Towards improved psychological outcomes for survivors of burn injuries

Editoria

Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells.

Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML

5-Year survival of pediatric anterior cruciate ligament reconstruction with living donor hamstring tendon grafts

Background: It is well accepted that there is a higher incidence of repeat anterior cruciate ligament (ACL) injuries in the pediatric population after ACL reconstruction (ACLR) with autograft tissue compared with adults. Hamstring autograft harvest may contribute to the risk for repeat ACL injuries in this high functional demand group. A novel method is the use of a living donor hamstring tendon (LDHT) graft from a parent; however, there is currently limited research on the outcomes of this technique, particularly beyond the short term. Purpose/Hypothesis: The purpose was to determine the medium-term survival of the ACL graft and the contralateral ACL (CACL) after primary ACLR with the use of an LDHT graft from a parent in those aged less than 18 years and to identify factors associated with subsequent ACL injuries. It was hypothesized that ACLR with the use of an LDHT provides acceptable midterm outcomes in pediatric patients. Study Design: Case series; Level of evidence, 4. Methods: Between 2005 and 2014, 247 (of 265 eligible) consecutive patients in a prospective database, having undergone primary ACLR with the use of an LDHT graft and aged less than 18 years, were included. Outcomes were assessed at a minimum of 2 years after surgery including data on ACL reinjuries, International Knee Documentation Committee (IKDC) scores, and current symptoms, as well as factors associated with the ACL reinjury risk were investigated. Results: Patients were reviewed at a mean of 4.5 years (range, 24-127 months [10.6 years]) after ACLR with an LDHT graft. Fifty-one patients (20.6%) sustained an ACL graft rupture, 28 patients (11.3%) sustained a CACL rupture, and 2 patients sustained both an ACL graft rupture and a CACL rupture (0.8%). Survival of the ACL graft was 89%, 82%, and 76% at 1, 2, and 5 years, respectively. Survival of the CACL was 99%, 94%, and 86% at 1, 2, and 5 years, respectively. Survival of the ACL graft was favorable in patients with Tanner stage 1-2 at the time of surgery versus those with Tanner stage 3-5 at 5 years (87% vs 69%, respectively; hazard ratio, 3.7; P = .01). The mean IKDC score was 91.7. A return to preinjury levels of activity was reported by 59.1%. Conclusion: After ACLR with an LDHT graft from a parent in those aged less than 18 years, a second ACL injury (ACL graft or CACL injury) occurred in 1 in 3 patients. The 5-year survival rate of the ACL graft was 76%, and the 5-year survival rate of the CACL was 86%. High IKDC scores and continued participation in sports were maintained over the medium term. Importantly, there was favorable survival of the ACL graft in patients with Tanner stage 1-2 compared with patients with Tanner stage 3-5 over 5 years. Patients with Tanner stage 1-2 also had a significantly lower incidence of second ACL injuries over 5 years compared with those with Tanner stage 3-5, occurring in 1 in 5 patients. Thus, an LDHT graft from a parent is an appropriate graft for physically immature children

The Pion Form Factor Within the Hidden Local Symmetry Model

We analyze a pion form factor formulation which fulfills the Analyticity requirement within the Hidden Local Symmetry (HLS) Model. We show that it implies an $s$--dependent dressing of the $\rho-\gamma$ VMD coupling and an account of several coupled channels. The corresponding function $F_\pi(s)$ provides nice fits of the pion form factor data from $s=-0.25$ to $s=1$ GeV$^2$. It is shown that the coupling to $K \bar{K}$ has little effects, while \omg \pi^0 improves significantly the fit quality below the $\phi$ mass. All parameters, except for the subtraction polynomial coefficients are fixed from the rest of the HLS phenomenology. The fits show consistency with the expected behaviour of $F_\pi(s)$ at $s=0$ up to ${\cal O} (s^2)$ and with the phase shift data on $\delta_1^1(s)$ from threshold to somewhat above the $\phi$ mass. The \omg sector is also examined in relation with recent data from CMD--2.We analyze a pion form factor formulation which fulfills the Analyticity requirement within the Hidden Local Symmetry (HLS) Model. We show that it implies an $s$--dependent dressing of the $\rho-\gamma$ VMD coupling and an account of several coupled channels. The corresponding function $F_\pi(s)$ provides nice fits of the pion form factor data from $s=-0.25$ to $s=1$ GeV$^2$. It is shown that the coupling to $K \bar{K}$ has little effects, while \omg \pi^0 improves significantly the fit quality below the $\phi$ mass. All parameters, except for the subtraction polynomial coefficients are fixed from the rest of the HLS phenomenology. The fits show consistency with the expected behaviour of $F_\pi(s)$ at $s=0$ up to ${\cal O} (s^2)$ and with the phase shift data on $\delta_1^1(s)$ from threshold to somewhat above the $\phi$ mass. The \omg sector is also examined in relation with recent data from CMD-2.We analyze a pion form factor formulation which fulfills the Analyticity requirement within the Hidden Local Symmetry (HLS) Model. We show that it implies an $s$--dependent dressing of the $\rho-\gamma$ VMD coupling and an account of several coupled channels. The corresponding function $F_\pi(s)$ provides nice fits of the pion form factor data from $s=-0.25$ to $s=1$ GeV$^2$. It is shown that the coupling to $K \bar{K}$ has little effects, while \omg \pi^0 improves significantly the fit quality below the $\phi$ mass. All parameters, except for the subtraction polynomial coefficients are fixed from the rest of the HLS phenomenology. The fits show consistency with the expected behaviour of $F_\pi(s)$ at $s=0$ up to ${\cal O} (s^2)$ and with the phase shift data on $\delta_1^1(s)$ from threshold to somewhat above the $\phi$ mass. The \omg sector is also examined in relation with recent data from CMD-2.We analyze a pion form factor formulation which fulfills the Analyticity requirement within the Hidden Local Symmetry (HLS) Model. We show that it implies an $s$--dependent dressing of the $\rho-\gamma$ VMD coupling and an account of several coupled channels. The corresponding function $F_\pi(s)$ provides nice fits of the pion form factor data from $s=-0.25$ to $s=1$ GeV$^2$. It is shown that the coupling to $K \bar{K}$ has little effects, while $\omega \pi^0$ improves significantly the fit quality below the $\phi$ mass. All parameters, except for the subtraction polynomial coefficients are fixed from the rest of the HLS phenomenology. The fits show consistency with the expected behaviour of $F_\pi(s)$ at $s=0$ up to ${\cal O} (s^2)$ and with the phase shift data on $\delta_1^1(s)$ from threshold to somewhat above the $\phi$ mass. The $\omega$ sector is also examined in relation with recent data from CMD-2

