Adapting nitric oxide: A review of its foundation, uses in austere medical conditions, and emerging applications.

Nitric oxide was first identified as a novel and effective treatment for persistent pulmonary hypertension of the newborn (PPHN), and has since been found to be efficacious in treating acute respiratory distress syndrome (ARDS) and pulmonary hypertension. Physicians and researchers have also found it shows promise in resource-constrained settings, both within and outside of the hospital, such as in high altitude pulmonary edema (HAPE) and COVID-19. The treatment has been well tolerated in these settings, and is both efficacious and versatile when studied across a variety of clinical environments. Advancements in inhaled nitric oxide continue, and the gas is worthy of investigation as physicians contend with new respiratory and cardiovascular illnesses, as well as unforeseen logistical challenges.

Revision of failed total ankle arthroplasty to a hindfoot fusion: 23 consecutive cases using the Phoenix nail.

Aims: The aim of this study was to present a series of patients with aseptic failure of a total ankle arthroplasty (TAA) who were treated with fusion of the hindfoot using a nail. Patients and Methods: A total of 23 TAAs, in 22 patients, were revised for aseptic loosening and balloon osteolysis to a hindfoot fusion by a single surgeon (NH) between January 2012 and August 2014. The procedure was carried out without bone graft using the Phoenix, Biomet Hindfoot Arthrodesis Nail. Preoperative investigations included full blood count, CRP and ESR, and radiological investigations including plain radiographs and CT scans. Postoperative plain radiographs were assessed for fusion. When there was any doubt, CT scans were performed. Results: The mean follow-up was 13.9 months (4.3 to 37.2). Union occurred at the tibiotalar joint in 22 ankles (95.6%) with one partial union. Union occurred at the subtalar joint in 20 ankles (87%) of cases with two nonunions. The nail broke in one patient with a subtalar nonunion and revision was undertaken. The only other noted complication was one patient who suffered a stress fracture at the proximal aspect of the nail, which was satisfactorily treated conservatively. Conclusion: This study represents the largest group of patients reported to have undergone revision TAA to fusion of the hindfoot with good results Cite this article: Bone Joint J 2018;100-B:475-9.

Fludarabine-based reduced intensity regimen for matched related donor hematopoietic stem cell transplantation in acquired severe aplastic anemia.

Different conditioning regimens have been evaluated in matched-related donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acquired severe aplastic anemia (SAA) with varying results. In this manuscript, we report our experience with fludarabine (120mg/m2), very low dose cyclophosphamide (1200mg/m2) and antithymocyte globulin (7.5mg/kg). Low dose total body irradiation (2Gy) was added to the conditioning regimen for patients older than 15 years. Nineteen patients (median age 23years) underwent transplant between 2008 and 2015. The majority (89%) were younger than 40 years. Stem cell source was BM (n=11) or PBSC (n=8). GvHD prophylaxis consisted of cyclosporine and either a short course of methotrexate (n=9) or mycophenolate mofetil (n=10). Eighteen (94.7%) patients achieved sustained engraftment. The median times to neutrophil and platelet engraftments were 19 (range: 14-34) and 17.1 (range: 12-25) days, respectively. The day-30 cumulative incidence of neutrophil and platelet engraftment was 89.4% and 94.7%, respectively. No secondary graft rejection was observed. The 1-year cumulative incidence of aGvHD (grade II-IV) and cGvHD was 11.7% and 0%, respectively. The 2-year GvHD-free survival rate was 78.6% (95% CI: 52.5-91.4%). Fludarabine-based reduced intensity regimen for MRD allo-HSCT in SAA compares favorably to other available regimens. This regimen deserves further investigations with larger cohort of patients.

Pregnancy and Dumping Syndrome post-bariatric surgery: a case report.

