Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1^asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1^asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1^asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1^asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Immuntherapeutische Behandlung therapierefraktärer und rezidivierter akuter lymphatischer Leukämien im Kindes- und Jugendalter

Acute lymphoblastic leukemia (ALL) represents the most frequent malignant disease in childhood and adolescence and offers a good prognosis with approximately 80% survival in first remission after polychemotherapy and radiotherapy. In addition,many children with relapsed or refractory ALL will still be cured by allogeneic hematopoietic stem cell transplantation (alloHSCT).However, therapeutic options are limited with a very poor prognosis in case of another relapse after alloHSCT.Here,immunotherapy strategies offer a promising alternative to another chemotherapy or second alloHSCT, which are mainly palliative and accompanied by high morbidity and mortality. Immunotherapy strategies aim at an improvement of the graft-versus-leukemia (GvL) effect.The therapeutic GvL effect is usually associated with graft-versus-host disease (GvHD).The definition of patients subgroups with an increased risk for relapse after alloHSCT gains growing importance for immunotherapy strategies.Promising approaches for separation of GvL-effect and GvHD after donor lymphocyte infusions, e.g. T-cell suicide gene therapy, will be described. Finally, vaccination strategies for ALL exist.     

Heterogeneous iodine-organic chemistry fast-tracks marine new particle formation

The gas-phase formation of new particles less than 1 nm in size and their subsequent growth significantly alters the availability of cloud condensation nuclei (CCN, >30–50 nm), leading to impacts on cloud reflectance and the global radiative budget. However, this growth cannot be accounted for by condensation of typical species driving the initial nucleation. Here, we present evidence that nucleated iodine oxide clusters provide unique sites for the accelerated growth of organic vapors to overcome the coagulation sink. Heterogeneous reactions form low-volatility organic acids and alkylaminium salts in the particle phase, while further oligomerization of small α-dicarbonyls (e.g., glyoxal) drives the particle growth. This identified heterogeneous mechanism explains the occurrence of particle production events at organic vapor concentrations almost an order of magnitude lower than those required for growth via condensation alone. A notable fraction of iodine associated with these growing particles is recycled back into the gas phase, suggesting an effective transport mechanism for iodine to remote regions, acting as a “catalyst” for nucleation and subsequent new particle production in marine air.

Marine aerosol formation contributes significantly to the global radiative budget given the high susceptibility of marine stratiform cloud radiative properties to changes in cloud condensation nuclei (CCN) availability. Atmospheric new-particle-formation is thought to involve nucleation of sulfuric acid with water, ammonia, or amines followed by condensation/growth in the presence of organic vapors (1, 2). Unique in the marine boundary layer (MBL), new particle formation involves sequential addition of HIO₃ or clustering of iodine oxides (I_xO_y) (3, 4). In specific source regions such as coastal zones, seaweed beds, or snowpack/pack-ice, iodine oxide nucleation can be a driving force for nucleation (5–7). Over Arctic waters, nonetheless, one study finds insufficient iodic acid vapors to grow nucleated particles to CCN sizes (8), whereas another study finds that both nucleation and growth are almost exclusively driven by iodic acid (9). Over the open ocean, the supply of iodine oxides has been thought to be limited; however, recent measurements suggest that significant reactive iodine chemistry can occur in these regions (10). Moreover, observational evidence exists for open ocean particle formation and growth, especially when oceanic productivity is high (11, 12). An increase in atmospheric iodine levels in the North Atlantic since the mid-20th century has been shown to be driven by growth of anthropogenic ozone and enhanced subice phytoplankton production (13). While the reported IO concentration (0.4–3.1 ppt) in the remote MBL (10, 14, 15) is likely sufficient for formation of prenucleation clusters (∼1 nm), growth of these initial clusters requires the presence of other condensable vapors (16). Since preexisting aerosol particles act as a strong sink for the nucleated clusters, thus inhibiting atmospheric aerosol and CCN formation (17, 18), this early growth phase is essential for their survival. Whereas sulfuric acid vapor is also involved in nucleation, its level in remote open ocean is generally too low (10⁵ molecules cm⁻³) to support subsequent particle growth, leaving organic vapors as the most plausible alternative for particle growth.In the marine atmosphere, condensing organics must originate from the oxidation of marine volatile organic compounds (VOCs), which predominantly comprise C₁–C₅ VOCs (e.g., isoprene) released from phytoplankton. Principal high volatility oxidation products consist of intermediate oxidized organics (IOOs), such as polyhydric alcohols (e.g., tetrols) or polyfunctional carbonyls (e.g., glyoxal) (19–22). Nonetheless, growth of available prenucleation clusters/nanometer particles requires condensing organic molecules of low effective volatilities (i.e., saturation mass concentration, C* < ∼10⁻³ μg m⁻³); otherwise, preferential condensation of the organic mass to larger-diameter particles would occur (23, 24). Formation of such extremely low-volatility organic compounds (ELVOCs) from gas-phase reaction is well established for monoterpene oxidation products (25, 26).A potential pathway for formation of low-volatility organics could also result from particle-phase chemical reactions induced by iodine oxides in the early stages of marine particle formation. When the underlying chemistry is sufficiently fast, kinetic condensation occurs, resulting in particles with diameters smaller than about 50 nm growing at the same rate (e.g., nm h⁻¹) (24). If, however, particle-phase chemistry is preferentially favored in the smallest particles (i.e., stemming from the higher relative concentration of iodine oxides in freshly formed marine particles), growth of the nucleated particles could proceed more rapidly, as compared to that in which gas-phase chemistry is the source of the low-volatility compounds (23).In this paper, we present experimental results from field measurements as well as laboratory studies of nanometer particle growth and derive a plausible chemical mechanism from the results that can explain the observations of ultrafine particle growth in the marine atmosphere. The results suggest that both iodine and condensed organics contribute to particle growth from a nascent nucleation mode into an ultrafine particle mode. Moreover, laboratory studies of the growth of seed iodine oxide particles (IOP) via heterogeneous reactions with organic vapors suggest a hitherto unrecognized mechanism that fast-tracks the growth of nucleation mode clusters into survivable aerosol particles. In this process, a notable fraction of the iodine associated with these growing particles is recycled back to the gas phase, suggesting a transport mechanism for iodine to remote regions.     

