Synthesis of 3 H, 13 C2 , 2 H414 C-SCH 430765 and 35 S-SCH 500946, potent and selective inhibitors of the NPY5 receptor.

SCH 430765 and SCH 500496 are potent and selective antagonists of the NPY5 receptor. NPY5 receptor antagonists have the potential for the treatment of obesity. [35 S]SCH 500946 was prepared for a competition binding assay which led to the identification of SCH 430765. Three distinct isotopically labelled forms of SCH 430765 were synthesized. [3 H]SCH 430765 was prepared for a preliminary absorption, distribution, metabolism and excretion data evaluation of the compound and [14 C]SCH 430765 for more definitive absorption, distribution, metabolism and excretion data work. In addition, [13 C2 ,2 H4 ]SCH 430765 was prepared as an internal standard for a LC-MS bioanalytical method. The paper discusses the synthesis of 3 isotopically labelled forms of SCH 430765 and [35 S]SCH 500946.

Synthesis of 3 H, 2 H4 , and 14 C-MK 3814 (preladenant).

MK 3814 is a potent and selective antagonist of the A2a receptor. A2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [3 H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [14 C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [2 H4 ]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method. This paper discusses the synthesis of 3 isotopically labelled forms of MK 3814.

Weakly acidic pH reduces inflammatory cytokine expression in airway epithelial cells.

BACKGROUND: Aspiration lung disease (ALD) is a common cause of respiratory morbidity in children and adults with severe neurodisability (sND). Recent studies suggest that chronic microaspiration of gastric contents is associated with mild rather than low, airway acidification. We investigated inflammatory responses to infection by airway epithelial cells (AECs) exposed to weakly acidic media. METHODS: Using pH measurements from children with sND at high risk of ALD as a guide, we incubated AECs in weakly acidic (pH5.5-7.4) media alone; in combination with lipopolysaccharide (LPS); or prior to LPS stimulation at normal pH. Interleukin (IL) -6 and IL-8 expression were measured. RESULTS: IL-6/8 expression in AECs simultaneously exposed to weakly acidic media and LPS for 4 h was reduced with no effect on cell viability. Pre-incubation of AECs at weakly acidic pH also reduced subsequent LPS-induced cytokine expression. Suppression of inflammation was greatest at lower pHs (pH 5.5-6.0) for prolonged periods (16/24 h), but this also adversely affected cell viability. CONCLUSION: AEC inflammatory responses to bacterial stimuli is markedly reduced in a mildly acidic environment.

Synthesis of (3) H, (2) H4 and (14) C-SCH 417690 (Vicriviroc).

Vicriviroc or SCH 417690 is a potent and selective antagonist of the CCR5 receptor. CCR5 receptor antagonists have the potential for the treatment of HIV infections. Four distinct isotopically labelled forms of SCH 417690 were synthesized. Low specific activity [(3) H]SCH 417690 was prepared for a preliminary absorption, distribution, metabolism and excretion evaluation of the compound and [(14) C]SCH 417690 for more definitive absorption, distribution, metabolism and excretion work, including an absorption, metabolism and excretion study in man. In addition, high specific activity [(3) H]SCH 417690 was prepared for CCR5 receptor binding work and [(2) H4 ]SCH 417690 was prepared as an internal standard for a liquid chromatography-mass spectrometry bioanalytical method. The paper discusses the synthesis of four isotopically labelled forms of SCH 417690.

Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial?

