The futures of pastoralism in the Horn of Africa: pathways of growth and change.

This paper reviews pastoralism in the Horn of Africa region with reference to the basic socio-economics of pastoralism, and the use of mobile livestock production to generate income and food for human consumption. The paper also examines long-term trends in pastoralist areas which, at first sight, appear to be contradictory. The first trend is the growth of a substantial domestic and export trade in livestock and meat across the region, driven largely by supplies from pastoralist areas and local and international demand. This trend indicates robust and responsive livestock production and marketing in pastoralist areas, despite recurrent drought, conflict and weak governance. In contrast, the second trend sees increasing levels of poverty and destitution in pastoralist areas, and continued high levels of human malnutrition. The co-existence of economic growth and increasing poverty in 'high-export' areas is explained by human population growth, drought, and the private control of pastures and water by wealthier producers. All of these factors combine to push poorer producers out of pastoralism. In areas with lower market orientation, other forms of declining land access are often evident, including the appropriation of land for mechanised farming, hydroelectric schemes, and bush encroachment. These changes, plus population growth and drought, also push people out of pastoralism. In all areas, pastoralism will continue to be the main economic activity but, at the same time, increasing numbers of people are seeking other livelihoods.

Cet article consacré au pastoralisme dans la Corne de l'Afrique au regard de ses principales caractéristiques socio-économiques décrit les utilisations du bétail nomade pour générer des revenus et produire des aliments destinés à la consommation humaine. Les auteurs analysent également les tendances à long terme des régions d'élevage pastoral, qui apparaissent à première vue comme étant contradictoires. La première tendance observée dans cette région a trait à la croissance d'un commerce important d'animaux et de viandes destiné aux marchés nationaux et d'exportation, sous l'impulsion conjointe de l'offre émanant des zones d'élevage pastoral et de la demande tant locale qu'internationale. Cette tendance démontre l'existence dans les zones d'élevage pastoral de capacités de production et commerciales robustes et adaptables, en dépit des épisodes récurrents de sécheresse, des conflits sociaux et d'une gouvernance déficiente. En revanche, la deuxième tendance révèle une aggravation croissante de la pauvreté et de la précarité dans les zones d'élevage pastoral, accompagnées d'une malnutrition importante et persistante dans les populations humaines. La coexistence d'une croissance économique et d'une plus grande pauvreté dans des zones à dominante exportatrice s'explique par la croissance démographique, par les sécheresses et par la mainmise des producteurs les plus riches sur les terres de pâture et sur l'eau. Ces facteurs cumulés détournent du pastoralisme les éleveurs les plus pauvres. Dans les régions à vocation exportatrice moins prononcée, le déclin de l'accès aux pâturages prend d'autres formes clairement identifiables, par exemple l'appropriation des terres en vue de leur exploitation mécanisée, la production d'énergie hydraulique ou l'extension de la brousse. Ces changements s'ajoutant à la croissance démographique et à la sécheresse rendent le pastoralisme beaucoup moins attractif pour les individus. Certes, le pastoralisme restera la principale activité économique des régions étudiées mais en même temps, de plus en plus de gens vont s'orienter vers d'autres moyens de subsistance.

Los autores pasan revista al pastoreo en la región del Cuerno de África, haciendo referencia a sus fundamentos socioeconómicos y a la producción de ganado móvil como medio de generar ingresos y alimentos para el consumo humano. Además, señalan la existencia de tendencias a largo plazo en las zonas de pastoreo que, a primera vista, parecen contradictorias. La primera es el auge de un comercio nacional o exportador de ganado y carne de considerables dimensiones en toda la región, impulsado básicamente por los suministros procedentes de las zonas de pastoreo y por la demanda local e internacional. Esta tendencia pone de manifiesto procesos robustos y flexibles de producción y comercialización de ganado en las zonas pastorales, pese a la recurrencia de sequías y conflictos y a la mala gestión de los asuntos públicos. La segunda tendencia, en acusado contraste, pone de manifiesto niveles crecientes de pobreza e indigencia en las zonas de pastoreo y niveles constantemente elevados de malnutrición humana. La concurrencia de crecimiento económico y pobreza en aumento en zonas eminentemente exportadoras se explica por el crecimiento de la población humana, las sequías y el control privado de los pastos y el agua que ejercen los ganaderos más pudientes. Todos estos factores se combinan para expulsar del pastoreo a los productores pobres. En zonas menos orientadas hacia el mercado aparecen a menudo otras causas de acceso decreciente a la tierra, como la apropiación de suelo para la producción agrícola mecanizada, la instalación de centrales hidroeléctricas o el avance de la maleza. Estos cambios, sumados al crecimiento demográfico y a la sequía, también inducen a las personas a dejar el pastoreo. Y aunque este seguirá siendo la principal actividad económica en todas las zonas, cada vez hay más gente que busca otras formas de ganarse la vida.

