Direct comparison of runoff of residual and knockdown herbicides in sugarcane using a rainfall simulator finds large difference in runoff losses and toxicity relative to diuron.

Runoff losses of herbicides have rarely been compared simultaneously under the same conditions. Our aim was to directly compare herbicide runoff losses, normalised for the amount present (relative runoff loads) and in absolute terms. Toxicity and runoff concentrations were combined to provide a risk ranking relative to diuron. Four rainfall simulation trials were conducted in sugarcane in the Great Barrier Reef catchment. Herbicides studied were older PSII residuals (atrazine, ametryn, diuron, hexazinone), alternative residuals (isoxaflutole, imazapic, metribuzin, metolachlor, pendimethalin) and knockdown herbicides (glyphosate, 2,4-D, fluroxypyr) and the tracer bromide (Br). Simulations were conducted two days after spraying, before differences due to half-lives were apparent. Two trials had bare soil and two had sugarcane trash. Herbicide runoff losses and concentrations were closely related to the amount applied, runoff amounts and partitioning coefficients. Relative runoff losses and absolute losses were similar for most older and alternative residual herbicides, 2,4-D and Br. Glyphosate and pendimethalin relative runoff losses were low, due to greater sorption. Isoxaflutole, imazapic, and fluroxypyr are applied at much lower rates and runoff losses were low. Herbicides were lost in the dissolved phase, except pendimethalin. There was a large range in toxicity relative to diuron. There is a range of herbicide choices posing less offsite risk than diuron and ametryn, which have high application rates and high toxicity. Herbicide choice should consider application rate, runoff losses, sorption, and toxicity.

Use of the Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity ('P-POSSUM') to predict morbidity in patients undergoing surgery with reconstruction for temporal bone malignancy.

OBJECTIVE: The Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity ('P-POSSUM') is a two-part scoring system that includes a physiological assessment and a measure of operative severity. This study sought to determine whether risk estimates for this scoring system could be used in major head and neck reconstructive surgery. METHOD: A retrospective review was performed of patients undergoing resection for a temporal bone malignancy in a single head and neck centre in Dublin, Ireland, from 2002 to 2021. RESULTS: The mean ± standard deviation morbidity estimate calculated using the scoring system was 47.6 per cent ± 19.5 per cent. The actual rate of complications was 47 per cent. The optimal cut-off for the scoring system was calculated using the Youden index from the receiver operating characteristic curve, which was 40.5 per cent in this case. CONCLUSION: The study indicates that the Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity is a useful tool for predicting morbidity risk in patients undergoing head and neck resection with reconstruction for temporal bone malignancies.

Burden of Uterine Fibroids: An African Perspective, A Call for Action and Opportunity for Intervention.

Black women carry the burden of uterine fibroids, (AKA uterine leiomyomas), at a much higher rate than their racial counterparts. Thus, increasing awareness and discovering a solution to an endemic problem that plagues Sub-Saharan Africa is of critical importance, not only for the region itself, but also for the medical community globally. A collaborative, patient oriented, cost effective, and culturally sensitive approach must be at the forefront of this endeavor. While the exact pathogenesis of uterine fibroid development remains elusive, the racial disparity is well documented. Moreover, in the developed world, women are able to seek treatment through surgical and non-surgical means; however, sub-Saharan regions face their own challenges that, if not addressed, can ultimately extinguish the lives of many suffering women. Unfortunately, the literature is scarce on how to prevent fibroid development, which may be critical for women who do not have access to effective interventions. Recent research from our group and others has shown that vitamin D deficiency plays an important role in fibroid development and may be a preventable risk factor. Daily vitamin D supplementation is a low cost, effective intervention that could be implemented throughout the Sub-Saharan region. Similarly, education and increased awareness as to the nature and symptoms of uterine fibroids could improve the quality of life, remove negative social stigma, and reduce morbidity and mortality rates in women who seek medical care with advanced uterine fibroids.

What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis? Data from a single-centre cohort.