This case report discusses dumping syndrome in the postbariatric mother. Diagnostically a challenge, the symptoms of postprandial hypoglycaemia mimic common early gestation complaints and may go undiagnosed, thus requiring a high index of suspicion. As weight-loss surgery gains traction, it is pertinent to note at booking and followups. The pregnancy is at-risk and multidisciplinary team management is central. The mainstay of management remains diet modification. There have been case reports of successful medical treatment of dumping syndrome in pregnancy with good maternal and fetal outcomes. However, more data is needed regarding the usage of these medical treatments in pregnancy.

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer.

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2-/- mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer.

Selective fusion in adolescent idiopathic scoliosis: a radiographic evaluation of risk factors for imbalance.

STUDY DESIGN: Retrospective database, chart and medical imaging review. OBJECTIVES: To report on the outcome and evaluate possible risk factors for postoperative complications following selective spinal fusion in patients with adolescent idiopathic scoliosis (AIS). MATERIALS AND METHODS: All patients with AIS who underwent either a selective thoracic or selective thoracolumbar/lumbar spinal fusion at our institution from January 2001 to December 2011 inclusive were included in this study. The minimum postoperative follow-up period of all patients was 2 years. RESULTS: During the 11-year study period, 157 patients with AIS underwent surgery for their progressive spinal deformity. Thirty patients (19 %) had a selective spinal fusion, with 16 patients (group A) having a selective thoracic, and 14 patients (group B) having a selective thoracolumbar/lumbar spinal arthrodesis. In both groups the main postoperative complications were adding-on (25 % group A, 36 % group B) and coronal decompensation (25 % group A, 29 % group B). In group A, no statistically significant risk factors for postoperative complications were identified. In group B, global coronal balance was identified as a significant risk factor for adding-on. Patients with adding-on had significantly higher coronal balance scores (mean 3.6) than those who did not experience adding-on (mean 1.9) (p = 0.03). In addition, those with adding-on had a significantly smaller bending lumbar Cobb angle (mean 15) than those without adding-on (mean 31.6) (p = 0.015). None of the patients who underwent selective spinal fusion required revision surgery. CONCLUSION: Although the complication rate after performing a selective spinal fusion is high, the revision rate remains low and the debate whether or not to perform a selective spinal fusion will continue.

Generation and screening of a comprehensive Mycobacterium avium subsp. paratuberculosis transposon mutant bank.

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne's Disease in ruminants. This enteritis has significant economic impact and worldwide distribution. Vaccination is one of the most cost effective infectious disease control measures. Unfortunately, current vaccines reduce clinical disease and shedding, but are of limited efficacy and do not provide long-term protective immunity. Several strategies have been followed to mine the MAP genome for virulence determinants that could be applied to vaccine and diagnostic assay development. In this study, a comprehensive mutant bank of 13,536 MAP K-10 Tn5367 mutants (P > 95%) was constructed and screened in vitro for phenotypes related to virulence. This strategy was designated to maximize identification of genes important to MAP pathogenesis without relying on studies of other mycobacterial species that may not translate into similar effects in MAP. This bank was screened for mutants with colony morphology alterations, susceptibility to D-cycloserine, impairment in siderophore production or secretion, reduced cell association, and decreased biofilm and clump formation. Mutants with interesting phenotypes were analyzed by PCR, Southern blotting and DNA sequencing to determine transposon insertion sites. These insertion sites mapped upstream from the MAP1152-MAP1156 cluster, internal to either the Mod operon gene MAP1566 or within the coding sequence of lsr2, and several intergenic regions. Growth curves in broth cultures, invasion assays and kinetics of survival and replication in primary bovine macrophages were also determined. The ability of vectors carrying Tn5370 to generate stable MAP mutants was also investigated.

Getting Australia more active: challenges and opportunities for health promotion.