Impact of opening a new emergency department on healthcare service and patient outcomes: analyses based on linking ambulance, emergency and hospital databases.

BACKGROUND: Emergency department (ED) crowding caused by access block is an increasing public health issue and has been associated with impaired healthcare delivery, negative patient outcomes and increased staff workload. AIM: To investigate the impact of opening a new ED on patient and healthcare service outcomes. METHODS: A 24-month time series analysis was employed using deterministically linked data from the ambulance service and three ED and hospital admission databases in Queensland, Australia. RESULTS: Total volume of ED presentations increased 18%, while local population growth increased by 3%. Healthcare service and patient outcomes at the two pre-existing hospitals did not improve. These outcomes included ambulance offload time: (Hospital A PRE: 10 min, POST: 10 min, P < 0.001; Hospital B PRE: 10 min, POST: 15 min, P < 0.001); ED length of stay: (Hospital A PRE: 242 min, POST: 246 min, P < 0.001; Hospital B PRE: 182 min, POST: 210 min, P < 0.001); and access block: (Hospital A PRE: 41%, POST: 46%, P < 0.001; Hospital B PRE: 23%, POST: 40%, P < 0.001). Time series modelling indicated that the effect was worst at the hospital furthest away from the new ED. CONCLUSIONS: An additional ED within the region saw an increase in the total volume of presentations at a rate far greater than local population growth, suggesting it either provided an unmet need or a shifting of activity from one sector to another. Future studies should examine patient decision making regarding reasons for presenting to a new or pre-existing ED. There is an inherent need to take a 'whole of health service area' approach to solve crowding issues.

VeriStrat(®) has prognostic value in advanced stage NSCLC patients treated with erlotinib and sorafenib.

BACKGROUND: The serum proteomic test VeriStrat has been shown to be able to classify advanced non-small cell lung cancer (NSCLC) patients for overall survival (OS) after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, VeriStrat was evaluated as a pre-treatment stratification tool in patients with advanced stage NSCLC for treatment with the combination of erlotinib and sorafenib, considering both OS and progression-free survival (PFS) as end points. METHODS: Serum samples from 50 patients treated within the context of a phase II trial of first-line erlotinib and sorafenib were analysed with VeriStrat, a fully locked mass spectrometry-based test that identifies patients likely to have good or poor outcome on EGFR therapy based on eight distinct features in mass spectra. Analysis was performed fully blinded to all clinical data, and then the outcome data were analysed with respect to the obtained serum classifications. RESULTS: VeriStrat classified pre-treatment samples into two groups, VeriStrat Good and VeriStrat Poor, which were significantly different in OS (hazard ratio (HR) 0.30, log-rank P=0.009) and in PFS (HR 0.40, log-rank P=0.035). CONCLUSION: VeriStrat has shown its potential for stratification of unselected, advanced stage NSCLC patients treated in first line with a combination of erlotinib and sorafenib.

Middle cerebral artery stenosis: transcranial color-coded sonography based on continuity equation versus CT-angiography.