OBJECTIVE: To determine whether serial ANA testing predicts biological disease modifying antirheumatic drugs (bDMARD)-associated ANA/dsDNA production in patients with rheumatoid arthritis (RA). METHODS: Serial autoantibody profiles, bDMARD treatment sequences and clinical data were collected from patients identified from our database that since 2005 received (i) a first bDMARD (tumour necrosis factor inhibitor (TNFi)) and (ii) tocilizumab and/or abatacept. RESULTS: Of over 1000 patients, 454 RA patients received a first TNFi. Infliximab group demonstrated higher ANA seroconversion rates (31.2%) compared with etanercept (11.8%) and adalimumab (16.1%) (p<0.001). Median (range) treatment duration prior to ANA seroconversion was 10.9 (1.3-80.0) months. Positive anti-dsDNA titres of IgG class (median (range) of 77 IU/mL (65-109)) were noted in six (7.2%) patients, within a median (range) of 2.0 (0.8-4.2) years. Three patients developed classifiable lupus. 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). Seven (9.5%) tocilizumab-treated patients changed to positive ANA; five (8.6%) abatacept-treated patients changed to positive ANA status. CONCLUSIONS: This study demonstrates no utility of serial ANA/dsDNA testing that could be used to predict onset of seroconversion and therefore the development of lupus/vasculitis. An association however between seroconversion and the development of a secondary non-response to bDMARD therapy is suggested.

NT5E CpG island methylation is a favourable breast cancer biomarker.

BACKGROUND: Relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. In the light of existing preclinical and clinical data, we studied NT5E (5'-nucleotidase, ecto) expression and NT5E CpG island methylation in breast cancer. METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse NT5E in breast carcinoma cell lines and primary and breast carcinomas. RESULTS: NT5E CpG island methylation was inversely associated with NT5E expression in breast carcinoma cell lines. In clinical series, patients whose primary tumours had NT5E CpG island methylation were less likely to develop metastasis (P=0.003, OR=0.34, 95% CI: 0.17-0.69). In 3/4 paired samples, NT5E was methylated in primary tumours and demethylated in CNS metastases. Patients progressing to non-visceral as compared with visceral metastases were more likely to have NT5E CpG island methylation in primary tumours (P=0.01, OR=11.8). Patients with tumours lacking detectable methylation had shorter disease-free survival (DFS) (P=0.001, HR=2.7) and overall survival (OS) (P=0.001, HR=3). The favourable prognostic value of NT5E methylation was confirmed in oestrogen receptor negative (P=0.011, HR=3.27, 95% CI: 1.31-8.12) and in triple negative cases (P=0.004; HR=6.2, 95% CI: 1.9-20). Moreover, we observed a more favourable outcome to adjuvant chemotherapy in patients whose tumours were positive for NT5E CpG island methylation: DFS (P=0.0016, HR=5.1, 95% CI: 1.8-14.37) and OS (P=0.0005, HR=7.4, 95% CI: 2.416-23.08). CONCLUSION: NT5E CpG island methylation is a promising breast cancer biomarker.

NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.

BACKGROUND: Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known. METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas. RESULTS: NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81-61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01). CONCLUSION: Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain.

The cerebroplacental Doppler ratio predicts postnatal outcome in fetuses with congenital heart block.

OBJECTIVE: Autoimmune-mediated congenital complete heart block (CCHB) is associated with significant perinatal morbidity and mortality, and prenatal monitoring of these fetuses is a significant challenge. The cerebroplacental Doppler ratio (CPR), defined as the ratio of the middle cerebral artery pulsatility index (MCA-PI) to the umbilical artery pulsatility index (UA-PI), is predictive of perinatal outcome in growth-restricted fetuses. This study tests the hypothesis that the CPR would be useful in monitoring fetal well-being in fetuses with CCHB. STUDY DESIGN: We reviewed data on all patients diagnosed prenatally with autoimmune-mediated CCHB at our institution over the past 2 years. The fetal echocardiograms from each patient were analyzed for: CPR, UA-PI, MCA-PI, cardiothoracic ratio, degree of tricuspid regurgitation, ventricular function and presence of effusions. We compared hemodynamic data from the fetal echocardiogram before delivery in patients who required urgent pacemaker placement postnatally to those patients that did not require an urgent pacemaker. RESULT: Five patients with autoimmune-mediated CCHB were identified, and two patients required urgent pacemaker placement. The CPR before delivery was significantly lower in the patients who required urgent pacemaker placement (0.97+/-0.06 versus 1.45+/-0.03; P=0.003), but there was no difference in other fetal echocardiographic markers between groups. Both patients requiring urgent pacemaker placement had a CPR less than 1.08. CONCLUSION: The CPR is predictive of postnatal outcome in fetuses with CCHB and is useful in prenatal monitoring of these patients.

A case of an infant with flail tricuspid valve due to spontaneous papillary muscle rupture: was neonatal lupus the culprit?

A 3-month-old infant presented in extremis with a flail tricuspid valve. The authors theorized that the genesis of her papillary muscle rupture was perinatal ischemia compounded by worsening pulmonary valvular stenosis leading to excessive fiber tension. Her underlying diagnosis of autoimmune-mediated heart block with endocardial fibroelastosis and prenatal glucocorticoid steroid treatment represents potentiating factors.