Childhood wheezing is common particularly in children under the age of 6 years and in this age group is generally referred to as preschool wheezing. Particular diagnostic and treatment uncertainties exist in these young children due to the difficulty in obtaining objective evidence of reversible airways narrowing and inflammation. A diagnosis of asthma depends on the presence of relevant clinical signs and symptoms and the demonstration of reversible airways narrowing on lung function testing, which is difficult to perform in young children. Few treatments are available and inhaled corticosteroids are the recommended preventer treatment in most international asthma guidelines. There is, however, considerable controversy about its effectiveness in children with preschool wheeze and a corticosteroid responder phenotype has not been established. These diagnostic and treatment uncertainties in conjunction with the knowledge of corticosteroid side effects, in particular the reduction of growth velocity, have resulted in a variable approach to inhaled corticosteroid prescribing by medical practitioners and a reluctance in carers to regularly administer the treatment. Identifying children who are likely responders to corticosteroid therapy would be a major benefit in the management of this condition. Eosinophils have emerged as a promising biomarker of corticosteroid responsive airways disease, and evaluation of this biomarker in sputum has successfully been employed to direct management in adults with asthma. Obtaining sputum from young children is time consuming and difficult, and it is hard to justify more invasive procedures such as a bronchoscopy in young children routinely. Recently, in children, interest has shifted to assessing the value of less invasive biomarkers of likely corticosteroid response and the biomarker 'blood eosinophils' has emerged as an attractive candidate. The aim of this review was to summarize the evidence for blood eosinophils as a predictive biomarker for corticosteroid responsive disease with a particular focus on the difficult area of preschool wheeze.

Synthesis of 3H, 13C,2H3,15N and 14C-labelled SCH 466036, a histamine 3 receptor antagonist.

The synthesis of [(3)H]SCH 466036, [Me-(3)H3]SCH 466036, [(13)C,(2)H3,(15)N]SCH 466036 and [(14)C]SCH 466036 is described. [(3)H]SCH 466036 was prepared in two steps via Raney Ni-catalysed exchange with tritiated water. [Me-(3)H3]SCH 466036 was prepared in a single step from [(3)H]methyl iodide in 45% yield. [(13)C,(2)H3,(15)N]SCH 466036 was prepared in two steps from [(15)N]hydroxylamine and [(13)C,(2)H3]methyl iodide with an overall yield of 16%. [(14)C]SCH 466036 was prepared in seven steps from [(14)C]potassium cyanide in an overall yield of 13%.

Biochar from Pyrolysis of Biosolids for Nutrient Adsorption and Turfgrass Cultivation.

At water resource recovery facilities, nutrient removal is often required and energy recovery is an ever-increasing goal. Pyrolysis may be a sustainable process for handling wastewater biosolids because energy can be recovered in the py-gas and py-oil. Additionally, the biochar produced has value as a soil conditioner. The objective of this work was to determine if biochar could be used to adsorb ammonia from biosolids filtrate and subsequently be applied as a soil conditioner to improve grass growth. The maximum carrying capacity of base modified biochar for NH3-N was 5.3 mg/g. Biochar containing adsorbed ammonium and potassium was applied to laboratory planters simulating golf course putting greens to cultivate Kentucky bluegrass. Planters that contained nutrient-laden biochar proliferated at a statistically higher rate than planters that contained biosolids, unmodified biochar, peat, or no additive. Nutrient-laden biochar performed as well as commercial inorganic fertilizer with no statistical difference in growth rates. Biochar from digested biosolids successfully immobilized NH3-N from wastewater and served as a beneficial soil amendment. This process offers a means to recover and recycle nutrients from water resource recovery facilities.

Postnatal cytomegalovirus infection and pulmonary vascular disease in extremely premature infants: A case series.

BACKGROUND: Pulmonary vascular disease (PVD) is a major determinant of both morbidity and mortality in extremely low birth weight infants. It is biologically plausible that postnatal cytomegalovirus (pCMV) infection may lead to PVD in premature infants secondary to pneumonitis or via derangement of pulmonary vascular development directly through endothelial dysfunction. Uncertainty remains, however, regarding thresholds for intervention in premature infants with cardiorespiratory instability and presumed CMV infection likely secondary to the limited understanding of the natural history of the disease. METHODS/RESULTS: We describe four cases of premature infants with clinical and echocardiography features of PVD, in the setting of postnatally acquired CMV. All patients had atypical PVD trajectories, refractory to vasodilator treatment, which improved after initiation of CMV treatment. CONCLUSION: We highlight the need to consider postnatally acquired CMV infection in patients with PVD non-responsive to standard pulmonary vasodilator therapies or disease severity which is out of proportion of the usual clinical trajectory. Treatment of extremely premature infants with CMV-associated PVD may have positive impact on cardiorespiratory health, although duration of therapy remains uncertain.