PURPOSE: Transcranial color-coded sonography (TCCS) and CT-angiography (CTA) are reliable tools for detection of intracranial stenosis. Current ultrasonographic criteria for middle cerebral artery (MCA) stenosis are usually limited to a dichotomized grading (< or ≥ 50 %). As for carotid arteries, continuity equation might provide a more accurate evaluation of degree of MCA stenosis. We aimed to apply continuity equation to calculate degree of MCA stenosis with TCCS and to compare these results with CTA. MATERIALS AND METHODS: All patients admitted to our Neurovascular Center with ischemic stroke or TIA underwent TCCS examination. Degree of MCA stenosis was calculated based on continuity equation as (1 - [PSVprestenotic/PSVintrastenotic] × 100) %. CTA was performed when TCCS detected MCA stenosis, and degree of stenosis was calculated by diameter (D) as: (1 - [Dprestenotic/Dintrastenotic] × 100) %. Correlation between TCCS and CTA results was tested. Continuity equation method was compared to cut-off velocity method for detection of ≥ 50 % MCA stenosis. To assess TCCS inter-observer agreement, evaluation of MCA stenosis was repeated by another neurosonographer in a subgroup of patients. RESULTS: The overall correlation coefficient between TCCS and CTA was 0.85 (p < 0.0001). Correlation coefficient for stenosis defined with CTA as ≥ 50 % was 0.94 (p < 0.0001). TCCS inter-observer agreement on degree of stenosis was 0.85 (p = 0.001). In detection of ≥ 50 % MCA stenosis, continuity equation method showed a sensitivity of 78 % (14/18) and a specificity of 86 % (19/22), while the cut-off velocity method showed a sensitivity of 67 % (12/18) and a specificity of 86 % (19/22). CONCLUSION: This study shows that ultrasonographic evaluation of MCA stenosis applying the continuity equation provides reproducible and accurate results, and is more sensitive in detection of ≥ 50 % MCA stenosis than cut-off velocity method.

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients.

BACKGROUND: Blood-based biomarkers may be particularly useful for patient selection and prediction of treatment response for angiogenesis inhibitors. Circulating endothelial cells (CECs) and haematopoietic progenitor cells (HPCs) might have a role in tumour angiogenesis and in tumour growth. Measurement of CECs and HPCs in the blood of patients could be a simple, non-invasive way to monitor or predict responses to treatment. METHODS: (VEGFR2(+)) CECs(,) (CD133(+)) HPCs, plasma vascular endothelial growth factor (VEGF) and erythropoietin were measured in blood from 25 non-small cell lung cancer (NSCLC) patients before and during treatment with sorafenib plus erlotinib (SO/ER). In order to assess the drug specificity of changes in CECs and HPCs, 18 patients treated with bevacizumab plus erlotinib (BV/ER) and 10 patients with erlotinib (ER) monotherapy were studied. Response was measured in all patient groups by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: At day 7, SO/ER-treated patients showed a three-fold increase in CECs (P<0.0001) comparable to BV/ER-treated patients (P<0.01), and the CECs did not change with erlotinib treatment (P=0.8). At day 7, CD133(+)/HPCs decreased with SO/ER treatment (P<0.0001). HPC numbers did not change with either BV/ER or erlotinib. In SO/ER-treated patients pre-treatment CD133(+)/HPCs were significantly lower in responders (P=0.01) and pre-treatment CD133(+)/HPC numbers lower than the median correlated with a longer time-to-progression (TTP) (P=0.037). CONCLUSION: Pre-treatment CD133(+)/HPCs are a promising candidate biomarker to further explore for use in selecting NSCLC patients who might benefit from SO/ER treatment.

Manic episodes are associated with grey matter volume reduction - a voxel-based morphometry brain analysis.

OBJECTIVE: To investigate whether the lifetime number of affective episodes or illness duration is associated with changes in local grey matter volume, in patients with bipolar I disorder without comorbid conditions. METHOD: Magnetic resonance imaging scans of 55 patients with bipolar I disorder were analysed using VBM. RESULTS: Smaller grey matter volume in the inferior frontal gyri of the dorsolateral prefrontal cortices (DLPFC) correlated significantly to the lifetime number of manic episodes. No association between local grey matter volume and the lifetime number of depression episodes or illness duration was found. CONCLUSION: We found strong evidence for a linear correlation between a decrease in DLPFC volume and the lifetime number of manic episodes in patients with bipolar I disorder. Interestingly, DLPFC is known to be important for executive functions and the findings in this study might hence be linked to the executive cognitive deficits associated with bipolar disorder.

Cardiac assessment of patients with late stage Duchenne muscular dystrophy.

Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, but is hampered by scoliosis and poor echocardiographic acoustic windows in adult DMD patients. Multigated cardiac radionuclide ventriculography (MUGA) does not suffer from these limitations. N-terminal proBNP (NTproBNP) has shown to be a diagnostic factor for heart failure. We present our initial experience with plasma NT-proBNP measurement in the routine screening and diagnosis of cardiomyopathy in adult mechanically ventilated DMD patients.Methods. Retrospective study, 13 patients. Echocardiography classified left ventricular (LV) function as preserved or depressed. NT-proBNP was determined using immunoassay. LV ejection fraction (LVEF) was determined using MUGA.Results. Median (range) NT-proBNP was 73 (25 to 463) ng/l. Six patients had an NT-proBNP >125 ng/l. Seven patients showed an LVEF <45% on MUGA. DMD patients with depressed LV function (n=4) as assessed by echocardiography had significantly higher median NT-proBNP than those (n=9) with preserved LV function: 346 (266 to 463) ng/l versus 69 (25 to 257) ng/l (p=0.003). NT-proBNP significantly correlated with depressed LV function on echocardiogram and with LVEF determined by MUGA.Conclusion. Although image quality of MUGA is superior to echocardiography, the combination of echocardiography and NT-proBNP achieves similar results in the evaluation of left ventricular function and is less time consuming and burdensome for our patients. We advise to add NT-proBNP to echocardiography in the routine cardiac assessment of DMD patients. (Neth Heart J 2009;17:232-7.).

Altered deactivation in individuals with genetic risk for Alzheimer's disease.

Regions that show task-induced deactivations may be part of a default-mode network related to processes that are more engaged during passive than active task conditions. Alteration of task-induced deactivations with age and dementia is indicated by atypical engagement of default-mode network regions. Genetic studies show a relation between the apolipoprotein E4 (APOE4) allele and the common form of Alzheimer's disease (AD), and altered functional brain activation has been observed in non-demented APOE4 carriers compared to non-carriers. Here we investigate the hypothesis of altered default-mode network brain responses in individuals with genetic risk for AD. Functional MRI was used to assess task-induced deactivation in 60 subjects of which 30 carried at least one copy of the APOE4 allele, and 30 non-carriers. Subjects were scanned while performing a semantic categorization task shown to promote episodic memory encoding. The results show patterns of deactivation consistent with the default-mode network. We also found reduced deactivation in non-demented APOE4 carriers compared to non-carriers, suggesting alterations in the default-mode network in the absence of dementia. These results implicate possibilities for investigating altered properties of task-induced deactivations in individuals with genetic risk for AD, and may prove useful for pre-clinical identification of individuals susceptible to memory problems and AD.

[New therapies for the treatment of advanced non-small cell lung cancer: inhibitors of the epidermal growth factor receptor and angiogenesis]. / Nieuwe middelen voor de behandeling van gemetastaseerd niet-kleincellig longcarcinoom: remmers van de epidermale groeifactorreceptor en van de angiogenese.

The recently developed 'targeted' therapies, epidermal growth factor receptor (EGFR) inhibitors and angiogenesis inhibitors, target specific tumour characteristics. EGFR inhibitors, such as gefitinib and erlotinib, can lead to remission, particularly in non-small cell lung cancer (NSCLC) with specific EGFR mutations. These mutations occur more frequently in Asians, women, non-smokers and those with adenocarcinomas. Other mutations in EGFR and K-ras genes lead to resistance. EGFR inhibitors offered no benefit to untreated patients with advanced NSCLC. In previously treated patients, however, erlotinib increased survival by 2 months. Optimal patient selection criteria for EGFR inhibitor therapy is still under investigation. The angiogenesis inhibitor bevacizumab is an antibody that targets vascular endothelial growth factor receptor. The addition of bevacizumab to chemotherapy increased median survival by 2 months when given as first-line therapy for advanced NSCLC. The combination of EGFR and angiogenesis inhibitors is a rational anticancer treatment and is being studied. These new therapies are expected to help improve and individualize the treatment of advanced NSCLC.

[Termination of pregnancy after the 20-week ultrasonographic examination: haste and caution]. / Zwangerschapsafbreking na de 20-wekenecho: haast en zorgvuldigheid.