Isolated infundibuloarterial inversion.

Isolated infundibuloarterial inversion is a rare conotruncal cardiac anomaly characterized by a leftward and posterior aortic valve in the face of ventriculoarterial concordance. It has previously been described only in cases associated with severe additional defects of substantial hemodynamic significance. We present a case of isolated infundibuloarterial inversion with a small, hemodynamically insignificant ventricular septal defect. The nature of this lesion, diagnostic methods of imaging, and features aiding its discrimination from the more commonly recognized anatomically corrected malposition of the great arteries are discussed.

The role of polymer membrane formation in sustained release drug delivery systems.

A discussion of the role of polymer membrane-based drug delivery systems is presented. This is followed with a review of recent studies in our laboratories of the membrane formation and drug delivery characteristics of injectable polymer solution platforms. Attention is focused on the role of depot formulation in terms of solvent quality and water miscibility and polymer type (amorphous versus crystallizable), as well as the effects of bath-side additives on the in vitro release behavior. A quantitative model describing the protein release dynamics in fast phase inverting systems (FPI) is also discussed.

Pericardial effusion and cardiac tamponade in pediatric stem cell transplant recipients.

Pericardial effusion and cardiac tamponade is a rarely reported complication following stem cell transplant (SCT). The incidence among pediatric SCT recipients is not well defined. To assess the frequency of clinically significant pericardial effusions, we retrospectively examined clinically significant cardiac effusions at our center. Between January of 1993 and August 2004, clinically significant pericardial effusions were identified in nine of 205 patients (4.4%). The median age at the time of transplant was 9 years (range 0.6-18 years) and seven received an allogeneic transplant. All nine had normal cardiac function prior to transplant. The effusion developed at a median of 30 days (range 18-210 days). All allogeneic recipients had acute or clinically extensive graft-versus-host disease (GVHD) at the time the effusion was diagnosed. Seven patients (78%) required pericardiocentesis or surgical creation of a pericardial window. No patient died as a complication of the effusion or the therapeutic procedures. Clinically significant pericardial effusions are more common than previously reported in pediatric SCT recipients. Acute and chronic GVHD is an associated factor.

A model for drug release from fast phase inverting injectable solutions.

A model is developed to describe protein release kinetics from injectable, polymer solution depots which undergo rapid phase inversion on injection. The model consists of a polymer-rich phase and a solvent-rich phase, consistent with experimentally observed phase inversion morphology. Equations in the polymer-rich phase are based on diffusion-reaction mass balances for solvent, water and dissolved drug, and the rate of dissolution of dispersed drug particles. Equations in the water-rich phase are also of the diffusion-reaction type. Transport parameters in the polymer-rich phase are coupled to the ternary thermodynamics through friction formalism, and remaining parameters are estimated from literature data, leaving two free parameters: volume fraction of water-rich phase (epsilon) and k, the mass-transfer coefficient for bath-side transfer of the protein. Variations of these parameters lead to predictions of release profiles that vary from a rapid, burst-like behavior followed by a locking-in of the polymer-rich phase, to a uniform, zero-order profile. Comparisons are made to lysozyme release data for three systems: PLGA solutions in N-methlypyrollidinone (NMP), PLA solutions in NMP, and the latter with added Pluronic. Good agreement between model predictions and data is shown; in particular, the transition from rapid release to zero-order kinetics that occurs on addition of Pluronic is illustrated.

The effect of Pluronic on the protein release kinetics of an injectable drug delivery system.

A new class of injectable controlled release depots has been prepared by incorporating materials that preferentially segregate during phase inversion. These consist of blends of poly(ethylene oxide) (PEO)/poly(propylene oxide) (PPO)/poly(ethylene oxide) (PEO) triblock copolymers (Pluronics) with poly(D,L-lactide) (PDLA)/1-methyl-2-pyrrolidinone (NMP) solutions. The effects of preferential segregation on the phase inversion dynamics and in vitro protein release kinetics were examined using dark ground imaging, high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), and confocal microscopy. Variations in Pluronic concentration and molecular weight had an insignificant effect on the internal depot morphologies, however, increasing the concentration and molecular weight did result in increased phase separation rates and, surprisingly, a decrease in the magnitude of the protein burst, though the release profiles still retained a typical burst-type shape. Additionally, increasing the Pluronic concentration beyond a critical point resulted in a transition from a burst-type profile to an extended-release profile. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.

Role of crystallization in the phase inversion dynamics and protein release kinetics of injectable drug delivery systems.

