant evidence that HD 195592 is a binary system, with a period that might be the variability time-scale of about 5 days. The second time scale may be the signature of an additional star moving along a wider orbit provided its mass is low enough, even though direct evidence for the presence of a third star is still lacking. Alternatively, the second time-scale may be the signature of a variability intrinsic to the stellar wind of the primary, potentially related to the stellar rotation.Comment: 9 pages, 5 postscript figures, accepted for publication in New Astronom

Utility of ambulatory electrocardiographic monitoring for predicting recurrence of sustained ventricular tachyarrhythmias in patients receiving amiodarone

The prognostic implications of changes in ventricular ectopic activity on serial 24 hour ambulatory electrocardiographic (Holter) recordings were prospectively evaluated in 107 patients with a history of sustained ventricular tachyarrhythmias treated with amiodarone for at least 30 days. Twenty-seven patients (25%) had insufficient ventricular ectopic activity < 10 ventricular premature complexes/h and no repetitive forms) on baseline Holter recordings for serial statistical analysis. In 53 (66%) of the remaining 80 patients, serial 24 hour Holter monitor recordings showed efficacy of treatment, defined as a 75% decrease in ventricular premature complexes, a 95% decrease in ventricular couplets and absence of ventricular tachycardia. During a mean followup period of 14.2 ± 9.9 months, 34 (32%) of the 107 patients had recurrence of a sustained ventricular tachyarrhythmia. Holter recording correctly predicted nine recurrences and correctly identified 37 patients who did not experience a recurrence. Holter efficacy failed to predict recurrence of a sustained ventricular tachyarrhythmia in 16 patients, and 18 patients remained free of recurrence despite failure to achieve Holter efficacy. The positive predictive value of Holter monitoring efficacy was 33% and the negative predictive value was 70%; however, these differences were not statistically significant by chi-square analysis. Similar results were obtained using Holter recordings performed relatively early in therapy (6 weeks and 4 months).Of the 27 patients without significant ventricular ectopic activity on the baseline Holter recording, 9 had an arrhythmia recurrence despite continued infrequent ventricular premature complexes and no repetitive forms on subsequent recordings. The recurrence rate in this group (33%) was similar to the overall recurrence rate.Therefore, among patients taking amiodarone for sustained ventricular tachyarrhythmias: 1) 25% will have insufficient ventricular ectopic activity on 24 hour Holter recordings for serial statistical analysis; and 2) in the remaining 75%, data obtained from serial Holter recordings are not predictive of arrhythmia recurrence

Synthesis of Organic Super-Electron-Donors by Reaction of Nitrous Oxide with N‐Heterocyclic Olefins

The reaction of nitrous oxide (N2O) with N-heterocyclic olefins (NHOs) results in cleavage of the N–O bond and formation of azo-bridged NHO dimers. The latter represent very electron-rich compounds with a low ionization energy. Cyclic voltammetry studies show that the dimers can be classified as new organic super-electron-donors, with a reducing power similar to what is found for tetraazafulvalene derivatives. Mild oxidants are able to convert the neutral dimers into radical cations, which can be isolated. Further oxidation gives stable dications

Prognostic implications of surrogate markers of atherosclerosis in low to intermediate risk patients with type 2 diabetes.

published_or_final_versio

Interleukin-1β Produced in Response to Islet Autoantigen Presentation Differentiates T-Helper 17 Cells at the Expense of Regulatory T-Cells: Implications for the Timing of Tolerizing Immunotherapy

OBJECTIVE-The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-kappa B inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1 beta is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1 beta production and the response to RelB(lo) DCs in the prediabetic period

Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of alpha-1 Antitrypsin Deficiency

Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create a recipient strain (NSG-PiZ) for human hepatocyte xenotransplantation. Results indicate that NSG-PiZ recipients support heightened engraftment of normal human primary hepatocytes as compared with NSG recipients. This model can therefore be used to test hepatocyte cell therapies for AATD, but more broadly it serves as a simple, highly reproducible liver xenograft model. Finally, a promoterless adeno-associated virus (AAV) vector, expressing a wild-type AAT and a synthetic miRNA to silence the endogenous allele, was integrated into the albumin locus. This gene-editing approach leads to a selective advantage of edited hepatocytes, by silencing the mutant protein and augmenting normal AAT production, and improvement of the liver pathology

Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of α-1 Antitrypsin Deficiency.

Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In α-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create a recipient strain (NSG-PiZ) for human hepatocyte xenotransplantation. Results indicate that NSG-PiZ recipients support heightened engraftment of normal human primary hepatocytes as compared with NSG recipients. This model can therefore be used to test hepatocyte cell therapies for AATD, but more broadly it serves as a simple, highly reproducible liver xenograft model. Finally, a promoterless adeno-associated virus (AAV) vector, expressing a wild-type AAT and a synthetic miRNA to silence the endogenous allele, was integrated into the albumin locus. This gene-editing approach leads to a selective advantage of edited hepatocytes, by silencing the mutant protein and augmenting normal AAT production, and improvement of the liver pathology. Mol Ther 2017 Nov 1; 25(11):2477-2489

Photospheric-Phase Spectropolarimetry and Nebular-Phase Spectroscopy of the Peculiar Type Ic Supernova 2002ap

The early-time optical spectrum of the Type Ic supernova (SN) 2002ap was characterized by unusually broad features, leading some authors to designate it a "hypernova." We present optical spectropolarimetry of this object 16 and 37 days after the estimated date of explosion. After correcting for interstellar polarization, we find evidence for a high level of intrinsic continuum polarization at both epochs: p >~ 1.3% on day 16 and p >~ 1.0% on day 37. Prominent line polarization is also seen, especially in the trough of the Ca II near-infrared triplet during the second epoch. When interpreted in terms of the oblate, electron-scattering model atmospheres of Hoeflich (1991), our results imply an asymmetry of at least 20% (day 16) and 17% (day 37). The data suggest a fair degree of axisymmetry, although the polarization angle of the dominant polarization axes are different by about 55 deg. between the two epochs, implying a complex morphology for the thinning ejecta. In particular, there exists some spectropolarimetric evidence for a different distribution of Ca relative to iron-group elements. We also present flux spectra of SN 2002ap taken 131 and 140 days after the explosion. The spectra are characterized by a very weak continuum and broad emission lines, indicating that SN 2002ap has entered the nebular phase. The spectral features are substantially similar to those of ``normal'' SNe Ic in the nebular phase, and the emission lines are not significantly broader. However, some of the broad lines are very sharply peaked, and may possess a narrow component (probably unresolved by our spectra, FWHM <~ 400 km/s that is redshifted by ~ 580$ km/s with respect to the systemic velocity of the host galaxy.Comment: Accepted by PASP. A new Appendix giving details of the observations has been added; minor text change