The recently introduced ultrasonographic screening programme for the detection of fetal structural anomalies at 20 weeks' gestation is leading to a growing number of cases with an unclear prognosis. This article presents the decision-making process which followed the screening of two women: one aged 36 years, where a post-screening work-up was conducted and swiftly led to well-balanced decision making to abort a fetus with trisomy 21, and one woman aged 30 years, in whom repeated non-decisive results of further diagnostic tests ultimately led to a hasty decision to abort the pregnancy. Up to 24 weeks, current Dutch law allows the couple to decide to have a termination of pregnancy; thereafter the legal possibility of having a termination is very limited. This may lead to rushed decision-making. It is argued that careful decisions in these matters are more important than staying within the 24-week limit. The national central committee ofexperts which is responsible for the evaluation of all abortions after 24 weeks gestation in the so-called category 2 cases (conditions which will lead to serious and irreparable functional disorders, such as severe spina bifida and hydrocephalus, but which are compatible with life) should take account of this dilemma ofhaste and caution.

[Assessment of late pregnancy terminations, 2004-2007]. / Toetsing van late zwangerschapsafbreking, 2004-2007.

OBJECTIVE: To provide an inventory of the reported late terminations of pregnancy because ofa severe anomaly of the unborn child, i.e. termination after 24 weeks of pregnancy, in The Netherlands for the period 2004-2007. DESIGN: Inventory and descriptive. METHOD: A description is given of the various assessment procedures for the termination of pregnancy after 24 weeks. A distinction is made between abortion for lethal foetal abnormalities (category 1) and severe functional impairments with a limited chance for survival of the unborn (category 2). The level of caution exercised in decision making and performing category 1 terminations is assessed by the professional group, namely by the assessment committee for Late Pregnancy Termination of the Dutch Association for Gynaecology and Obstetrics. Since 15 March 2007, late pregnancy terminations that fall under category 2 have by law been assessed by a national central committee of experts. An overview of the reported cases of late terminations of pregnancy in the Netherlands for the period 2004-2007 is given. RESULTS AND CONCLUSION: The number of reported terminations of pregnancy after 24 weeks (n = 72) has declined considerably since the early 1990s. A possible explanation is that due to increasing technological improvements and the implementation of prenatal screening in early preg-nancy, an abortion can be performed before the 24th week of pregnancy if any severe abnormalities are observed.

Linking initial microstructure and local response during quasistatic granular compaction.

We performed experiments combining three-dimensional x-ray diffraction and x-ray computed tomography to explore the relationship between microstructure and local force and strain during quasistatic granular compaction. We found that initial void space around a grain and contact coordination number before compaction can be used to predict regions vulnerable to above-average local force and strain at later stages of compaction. We also found correlations between void space around a grain and coordination number, and between grain stress and maximum interparticle force, at all stages of compaction. Finally, we observed grains that fracture to have an above-average initial local void space and a below-average initial coordination number. Our findings provide (1) a detailed description of microstructure evolution during quasistatic granular compaction, (2) an approach for identifying regions vulnerable to large values of strain and interparticle force, and (3) methods for identifying regions of a material with large interparticle forces and coordination numbers from measurements of grain stress and local porosity.

Dynamic Behavior of Engineered Lattice Materials.

Additive manufacturing (AM) is enabling the fabrication of materials with engineered lattice structures at the micron scale. These mesoscopic structures fall between the length scale associated with the organization of atoms and the scale at which macroscopic structures are constructed. Dynamic compression experiments were performed to study the emergence of behavior owing to the lattice periodicity in AM materials on length scales that approach a single unit cell. For the lattice structures, both bend and stretch dominated, elastic deflection of the structure was observed ahead of the compaction of the lattice, while no elastic deformation was observed to precede the compaction in a stochastic, random structure. The material showed lattice characteristics in the elastic response of the material, while the compaction was consistent with a model for compression of porous media. The experimental observations made on arrays of 4 × 4 × 6 lattice unit cells show excellent agreement with elastic wave velocity calculations for an infinite periodic lattice, as determined by Bloch wave analysis, and finite element simulations.

Brain microbiota disruption within inflammatory demyelinating lesions in multiple sclerosis.

