In silico and in vitro evaluation of two novel oximes (K378 and K727) in comparison to K-27 and pralidoxime against paraoxon-ethyl intoxication

Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigated in silico and in vitro and compared with an experimental oxime (kamiloxime; K-27) and pralidoxime. In silico the molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated. In vitro the intrinsic ability of the oximes to inhibit AChE (IC₅₀) and their reactivation potency (R₅₀) when used in paraoxon inhibited human RBC-AChE was determined. Molecular docking revealed that K378 and K727 bind to the peripheral site(s) with high binding energies in contrast to the central binding of K-27 and pralidoxime. LogP values indicating that the novel compounds are significantly less hydrophilic than K-27 or pralidoxime. IC₅₀ of K378 and K727 were comparable (0.9 and 1?µM, respectively) but orders of magnitude lower than comparators. R₅₀ values revealed their inability to reactivate paraoxon inhibited AChE. It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful. The in silico and in vitro studies described allow avoidance of unnecessary in vivo animal work and contribute to the reduction of laboratory animal use.     

Reduction in Mortality after Umbilical Cord Blood Transplantation in Children Over a 20-Year Period (1995-2014)

Infections and graft-versus-host disease (GVHD) have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients. We conducted a retrospective cohort study of children (<18years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared 2-year all-cause and cause-specific mortality during 3 time periods based on year of transplantation (1995 to 2001, 2002 to 2007, and 2008 to 2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period. During the 20-year study period 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995 to 2001 to 30% in 2008 to 2014 (P?=?.0002). White race and nonmalignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which GVHD (18% versus 11%; P?=?.06) or graft failure (9% versus 3%; P?=?.01) were contributory than white children. Comparing 2008 to 2014 with 1995 to 2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex (hazard ratio, .09; 95% confidence interval, .01 to .76). With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequentinfectious causes of death in children after UCBT. Advances in clinical practice over the past 20years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis.     

Intraoperative transfusion-related acute lung injury in a child during calvarial vault remodeling

Transfusion-related acute lung injury (TRALI) is currently recognized by the US Food and Drug Administration as the number one cause of mortality related to blood transfusion. Although various pathophysiologic mechanisms have been proposed, it is thought to be related to the presence of anti-HLA antibodies or bioactive lipid components in the donor blood product, which results in activation of recipient leukocytes and the resultant pulmonary damage from the release of bioactive substances including cytokines. As TRALI manifests as acute lung injury with signs and symptoms consistent with acute respiratory distress syndrome, it is frequently underdiagnosed, as the acute lung injury may be attributed to other factors. Transfusion-related acute lung injury is an important clinical entity for anesthesia providers to recognize and diagnose accurately, as many transfusions occur in the surgical patient. We present a case report of a pediatric patient who developed intraoperative TRALI during calvarial vault remodeling to treat craniosynostosis. The history, pathophysiology, and treatment of TRALI are discussed. Potential preventive measures are reviewed.     

Early composite cranioplasty in infants with severe aplasia cutis congenita: a report of two cases.

OBJECTIVE: Severe cutis aplasia congenita has traditionally been treated with initial soft tissue coverage and delayed cranioplasty. We advocate the technique of early composite reconstruction of both bone and soft tissues. METHODS: Two cases of cutis aplasia congenita with large skull defects (6 x 10 cm, 8 x 8 cm) of superficial layers, skull, and dura are presented. In each case, composite reconstruction was undertaken before 2 weeks of age with restoration of bony and soft tissue coverage through autologous, full-thickness cranial bone grafts and scalp flaps. Both children have been followed up over 2 years with clinical examination and computed tomography (CT) scans. RESULTS: In both cases, defects were completely repaired postoperatively and remained closed 2 years later. Complete regeneration of calvarial bone graft donor sites were documented by CT scan. Head shape and circumference were normal at 2-year follow up.     