A growing body of evidence demonstrates that regular physical activity promotes health and assists in the prevention of non-communicable diseases but this is presently curtailed by low and unhealthy participation rates in Australia and comparable industrialised countries. Compounding the problem is knowledge that physical inactivity is independently associated with poor health outcomes. Despite physical activity being described as public health's 'best bet' or 'best buy', motivating individuals and groups to adopt and maintain physical activity continues to be a major challenge for health professionals. Global advocacy for prevention efforts must be operationalised through national to local strategies to promote and support physical activity in multiple settings including the home, schools and workplace. The Australian health promotion community has and continues to play a leadership role in physical activity promotion. However, there is an urgent need to continue to promote the importance of physical activity, along with its pivotal role in the prevention of non-communicable diseases, alongside related agendas including healthy diets, tobacco control and environmental sustainability. This commentary overviews the contemporary status of physical activity promotion in Australia and identifies key challenges and opportunities moving forward.

Management of arterial lines and blood sampling in intensive care: a threat to patient safety.

In 2008, the UK National Patient Safety Agency (NPSA) made recommendations for safe arterial line management. Following a patient safety incident in our intensive care unit (ICU), we surveyed current practice in arterial line management and determined whether these recommendations had been adopted. We contacted all 241 adult ICUs in the UK; 228 (94.6%) completed the survey. Some NPSA recommendations have been widely implemented - use of sodium chloride 0.9% as flush fluid, two-person checking of fluids before use - and their practice was consistent. Others have been incompletely implemented and many areas of practice (prescription of fluids, two-person checking at shift changes, use of opaque pressure bags, arterial sampling technique) were highly variable. More importantly, the use of the wrong fluid as an arterial flush was reported by 30% of respondents for ICU practice, and a further 30% for practice elsewhere in the hospital. Our survey provides evidence of continuing risk to patients.

Intraocular pressure is not associated with acute mountain sickness.

OBJECTIVE: Acute mountain sickness (AMS) is common at high altitude and may lead to high altitude cerebral edema (HACE) if not properly recognized. Previous studies have suggested that AMS is associated with increases in intracranial pressure (ICP). Increased ICP has been associated with increased intra-ocular pressure (IOP). This study was designed to determine the association between IOP and AMS. METHODS: Subjects were recruited from a convenience sample of travelers in the Khumbu region of Nepal, elevation 14,410 ft (4392 m). Study participation involved completion of a questionnaire to assess for AMS by the Lake Louise Score (LLS), followed by three IOP measurements in each eye. Investigators were blinded to the LLS. Subjects with a history of ocular surgery were excluded. Three IOP measurements per eye were made using an applanation tonometer (Tono-Pen XL(®), Reichart Technologies) and averaged across both eyes. Multivariable logistic regression analysis was used to estimate the association between IOP and AMS while adjusting for age, ascent or descent, and use of acetazolamide. IOP and blood O2 saturation were compared using a Spearman correlation coefficient. RESULTS: 161 subjects were enrolled with a median age of 36 (IQR: 29-45) years; 60% were male, 75% were ascending, and 64% were taking acetazolamide; additionally, 38%, (95% CI: 31%-47%) were diagnosed with AMS (LLS ≥3). The median IOP was 21 (IQR 18-24) mmHg. The logistic regression model demonstrated no association between IOP and AMS as measured by LLS (odds ratio [OR] 1.0, 95% CI: 0.9-1.1),age (OR 1.0, 95% CI: 0.9-1.0) or with use of acetazolamide (OR 1.4, 95% CI: 0.6-2.6). Ascent (OR 0.4, 95% CI: 0.2-0.9) was negatively associated with IOP but not significantly so. IOP and O2 saturation were not correlated (p=0.93). CONCLUSIONS: IOP measured at high altitude is not associated with the diagnosis of AMS. Other approaches to diagnose AMS easily and accurately are needed.

The effect of platelet-rich plasma on normal soft tissues in the rabbit.