Respiratory syncytial virus infection of airway epithelial cells, in vivo and in vitro, supports pulmonary antibody responses by inducing expression of the B cell differentiation factor BAFF.

BACKGROUND: The mechanisms regulating antibody expression within the human lung during airway infection are largely unknown. In this study, our objectives were to determine if infection with respiratory syncytial virus (RSV) upregulates expression of the B cell differentiation factors A proliferation inducing ligand (APRIL) and B cell activating factor of the TNF family (BAFF), if this is a common feature of viral airway infection, and how this is regulated in human airway epithelial cells. METHODS: We measured BAFF and APRIL protein expression in bronchoalveolar lavage (BAL) fluid from infants with severe RSV disease, and healthy control children, and in nasopharyngeal aspirates from preschool children with other single respiratory viral infections. We also measured mRNA expression in bronchial brushings from RSV-infected infants, and in RSV-infected paediatric primary airway epithelial cell cultures (pAEC). Beas-2B cell cultures were used to examine mechanisms regulating BAFF expression. RESULTS: BAFF protein and mRNA were elevated (in marked contrast with APRIL) in BAL and bronchial brushings, respectively, from RSV-infected infants. BAFF protein was also found in upper airway secretions from children with human metapneumovirus, H1N1, bocavirus, rhinovirus, RSV and Mycoplasma pneumoniae infection. BAFF mRNA and protein were expressed following in vitro RSV infection of both pAEC and Beas-2B cultures, with mRNA expression peaking 12-h postinfection. BAFF induction was blocked by addition of a neutralising anti-interferon-ß antibody or palivizumab. CONCLUSIONS: BAFF, produced through an interferon-ß-dependent process, is a consistent feature of airway infection, and suggests a role for the airway epithelia in supporting protective antibody and B cell responses in the lung.

Limitations to the identification of HIV-associated neurocognitive disorders in clinical practice.

OBJECTIVES: The objective of this study was to establish the level of awareness of HAND among healthcare providers, the screening tools that are currently used in its detection and factors that limit cognitive assessments. METHODS: We distributed a 12-item questionnaire to doctors and nurses who work in the Department of Genitourinary Medicine and Infectious Disease (GUIDE) service and also to doctors who work in the emergency department (ED) at St James Hospital. RESULTS: 35 surveys were collected, 54% (n = 19) from the GUIDE service and 46% (n = 16) from the ED. 82% (n = 29) of participants were doctors from interns to consultants. There was reasonable appreciation among participants with regards the prevalence of neurocognitive impairment (estimated at 29.1% among patients on HAART, and 39.3% among patients not on HAART). Screening tools were rarely used by GUIDE and ED clinicians (25% vs. 15% of the time). The Mini Mental State Examination (MMSE) was previously used by 37% (n = 13) of the group. Very few people had used the HIV Dementia Scale (HIVDS) 6% (n = 2). 34% of respondents felt that 'Orientation in Person, Place and Time was a sufficient screening tool for cognitive assessment'. Lack of time, exposed environment and lack of availability of screening tool were cited as limitations to cognitive screening in the ED environment. CONCLUSIONS: This study examines awareness of HAND among healthcare providers and also reasons for inadequate assessment. There is a need for consensus on screening guidelines. A quick, easy to use and readily available screening tool may have a role in the acute setting in identifying high-risk patients.