Microbial communities reside in healthy tissues but are often disrupted during disease. Bacterial genomes and proteins are detected in brains from humans, nonhuman primates, rodents and other species in the absence of neurological disease. We investigated the composition and abundance of microbiota in frozen and fixed autopsied brain samples from patients with multiple sclerosis (MS) and age- and sex-matched nonMS patients as controls, using neuropathological, molecular and bioinformatics tools. 16s rRNA sequencing revealed Proteobacteria to be the dominant phylum with restricted diversity in cerebral white matter (WM) from MS compared to nonMS patients. Both clinical groups displayed 1,200-1,400 bacterial genomes/cm3 and low bacterial rRNA:rDNA ratios in WM. RNAseq analyses showed a predominance of Proteobacteria in progressive MS patients' WM, associated with increased inflammatory gene expression, relative to a broader range of bacterial phyla in relapsing-remitting MS patients' WM. Although bacterial peptidoglycan (PGN) and RNA polymerase beta subunit immunoreactivities were observed in all patients, PGN immunodetection was correlated with demyelination and neuroinflammation in MS brains. Principal component analysis revealed that demyelination, PGN and inflammatory gene expression accounted for 86% of the observed variance. Thus, inflammatory demyelination is linked to an organ-specific dysbiosis in MS that could contribute to underlying disease mechanisms.

Extracellular matrix assembly in diatoms (Bacillariophyceae). Iii. Organization Of fucoglucuronogalactans within the adhesive stalks of achnanthes longipes

Achnanthes longipes is a marine, biofouling diatom that adheres to surfaces via adhesive polymers extruded during motility or organized into structures called stalks that contain three distinct regions: the pad, shaft, and collar. Four monoclonal antibodies (AL.C1-AL.C4) and antibodies from two uncloned hybridomas (AL.E1 and AL.E2) were raised against the extracellular adhesives of A. longipes. Antibodies were screened against a hot-water-insoluble/hot-bicarbonate-soluble-fraction. The hot-water-insoluble/hot-bicarbonate-soluble fraction was fractionated to yield polymers in three size ranges: F1, >/= 20,000, 000 Mr; F2, congruent with100,000 Mr; and F3, <10,000 Mr relative to dextran standards. The congruent with100,000-Mr fraction consisted of highly sulfated (approximately 11%) fucoglucuronogalactans (FGGs) and low-sulfate (approximately 2%) FGGs, whereas F1 was composed of O-linked FGG (F2)-polypeptide (F3) complexes. AL.C1, AL.C2, AL.C4, AL.E1, and AL.E2 recognized carbohydrate complementary regions on FGGs, with antigenicity dependent on fucosyl-containing side chains. AL.C3 was unique in that it had a lower affinity for FGGs and did not label any portion of the shaft. Enzyme-linked immunosorbent assay and immunocytochemistry indicated that low-sulfate FGGs are expelled from pores surrounding the raphe terminus, creating the cylindrical outer layers of the shaft, and that highly sulfated FGGs are extruded from the raphe, forming the central core. Antibody-labeling patterns and other evidence indicated that the shaft central-core region is related to material exuded from the raphe during cell motility.

Pulse radiolysis study of the reactivity of Trolox C phenoxyl radical with superoxide anion.

The reaction between the phenoxyl radical of Trolox C, a water-soluble vitamin E analogue, and superoxide anion radical was examined by using the pulse radiolysis technique. The results indicate that the Trolox C phenoxyl radical may undergo a rapid one-electron transfer from superoxide radical [k = (4.5 +/- 0.5) x 10(8) M-1.S-1] to its reduced form. This finding indicates that superoxide radical might play a role in the repair of vitamin e phenoxyl radical.

Prediction of 24-h energy expenditure and its components from physical characteristics and body composition in normal-weight humans.