Structural Evidence of a Major Conformational Change Triggered by Substrate Binding in DapE Enzymes: Impact on the Catalytic Mechanism

The X-ray crystal structure of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase from Haemophilus influenzae (HiDapE) bound by the products of hydrolysis, succinic acid and l,l-DAP, was determined at 1.95 Å. Surprisingly, the structure bound to the products revealed that HiDapE undergoes a significant conformational change in which the catalytic domain rotates ∼50° and shifts ∼10.1 Å (as measured at the position of the Zn atoms) relative to the dimerization domain. This heretofore unobserved closed conformation revealed significant movements within the catalytic domain compared to that of wild-type HiDapE, which results in effectively closing off access to the dinuclear Zn(II) active site with the succinate carboxylate moiety bridging the dinculear Zn(II) cluster in a μ-1,3 fashion forming a bis(μ-carboxylato)dizinc(II) core with a Zn–Zn distance of 3.8 Å. Surprisingly, His194.B, which is located on the dimerization domain of the opposing chain ∼10.1 Å from the dinuclear Zn(II) active site, forms a hydrogen bond (2.9 Å) with the oxygen atom of succinic acid bound to Zn2, forming an oxyanion hole. As the closed structure forms upon substrate binding, the movement of His194.B by more than ∼10 Å is critical, based on site-directed mutagenesis data, for activation of the scissile carbonyl carbon of the substrate for nucleophilic attack by a hydroxide nucleophile. Employing the HiDapE product-bound structure as the starting point, a reverse engineering approach called product-based transition-state modeling provided structural models for each major catalytic step. These data provide insight into the catalytic reaction mechanism and also the future design of new, potent inhibitors of DapE enzymes

Fatalities due to intestinal obstruction following the ingestion of foreign bodies

Two fatalities due to an occlusive ileus following the ingestion of foreign bodies in patients with psychiatric disorders are described. A severely mentally handicapped young man developed a temperature and died 1 h after admission to a surgical ward. At autopsy, not, vert, similar 2000 cm3 of foreign material, including broken glass and porcelain, branches, buttons, parts of clothing and other material were found in the gastrointestinal tract, leading to a complete obstruction of the distal intestine and colon with resulting faecal vomiting. The other case was even more unusual as a hair fetishist had swallowed a thick strand of his own hair, 50 cm long, also resulting in mechanical obstruction of the distal intestine

Large-area scanning probe nanolithography facilitated by automated alignment of probe arrays

A method for the automated alignment of scanning probe polymer pen arrays is reported. This system enables nanolithography over large (cm2) areas with high uniformity, with any misalignment being ≤0.0003°.</p

Nimbus 7 solar backscatter ultraviolet (SBUV) ozone products user's guide

Three ozone tape products from the Solar Backscatter Ultraviolet (SBUV) experiment aboard Nimbus 7 were archived at the National Space Science Data Center. The experiment measures the fraction of incoming radiation backscattered by the Earth's atmosphere at 12 wavelengths. In-flight measurements were used to monitor changes in the instrument sensitivity. Total column ozone is derived by comparing the measurements with calculations of what would be measured for different total ozone amounts. The altitude distribution is retrieved using an optimum statistical technique for the inversion. The estimated initial error in the absolute scale for total ozone is 2 percent, with a 3 percent drift over 8 years. The profile error depends on latitude and height, smallest at 3 to 10 mbar; the drift increases with increasing altitude. Three tape products are described. The High Density SBUV (HDSBUV) tape contains the final derived products - the total ozone and the vertical ozone profile - as well as much detailed diagnostic information generated during the retrieval process. The Compressed Ozone (CPOZ) tape contains only that subset of HDSBUV information, including total ozone and ozone profiles, considered most useful for scientific studies. The Zonal Means Tape (ZMT) contains daily, weekly, monthly and quarterly averages of the derived quantities over 10 deg latitude zones

Tunable dipolar magnetism in high-spin molecular clusters

We report on the Fe17 high-spin molecular cluster and show that this system is an exemplification of nanostructured dipolar magnetism. Each Fe17 molecule, with spin S=35/2 and axial anisotropy as small as D=-0.02K, is the magnetic unit that can be chemically arranged in different packing crystals whilst preserving both spin ground-state and anisotropy. For every configuration, molecular spins are correlated only by dipolar interactions. The ensuing interplay between dipolar energy and anisotropy gives rise to macroscopic behaviors ranging from superparamagnetism to long-range magnetic order at temperatures below 1K.Comment: Replaced with version accepted for publication in Physical Review Letter