Arterial pressure is not reflective of right ventricular function in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

AIM: to evaluate the correlation of recovery of arterial pressure with physiological recovery among patients with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia. METHODS: At 24 h postnatal age, we compared 53 neonates of whom 22 (41%) were inotrope-treated to those untreated with cardiovascular medications. RESULTS: Inotrope-treated patients had persistent severe right ventricular (RV) dysfunction and evidence of abnormal brain tissue oxygen delivery, despite recovered arterial pressure. CONCLUSION: Arterial pressure is not reflective of RV function and the need for inotropic agents may be reflective of abnormal brain tissue oxygen delivery.

Impact of early screening echocardiography and targeted PDA treatment on neonatal outcomes in "22-23" week and "24-26" infants.

The hemodynamically significant patent ductus arteriosus (hsPDA) is a controversial topic in neonatology, particularly among neonates at the earliest gestational ages of 22+0-23+6 weeks. There is little, to no data on the natural history or impact of the PDA in extremely preterm babies. In addition, these high-risk patients have typically been excluded from randomized clinical trials of PDA treatment. In this work, we present the impact of early hemodynamic screening (HS) of a cohort of patients born 22+0-23+6 weeks gestation who either were diagnosed with hsPDA or died in the first postnatal week as compared to a historical control (HC) cohort. We also report a comparator population of 24+0-26+6 weeks gestation. All patients in the HS epoch were evaluated between 12-18h postnatal age and treated based on disease physiology whereas the HC patients underwent echocardiography at the discretion of the clinical team. We demonstrate a two-fold reduction in the composite primary outcome of death prior to 36 weeks or severe BPD and report a lower incidence of severe intraventricular hemorrhage (n=5, 7% vs n=27, 27%), necrotizing enterocolitis (n=1, 1% vs n=11, 11%) and first-week vasopressor use (n=7, 11% vs n=40, 39%) in the HS cohort. HS was also associated with an increase in survival free of severe morbidity from the already high rate of 50% to 73% among neonates <24 weeks gestation. We present a biophysiological rationale behind the potential modulator role of hsPDA on these outcomes and review the physiology relevant to neonates born at these extremely preterm gestations. These data highlight the need for further interrogation of the biological impact of hsPDA and impact of early echocardiography directed therapy in infants born less than 24 weeks gestation.

Primary airway epithelial cultures from children are highly permissive to respiratory syncytial virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection of airway epithelial cells (AECs) is an important initial event in RSV bronchiolitis. AEC immunological responses are thought to be critical in driving the subsequent inflammation in the airway. This study examined viral replication, cytotoxicity and cytokine production in cultures of primary AECs from children compared with responses to RSV infection in an immortalised epithelial cell line and to those from infants with RSV bronchiolitis. METHODS: RSV replication, proinflammatory cytokine responses and cytotoxicity in RSV-infected primary AEC cultures derived from bronchial brushings from the lungs of children were compared with those seen in BEAS-2B cultures, as well as AECs and bronchoalveolar lavage fluid collected from children with and without RSV bronchiolitis. RESULTS: Viral replication, cytotoxicity and inflammatory cytokine production were greater in primary AEC cultures than in BEAS-2B cells. Different response patterns were observed, with RSV infection of primary AEC cultures causing distinct peaks of viral replication and matched cytotoxic responses. Some primary AEC culture immunological responses, such as interleukin 8, were similar in magnitude to those seen in clinical samples from the lungs of children with RSV bronchiolitis. Although variable amounts of RSV were detected by PCR in freshly isolated primary AECs, RSV was not detected by immunocytochemistry. CONCLUSION: This is one of the first studies to examine comprehensively the responses to RSV infection in primary AEC cultures from children and shows marked differences from those of a commercially available immortalised human cell line but reassuring similarities to results found in vivo. This suggests that future work investigating responses of AECs to RSV infection should use primary AEC cultures.

Assessing the Liverpool Respiratory Symptom Questionnaire in children with cystic fibrosis.