Is faster better? Impact of operative time on postoperative outcomes after VATS anatomical pulmonary resection

BackgroundVideo-assisted thoracic surgery (VATS) is now the preferred approach for standard anatomical pulmonary resections. This study evaluates the impact of operative time (OT) on post-operative outcomes after VATS anatomical pulmonary resection for non-small cell lung cancer (NSCLC).MethodsWe retrospectively reviewed all consecutive patients undergoing VATS lobectomy or segmentectomy for NSCLC between November 2010 and December 2019. Postoperative outcomes were compared between short (<150 minutes) and long (≥150 minutes) OT groups. A multivariable analysis was performed to identify predictors of long OT and overall post-operative complications.ResultsA total of 670 patients underwent lobectomy (n=496, 74%) or segmentectomy (n=174, 26%) for NSCLC. Mediastinal lymph node dissection was performed in 621 patients (92.7%). The median OT was 141 minutes (SD: 47 minutes) and 387 patients (57.8%) were operated within 150 minutes. Neoadjuvant chemotherapy was given in 25 patients (3.7%). Conversion thoracotomy was realized in 40 patients (6%). Shorter OT was significantly associated with decreased post-operative overall complication rate (30% vs. 41%; P=0.003), shorter median length of drainage (3 vs. 4 days; P<0.001) and shorter median length of hospital stay (6 vs. 7 days; P<0.001). On multivariable analysis, long OT (≥150 minutes) (OR 1.64, P=0.006), ASA score >2 (OR 1.87, P=0.001), FEV₁ <80% (OR 1.47, P=0.046) and DLCO <80% (OR 1.5, P=0.045) were significantly associated with postoperative complications. Two predictors of long OT were identified: neoadjuvant chemotherapy (OR 3.11, P=0.01) and lobectomy (OR 1.5, P=0.032).ConclusionsA prolonged OT is significantly associated with postoperative complications in our collective of patients undergoing VATS anatomical pulmonary resection.     

Material differentiation by dual energy CT: initial experience

The aim of this study was to assess the feasibility of a differentiation of iodine from other materials and of different body tissues using dual energy CT. Ten patients were scanned on a SOMATOM Definition Dual Source CT (DSCT; Siemens, Forchheim, Germany) system in dual energy mode at tube voltages of 140 and 80 kVp and a ratio of 1:3 between tube currents. Weighted CT Dose Index ranged between 7 and 8 mGy, remaining markedly below reference dose values for the respective body regions. Image post-processing with three-material decomposition was applied to differentiate iodine or collagen from other tissue. The results showed that a differentiation and depiction of contrast material distribution is possible in the brain, the lung, the liver and the kidneys with or without the underlying tissue of the organ. In angiographies, bone structures can be removed from the dataset to ease the evaluation of the vessels. The differentiation of collagen makes it possible to depict tendons and ligaments. Dual energy CT offers a more specific tissue characterization in CT and can improve the assessment of vascular disease. Further studies are required to draw conclusions on the diagnostic value of the individual applications.     

The entire dural sinus tree is compressed in patients with idiopathic intracranial hypertension: a longitudinal, volumetric magnetic resonance imaging study

Introduction  

The objective of this study was to explore the volumetric alterations of dural sinuses in patients with idiopathic intracranial hypertension (IIH).     

Questioning a “Compulsory Ontology of Pathology” Regarding Suicide and the Suicidal

The death of a neonate can be traumatic for mothers, resulting in profound grief, which ruptures their sense of coherence and identity. A narrative approach was used to explore how six Xhosa-speaking women tell stories about the death of their baby to help them understand the significance of the loss. They struggled to establish a sense of their baby as a person to be mourned, to redefine their own identity, and to find reasons for the death. Their meaning-making was influenced by the baby's father, older women in their community, and the context of deprivation in which they live.     

Intracellular Tracking of Single-plasmid DNA Particles After Delivery by Electroporation

Electroporation is a physical method of transferring molecules into cells and tissues. It takes advantage of the transient permeabilization of the cell membrane induced by electric field pulses, which gives hydrophilic molecules access to the cytoplasm. This method offers high transfer efficiency for small molecules that freely diffuse through electrically permeabilized membranes. Larger molecules, such as plasmid DNA, face several barriers (plasma membrane, cytoplasmic crowding, and nuclear envelope), which reduce transfection efficiency and engender a complex mechanism of transfer. Our work provides insight into the way electrotransferred DNA crosses the cytoplasm to reach the nucleus. For this purpose, single-particle tracking experiments of fluorescently labeled DNA were performed. Investigations were focused on the involvement of the cytoskeleton using drugs disrupting or stabilizing actin and tubulin filaments as the two relevant cellular networks for particle transport. The analysis of 315 movies (~4,000 trajectories) reveals that DNA is actively transported through the cytoskeleton. The large number of events allows a statistical quantification of the DNA motion kinetics inside the cell. Disruption of both filament types reduces occurrence and velocities of active transport and displacements of DNA particles. Interestingly, stabilization of both networks does not enhance DNA transport.