BACKGROUND: Platelet-rich plasma is reported to contain multiple growth factors, and has been utilized in orthopaedic surgery to aid healing in multiple tissues. To date, the use of autologous platelet-rich plasma has not been studied for its effects on normal soft tissue. METHODS: Eighteen adult New Zealand White rabbits were injected with 0.5 mL of autologous platelet-rich plasma in the right or left quadriceps muscle, Achilles tendon, medial collateral ligament, subcutaneous tissue, tibial periosteum, and ankle joint. Saline solution was injected on the contralateral side as a control. The soft tissues were examined histologically at two weeks (six rabbits) and six weeks (six rabbits), and soft tissues from six rabbits that had been reinjected at six weeks were examined at twelve weeks. RESULTS: Inflammatory skin lesions were visible at forty-eight hours at superficial platelet-rich plasma sites. All lesions resolved by six days. Compared with findings in control specimens, histological analysis of platelet-rich plasma injection sites at two weeks showed a marked inflammatory infiltrate with lymphocytic and monocytic predominance. Intra-articular injection showed villous synovial hyperplasia and chronic synovitis. Tendon and ligament sites showed new collagen deposition. Intramuscular injection sites showed thrombosis, necrosis, and calcium deposition. Subcutaneous sites also showed calcium deposition without necrosis as well as collagen nodules representing early scar tissue. Histological examination of platelet-rich plasma injection sites at six and twelve weeks demonstrated a persistent but diminished inflammatory infiltrate. Focal areas of scar tissue were seen with fibroblasts, collagen formation, and neovascularity. All saline solution sites at all times were nonreactive. CONCLUSIONS: Platelet-rich plasma can initiate an inflammatory response in the absence of an inciting injury in normal soft tissue in rabbits.

Is there a role for total ankle replacement in polio patients?: A case report and review of the literature.

Although poliomyelitis is almost eradicated, as orthopaedic surgeons we occasionally encounter residual deformities in patients who suffered the disease in the past. An equino-varus deformity of the foot is the commonest deformity seen. In this report we present a 53 years old lady who had poliomyelitis as a child and presented with a painful, degenerate ankle and 12 degrees of varus deformity. CT confirmed advanced degenerative changes. The management options included realignment and fusion, supramalleolar ostoetomy or total ankle replacement. In view of the satisfactory active range of motion and advanced OA confirmed by CT scan we considered the option of total ankle replacement. To our knowledge this has never been reported before. At two and half years follow up the patient showed satisfactory functional results (AOFAS score 88/100) and high satisfaction. Plain radiographs revealed a well aligned joint with no evidence of loosening or osteolysis.

The impact of moderate-altitude staging on pulmonary arterial hemodynamics after ascent to high altitude.

Staged ascent (SA), temporary residence at moderate altitude en route to high altitude, reduces the incidence and severity of noncardiopulmonary altitude illness such as acute mountain sickness. To date, the impact of SA on pulmonary arterial pressure (PAP) is unknown. We tested the hypothesis that SA would attenuate the PAP increase that occurs during rapid, direct ascent (DA). Transthoracic echocardiography was used to estimate mean PAP in 10 healthy males at sea level (SL, P(B) approximately 760 torr), after DA to simulated high altitude (hypobaric chamber, P(B) approximately 460 torr), and at 2 times points (90 min and 4 days) during exposure to terrestrial high altitude (P(B) approximately 460 torr) after SA (7 days, moderate altitude, P(B) approximately 548 torr). Alveolar oxygen pressure (Pao(2)) and arterial oxygenation saturation (Sao(2)) were measured at each time point. Compared to mean PAP at SL (mean +/- SD, 14 +/- 3 mmHg), mean PAP increased after DA to 37 +/- 8 mmHg (Delta = 24 +/- 10 mmHg, p < 0.001) and was negatively correlated with both Pao(2) (r(2) = 0.57, p = 0.011) and Sao(2) (r(2) = 0.64, p = 0.005). In comparison, estimated mean PAP after SA increased to only 25 +/- 4 mmHg (Delta = 11 +/- 6 mmHg, p < 0.001), remained unchanged after 4 days of high altitude residence (24 +/- 5 mmHg, p = not significant, or NS), and did not correlate with either parameter of oxygenation. SA significantly attenuated the PAP increase associated with continuous direct ascent to high altitude and appeared to uncouple PAP from both alveolar hypoxia and arterial hypoxemia.