Monitoring respiratory status in cystic fibrosis (CF) is challenging, particularly in young children. We aimed to test whether the Liverpool Respiratory Symptom Questionnaire (LRSQ) could distinguish well, pre-school and older children with and without CF, whether it could distinguish well and unwell children with CF and, finally, whether LRSQ scores in older children with CF correlated with established measures of disease severity. 20 stable pre-school children with CF had significantly higher total LRSQ scores than 51 pre-school controls, and higher scores in two out of eight domains. Similarly, 21 stable 6- to 12-yr-old children with CF had higher total scores than 97 6- to 12-yr-old controls, and higher scores in seven out of eight domains. In older children with CF, LRSQ scores correlated negatively with Shwachman score and forced expiratory volume in 1 s (r = -0.58, p < 0.001, n = 31; and r = -0.46, p < 0.010, n = 34, respectively). Within the CF group, patients who cultured Pseudomonas aeruginosa, who used more "back-up" antibiotics or whose school attendance was lower also had higher LRSQ scores. The LRSQ differentiates well children from those with CF in both pre-school and the 6- to 12-yr-old age group, even at a point of stability. It also differentiates stable from unwell children with CF, and scores correlate with other measures of respiratory disease, highlighting its potential as a clinical monitoring tool in paediatric CF.

The case for cognitive screening in HIV clinics.

A retrospective chart review was carried out at the HIV clinic in St. James's Hospital, Dublin to examine the rate of cognitive impairment through the use of surrogate markers for cognitive impairment. 500 consecutive hospital charts were reviewed. There were 306 men and 194 women. Median age was 37. The most common mode of transmission was heterosexual. 45% had a nadir CD4 < 200. 78.6% were on antiretroviral therapy and 72.26% were virally suppressed. 69/500 patients (13.8%) had one or more positive surrogate markers for cognitive impairment. The surrogate markers used were subjective complaints, a new onset of a psychiatric diagnosis post diagnosis with HIV, neurological complications and radiological evidence of atrophy. Multivariate analysis using logistic regression showed significant relationships only with gender and year of diagnosis. This figure is lower than reported international prevalence rates of cognitive impairment and demonstrates that surrogate markers are no match for structured cognitive screening. We have since commenced structured prospective screening to obtain a true prevalence of cognitive impairment in this population.

How to diagnose and treat acute pulmonary hypertension when you have no cardiology support.

Acute pulmonary hypertension (aPH) is a complex, physiology-driven disorder that causes critical illness in newborns, the hallmark of which is elevated pressure in the pulmonary vascular bed. Several underlying hemodynamic phenotypes exist, including classic arterial aPH with resistance-driven elevations in pulmonary arterial pressure (PAP), alongside flow-driven aPH from left-to-right shunt lesions, and primary left ventricular dysfunction with pulmonary venous hypertension and elevated left atrial pressure. Targeted neonatal echocardiography (TnECHO) is an important tool for evaluation of hemodynamics in aPH and is highly useful for evaluating modulators of disease and targeting cardiovascular therapy. The diagnostic approach to aPH includes confirmation of elevation of PAP, evaluation of the cause and exclusion of structural cardiac disease, assessment of the response of the myocardium to adverse loading conditions, and appraisal of the adequacy of systemic blood flow. Therapeutic goals include support of right ventricular (RV) function, RV afterload reduction, and selection of cardiotropic agents that support underlying pathophysiology without adverse effects on heart rate or pulmonary vascular resistance in addition to routine supportive intensive care. Training programs for TnECHO exist across multiple jurisdictions and strong correlation with pediatric cardiology assessment has been demonstrated. Future directions include adapting TnECHO training with a greater focus on achieving competency, and further research into the role of the modality in providing individualized cardiovascular care for patients with heterogenous underlying physiology, and its effect on key neonatal outcomes.

Management of cardiac dysfunction in neonates with pulmonary hypertension and the role of the ductus arteriosus.

Pulmonary hypertension in the neonate is associated with cardiopulmonary disturbances and neurodevelopment morbidity. The patent ductus arteriosus is a persistent fetal shunt that can be pathologic vs supportive in the setting of neonatal pulmonary hypertension. Understanding the underlying pathophysiology of pulmonary hypertension and the cardiopulmonary effects of various phenotypes can guide management in this vulnerable population. In this narrative, we will summarize the physiologic principles of pulmonary hypertension, the impact of the patent ductus arteriosus on various phenotypes, and the utility of serial targeted neonatal echocardiography to individualize clinical assessment and management.