The applicability of body composition as estimated by the bioimpedance method to predict energy expenditure (EE) was studied. Ten healthy subjects underwent measurement of body composition and 24-h energy expenditure (24-h EE) twice in a respiration chamber on a fixed program. The 24-h EE and its components, sleeping EE (SEE), basal EE (BEE), and daytime EE, for an individual were very reproducible (coefficient of variation 2.3%, 1.4%, 5.0%, & 3.1%, respectively). The variability of 24-h EE among subjects was 11.4% but only 4.1% when adjusted for differences in lean body mass (LBM). LBM was the best determinant of 24-h EE, BEE, and SEE and accounted for 91-93% of the interindividual variance of EE. The prediction equations were 24EE (kcal/d) = 390 + 33.3 LBM (r2 = 0.93, P = 0.000001), SEE (kcal/h) = 9.8 + 1.1 LBM (r2 = 0.92, P = 0.000001), and BEE (kcal/h) = -3.1 + 1.35 LBM (r2 = 0.91, P = 0.000002). In conclusion, 24EE, BEE, and SEE can be predicted with a high degree of precision from LBM as estimated by bioimpedance in normal-weight subjects.

N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides as orally active antiallergy agents.

A series of N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides were evaluated for their ability to antagonize slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea and to inhibit thromboxane synthase in vitro. The results indicated that those pyrido[2,1-b]quinazoline-8-carboxamides bearing a branched-chain alkyl moiety in the 2-position and a four to six atom linear chain between a 3- or 4-substituted pyridine or a 1-substituted imidazole ring and the carboxamide nitrogen atom showed the best combination of potencies in the two assays. Several of these compounds were found to be orally active inhibitors of LTE4-induced bronchoconstriction in the guinea pig and LTE4-induced skin wheal formation in the rat. One of the most potent analogues, 2-(1-methyl-ethyl)-N-(1H-imidazol-1-ylbutyl)-11-oxo-11H-pyrido [2,1-b]quinazoline-8-carboxamide (36), was selected for extensive pharmacological investigation. It was found that this compound was not a specific inhibitor of LTE4-induced symptomatology, but exhibited more general activity by inhibiting bronchospasm in guinea pigs induced by LTC4, LTD4, PAF, and histamine and skin wheal formation in rats and guinea pigs induced by LTC4, LTD4, and PAF. In addition, 36 was orally active in the passive cutaneous anaphylaxis assay, suggesting that it also exhibits mediator release inhibitory activity. On the basis of the overall pharmacological profile of 36 and its closely related analogues, it was concluded that these compounds may be useful for the treatment of asthma.

Synthesis, cardiac electrophysiology, and beta-blocking activity of novel arylpiperazines with potential as class II/III antiarrhythmic agents.

A series of novel arylpiperazines have been prepared in an attempt to incorporate both class II (beta-receptor blocking) and class III antiarrhythmic properties in a single molecule. The key step in the preparation of the new compounds involves a regioselective heterocyclic ring formation. All but four compounds significantly prolonged action potential duration in canine cardiac Purkinje fibers (class III activity). All but one of the compounds demonstrated beta-receptor affinity in a competitive binding assay and three had beta 1-receptor selectivity. Compared to sotalol, a reference class II/III agent, arylpiperazine 7a (4-[(methylsulfonyl)amino]-N-[(4- phenylpiperazin-2-yl)methyl]benzamide) demonstrated beta 1-selectivity and was 1 order of magnitude more potent in the in vitro class III and the beta 1-receptor screens. Compound 7a was evaluated further and found to be effective in preventing programmed electrical stimulation-induced arrhythmias in conscious dogs (class III activity) and against epinephrine-induced arrhythmias in halothane anesthetized dogs (class II activity).

Synthesis and cardiac electrophysiological activity of aryl-substituted derivatives of the class III antiarrhythmic agent sematilide. Potential class I/III agents.

Twelve novel derivatives of the selective class III antiarrhythmic agent sematilide were prepared in an attempt to incorporate both class I and class III electrophysiological properties into a single molecule. Electrophysiological activity was determined by standard microelectrode techniques in canine cardiac Purkinje fibers. Initial assessment of class I efficacy was carried out in a ouabain-induced arrhythmia model in guinea pigs. All of the compounds prolonged action potential duration in Purkinje fibers (class III activity), and three were active against ouabain-induced arrhythmias (class I activity). Selected compounds were evaluated further in dogs for efficacy against arrhythmias occurring 24 h following coronary ligation (automatic arrhythmias) and induced by using programmed electrical stimulation techniques (reentrant arrhythmias). The most effective compounds from the series are 3g and -j, which were effective in both canine models. Molecular modeling and structure-activity relationships are discussed.