Targeted mapping of Cdu1, a major locus regulating grain cadmium concentration in durum wheat (Triticum turgidum L. var durum).

Some durum wheat (Triticum turgidum L. var durum) cultivars have the genetic propensity to accumulate cadmium (Cd) in the grain. A major gene controlling grain Cd concentration designated as Cdu1 has been reported on 5B, but the genetic factor(s) conferring the low Cd phenotype are currently unknown. The objectives of this study were to saturate the chromosomal region harboring Cdu1 with newly developed PCR-based markers and to investigate the colinearity of this wheat chromosomal region with rice (Oryza sativa L.) and Brachypodium distachyon genomes. Genetic mapping of markers linked to Cdu1 in a population of recombinant inbred substitution lines revealed that the gene(s) associated with variation in Cd concentration resides in wheat bin 5BL9 between fraction breakpoints 0.76 and 0.79. Genetic mapping and quantitative trait locus (QTL) analysis of grain Cd concentration was performed in 155 doubled haploid lines from the cross W9262-260D3 (low Cd) by Kofa (high Cd) revealed two expressed sequence tag markers (ESMs) and one sequence tagged site (STS) marker that co-segregated with Cdu1 and explained >80% of the phenotypic variation in grain Cd concentration. A second, minor QTL for grain Cd concentration was also identified on 5B, 67 cM proximal to Cdu1. The Cdu1 interval spans 286 kbp of rice chromosome 3 and 282 kbp of Brachypodium chromosome 1. The markers and rice and Brachypodium colinearity described here represent tools that will assist in the positional cloning of Cdu1 and can be used to select for low Cd accumulation in durum wheat breeding programs targeting this trait. The isolation of Cdu1 will further our knowledge of Cd accumulation in cereals as well as metal accumulation in general.

Total ankle replacement by the Ankle Evolution System: medium-term outcome.

We present the outcomes in 38 consecutive patients who had total ankle replacement using the Ankle Evolution System with a minimum follow-up of four years. Pain and function were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) score and regular standardised anteroposterior and lateral weight-bearing radiographs were obtained. Patient satisfaction and complications were recorded and the survival of the implants was demonstrated by the Kaplan-Meier method. The mean follow-up was for 57.8 months (48 to 80). The cumulative survival rate at six years was 94.7% (95% confidence interval 80.3 to 98.7). The mean total AOFAS score was 88.1 (53 to 100). The mean score for pain was 35.8 (20 to 40). Ten patients presented with edge-loading of whom nine had corrective surgery. Two ankles were revised, one to an arthrodesis and the other to replace the tibial component. Nine patients showed radiological evidence of osteolysis. They had minimal non-progressive symptoms and further surgery was not undertaken. Nevertheless, the concerns about osteolysis led to the implant being withdrawn by the manufacturer. The medium-term results of the ankle evolution system ankle replacement are satisfactory with high patient satisfaction, but the rate of osteolysis is of some concern. The long-term benefit of this procedure has yet to be determined.

Chemokine receptor-derived peptides as multi-target drug leads for the treatment of inflammatory diseases.

The rationale for multi-target drugs has been strengthened both on theoretical and empirical grounds. Serious diseases that are intractable to treatment were found to have multiple pathogenic factors and examples of successful drugs were shown to affect multiple disease targets. The salient features of multiple-target drugs, low target affinity and rapid binding kinetics, have been responsible for their late discovery and slow development. We predicted that peptides from the ligand-binding domains of chemokine (CK) receptors could be used to modulate the activities of disease-related chemokines (CKs) for therapeutic effect. We developed innovative technologies to produce, screen and optimize low affinity, chemokine-binding peptides (CBPs) derived from chemokine receptors (CRs). The peptides were found to have therapeutic activity in animal models of disease, confirming our prediction and validating the related technologies.

Revision of STAR total ankle replacement to hybrid AES-STAR total ankle replacement-a report of two cases.