The influence of professional factors in determining primary school teachers' commitment to health promotion.

The objectives of the study were to identify the professional issues that teachers perceived as important in their commitment to a health promotion (HP) programme launched in their schools and to understand their perceptions of the impact of the programme on themselves as professionals, individuals, on students, on school staff and on the relationship with students' families. A mixed methods design was used. An anonymous questionnaire was distributed to 54 participating teachers exploring their practices and perceptions of the programme and 26 semi-structured interviews were conducted which examined their professional commitment to the programme. The main factors that teachers identified as shaping their commitment were (1) their perceptions of the programme, specifically, its congruence with their own role and practice and also their perceived impact of the programme upon whole staff relations and (2) the specific school environment including school organization, quality of the relationships with parents and student behaviour. If HP programmes are to be successfully developed in schools, it is necessary to anchor them within the schools' mission. HP programmes need to make sense to teachers' educational perspectives. They need to be responsive to school needs. They also need to be cognisant of the internal tensions that programme implementation can engender among the whole staff, some of whom may be committed to HP in their school, while others, may not value HP in the same way. Therefore, implementation processes that are respectful of the challenges schools encounter and of the differing ontological perspectives that teachers may hold with regard to HP is important.

Association of hemoglobin and spontaneous closure of the ductus arteriosus during the transitional period in very low birth weight infants.

OBJECTIVES: To determine the association between plasma hemoglobin (HB) at three time-points (birth, postnatal days 0-3 and 0-10) and spontaneous closure of the ductus arteriosus (sDAC). STUDY DESIGN: A retrospective case-control study of preterm infants born (2013-2016) between 24 and 29 weeks of gestational age (GA) was conducted in a level three perinatal center in Switzerland. We collected hemoglobin at birth, between days 0-3 and 0-10 in two distinct groups: (i) patients treated for a PDA and (ii) patients with spontaneous closure of the ductus arteriosus (sDAC). Antenatal and postnatal demographic data and neonatal morbidity were collected. Bivariate analysis was performed and a stepwise logistic regression was done to investigate factors associated with sDAC. RESULTS: We reviewed the medical chart of 184 premature infants of whom 146 (79.3%) satisfied eligibility criteria. Of these, 74 (51%) were classified as sDAC. Patients with sDAC were older (GA: 28 vs 27, p < 0.001), more stable (clinical risk index for babies score (CRIB score): 2 vs 5, p < 0.001) and had better clinical outcomes than patients who received treatment for a PDA. Infants in the sDAC group had a higher level of hemoglobin during the first ten postnatal days. Multiple logistic regression analysis revealed that lower HB level (day 0-10) were associated with failure of sDAC (p < 0.05). CONCLUSIONS: This is one of the first studies to highlight a potential association between hemoglobin during the transitional period and sDAC. The biological nature of this observation requires prospective clarification.

Survivorship of the bio-action metatarsophalangeal joint arthroplasty for hallux rigidus: 5-year follow-up.

BACKGROUND: Metatarsophalangeal joint arthroplasty is an accepted treatment for hallux rigidus. There are few reports of the long-term results of this procedure. METHODS: A series of 15 consecutive bio-action first metatarsophalangeal total joint replacements were retrospectively reviewed after a minimum follow-up of 5 years. The patients were assessed using the American Orthopaedic Foot and Ankle Society Score. Patient satisfaction and standard radiographs were also examined. RESULTS: Subjectively, just over half the patients were satisfied with the results of the surgery. Objectively, however mechanical failure of the implant was universal, as determined radiographically. DISCUSSION: Despite some success in relieving symptoms in patients, we have abandoned this procedure because of the high and increasing rate of failure, as demonstrated both clinically and radiologically.