The role of polymer crystallization in the phase inversion dynamics and in vitro protein release kinetics of semi-crystalline poly (epsilon-caprolactone) and amorphous poly (D,L-lactide) (PDLA) blend solutions has been examined using high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) techniques. Varying the degree of crystallizability of the solutions led to the emergence of two general classes of depots. Depots with a high degree of crystallinity are characterized by porous morphologies indicative of solid-liquid (s--l) de-mixing and delayed burst release profiles. Alternatively, depots with a low degree of crystallinity are characterized by dense morphologies formed by mild liquid-liquid (l--l) phase separation and slow, uniform protein release rates. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.

Modified Norwood operation for hypoplastic left heart syndrome.

BACKGROUND: We examined early results in infants with hypoplastic left heart syndrome undergoing the Norwood operation with perioperative use of inhaled nitric oxide and application of extracorporeal membrane oxygenation. METHODS: Medical records were reviewed retrospectively. RESULTS: Between April 1997 and March 2001, 50 infants underwent a modified Norwood operation for hypoplastic left heart syndrome. Mean age at operation was 7.5 +/- 5.7 days, and mean weight was 3.1 +/- 0.5 kg. Five infants had a delayed operation because of sepsis. The mean diameter of the ascending aorta by echocardiography was 3.6 +/- 1.8 mm. Ductal cannulation was used to establish cardiopulmonary bypass in all patients. Mean circulatory arrest time was 39.4 +/- 4.8 minutes. The size of the pulmonary-systemic shunt was 3.0 mm in 6 infants, 3.5 mm in 37, and 4.0 mm in 7. Infants with persistent hypoxia (partial pressure of oxygen < 30 mm Hg) received nitric oxide after they were weaned from cardiopulmonary bypass. Extracorporeal membrane oxygenation was initiated in 8 infants in the pediatric intensive care unit primarily for low cardiac output and in 8 in the operating room because of the inability to separate them from cardiopulmonary bypass. The 30-day mortality rate was 22% (11 of 50 patients), and the hospital mortality rate was 32% (16 of 50 patients). Mean follow-up was 17 months. Ten patients (20%) underwent stage-two repair, with one operative death. One survivor had a Fontan procedure, and 2 underwent heart transplantation, with one death. CONCLUSIONS: Early application of extracorporeal membrane oxygenation for hemodynamic instability and selective use of nitric oxide for persistent hypoxia in the immediate postoperative period may improve survival of patients with hypoplastic left heart syndrome. Renal failure requiring hemofiltration during extracorporeal membrane oxygenation (p < 0.05) and cardiopulmonary arrest in the pediatric intensive care unit (p < 0.05) were predictors of hospital mortality.

Analysis of genetically modified plant gene expression using GUS fluorimetry.

A fluorimetric assay method for the analysis of beta-glucuronidase (GUS) reporter gene expression in genetically modified plants is described. Optimization of this method for woody plants and a statistical approach suitable for comparisons of gene expression in different transformants or tissues of the same plant is described. Example data from elm (Ulmus procera) SR4 regenerant plants, shown to be genetically modified by PCR and DNA-DNA hybridizations, in which higher GUS expression levels are found in stems than in leaves demonstrates the utility of this approach.

Transesophageal echocardiography in pediatric congenital heart disease.

The uses of transesophageal echocardiography have expanded dramatically over the last decade. With advances in technology, this imaging modality has become readily available for evaluation of the complex pediatric population with congenital heart disease. This article discusses the many uses of transesophageal echocardiography in this population, in the outpatient setting, in the peri-operative period, and in the cardiac catheterization laboratory.

Regeneration of phenotypically normal English elm (Ulmus procera) plantlets following transformation with an Agrobacterium tumefaciens binary vector.

A transformation system was developed for English elm (Ulmus procera Salisbury) using Agrobacterium tumefaciens C58 pMP90 p35SGUS/INTRON, allowing for the transfer of foreign genes and regeneration of phenotypically normal elm plantlets. The PCR analysis indicated that both nptII and uidA genes were stably inserted in the plant genome. beta-Glucuronidase histochemical and fluorimetric assays revealed expression of the uidA gene in the shoots, leaves, stems and roots of regenerated transgenic plants. The DNA-DNA hybridizations confirmed the presence of the uidA gene in regenerant plants. Factors influencing successful transformation and regeneration of elms included: identifying gene-transfer-proficient Agrobacterium strains for use with elms; developing an infection protocol allowing T-DNA transfer while retaining the ability to remove inciting bacteria; and identifying selection conditions to eliminate non-transformed material and choice of regeneration medium to allow shoot production. The potential utility of an effective elm transformation and regeneration system in the control of Dutch elm disease is discussed.

Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.

Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein's anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.