Revision of a failed total ankle replacement is a surgical challenge due to paucity of the revision ankle implants. We report early results of two cases in which Scandinavian Total Ankle Replacements (STAR) were revised to hybrid AES (Ankle Evolution System)-STAR replacements for aseptic loosening of the tibial components. We are not aware of any similar case report in the literature reporting hybrid total ankle replacements.

Disseminated panniculitis in a bottlenose dolphin (Tursiops truncatus) due to Mycobacterium chelonae infection.

A 14-year-old female bottlenose dolphin was diagnosed with mycobacterial panniculitis based on punch biopsy specimens. The necropsy revealed numerous pyogranulomas in the blubber, as well as marked acute multifocal necrosuppurative pneumonia and lymphadenitis. In addition, the animal had marked scoliosis, which had first been noted clinically in the dolphin at about 1 mo of age. The animal had been treated with low-dose dexamethasone for approximately the last 19 mo to reduce perceived discomfort from spondyloarthritis and with the progestational agent altrogenest for approximately 8 yr to prevent pregnancy. Acid-fast positive bacilli were detected in the dermis but not in lung or lymph nodes. Mycobacterium chelonae was isolated from pooled skin, lung, and peripheral lymph-node tissue. Mycobacterial infection may be considered as a differential diagnosis in bottlenose dolphins with generalized cutaneous inflammation, particularly if chronic steroid and progesterone treatments were administered, both of which may have an immunomodulatory effect.

The impact of a good practice manual on professional practice associated with psychotropic PRN in acute mental health wards: an exploratory study.

BACKGROUND: As required or pro re nata (PRN) psychotropic medicines are frequently used in acute mental health wards. PRN is known to contribute to polypharmacy and high doses of antipsychotic medication. Few studies have attempted to improve clinician's use of these potentially harmful drugs. AIMS: The objectives of the study were to determine the impact and acceptability of a good practice manual on prescribing and administration practices of PRN psychotropic medication in acute mental health wards. DESIGN: The study used a pre-post exploratory design with two acute mental health wards in the NW of England. RESULTS: Over the total trial period of 10 weeks, 28 of 35 patients received 484 doses of PRN. Patients had a mean of 3.6 prescriptions of 14 different PRN medications in 34 different dose combinations prescribed. Medication errors beyond poor quality of prescribing occurred in 23 of the 35 patients (65.7%). Prescription quality improved following the introduction of the intervention but quality of nursing notes reduced. Acceptability of the manual to both nursing and medical staff was high. CONCLUSION: The introduction of the manual appeared to influence some of the practices associated with the prescribing and administration of PRN psychotropic medications. Further, larger, more robust studies are required in this area. In particular research is required to identify the reasons why professionals continue to rely so heavily on using PRN medication.

Are routine cranial ultrasounds necessary in premature infants greater than 30 weeks gestation?

The purpose of this study was to validate the recommendation of the American Academy of Neurology and the Child Neurology Society that screening cranial ultrasonography be performed routinely on all infants of less than 30 weeks gestation at 7 to 14 days of age and again between 36 and 40 weeks postmenstrual age, and, by using this practice parameter, to determine the number of babies with a clinically significant abnormal screening cranial ultrasound (US) who would otherwise have been missed. A retrospective study of 486 infants of 30 to 33 weeks gestation born January 1, 1999 to June 30, 2004 was done. All had screening cranial ultrasounds. Grade III and/or grade IV intraventricular hemorrhage (IVH) occurred in 4 (0.8%) infants of 30 to 31 weeks gestation. Infants with significant IVH had either risk factors for brain injury or symptoms that would eventually warrant US during their hospitalization. Seven (1.4%) infants had periventricular leukomalacia (PVL). All infants with a final diagnosis of PVL had pre- and/or perinatal risk factors associated with PVL. There was a significant trend toward fewer abnormal cranial ultrasounds from 30 to 33 weeks gestation (p=0.04). Our study supports the recommendation by the American Academy of Neurology and the Child Neurology Society that screening US can be limited but suggests that the gestational age cut off should be 30 weeks or less.