Massive repeated nose bleeding after bimaxillary osteotomy

In LeFort I surgery, the separation of the pterygomaxillary junction is done by osteotomy. Although the osteotome is positioned too close to the maxillary artery and its branches during pterygomaxillary separation, postoperative complications from vascular injuries are uncommon. We describe an unusual occurrence of a maxillary artery pseudoaneurysm after LeFort I and bilateral sagittal split osteotomies for maxillary advancement and mandibular setback as well as (anterior sliding) genioplasty. In a patient with class III occlusion and midface retrusion, the significant bleeding began 10 days postoperatively, which was controlled by anterior and posterior nasal packing. The bleeding recurred 28 days after surgery; thus, vascular anatomy in the pterygomaxillary area is reviewed, pseudoaneurysm was diagnosed on selective carotid angiography and successfully treated by embolization; and 2-year follow up was uneventful.     

Inferiorly based thigh flap for reconstruction of defects around the knee joint

Background:

Soft-tissue defects around the knees are common in injured limbs and in the same injury the leg is often involved and the thigh is spared. Furthermore due to pliable and relatively lax skin, we have used inferiorly based thigh flap to reconstruct defects around knee joint.

Aims and Objectives:

The aim of this study is to evaluate the use of inferiorly based thigh flap to cover soft-tissue defects over the proximal one-third of the leg, patellar region, knee, and lower thigh.

Materials and Methods:

This study was conducted during the period between October 2011 and February 2013. Inferiorly based anteromedial thigh fasciocutaneous flap was performed on 12 patients and inferiorly based anterolateral thigh fasciocutaneous flap on four patients. The sites of the soft-tissue defects included patellar regions, infrapatellar region, upper one-third of leg, lower thigh, and over the knee joint.

Results:

Patients were evaluated post-operatively in terms of viability of flap, the matching of the flap with the recipient site, and donor site morbidity. All the flaps survived well except one which developed distal marginal flap loss, one in which wound dehiscence was noticed, and two in which mild venous congestion was observed. Venous congestion in two patients subsided on its own within 3 days. One patient with wound dehiscence achieved complete healing by secondary intention. Patient who developed distal flap loss required debridement and skin grafting. No appreciable donor site morbidity was encountered. Skin colour and texture of the flap matched well with the recipient site.

Conclusions:

The inferiorly based thigh flap is a reliable flap to cover the defect over proximal one-third of the leg, patellar region, knee, and lower thigh.KEY WORDS: Defect around the knee joint, inferiorly based thigh flap, perforator based flap     

The impact of donor body mass index on outcomes after deceased kidney transplantation – a national population‐cohort study

The aim of this study was to determine the effect of donor body mass index (BMI) on deceased donor kidney transplant outcomes. Data were collected from the UK Transplant Registry for all deceased donor kidney transplant recipients between January 2003 and January 2015. Univariable and multivariable analyses were undertaken to assess the impact of donor BMI on a range of outcomes. Donor BMI (kg/m²) was stratified as <18.5 (n = 380), 18.5–25.0 (n = 6890), 25.1–30.0 (n = 6669), 30.1–35.0 (n = 2503) and >35.0 (n = 1148). The prevalence of delayed graft function increased significantly with donor BMI (P < 0.001), with an adjusted odds ratio of 1.38 (95% CI: 1.16–1.63) for the >35.0 vs. 18.5–25.0 groups. However, there was no significant association between donor BMI and 12‐month creatinine (P = 0.550), or patient (P = 0.109) or graft (P = 0.590) survival. In overweight patients, increasing donor BMI was associated with a significant increase in warm ischaemia time and functional warm ischaemia time, by an average of 4.6% (P = 0.043) and 5.2% (P = 0.013) per 10.0 kg/m². However, rising warm ischaemic time and functional warm ischaemic time was not significantly associated with delayed graft function, 12‐month creatinine levels, graft loss or patient death. In this population cohort study, we identified no significant association between donor BMI and long‐term clinical outcomes in deceased donor kidney transplantation.