Characterisation of biomass resources in Nepal and assessment of potential for increased charcoal production.

Characterisation of 27 types of biomass was performed together with an assessment of regional resource availability. Charcoal was produced under two conditions from all samples and their yields were compared. Sugarcane bagasse, sal and pine produced the best charcoal with a low volatile matter and high calorific value. The amount of high-quality charcoal which can be made within Nepal from the biomass types tested is equivalent to 8,073,000 tonnes of firewood a year or 51% of the yearly demand. The areas which would benefit the most from charcoal making facilities are the Mid-hills of the Western, Central and Eastern Development Regions, as well as the Terai in the Central and Eastern Development Regions. The main potential benefit is to convert agricultural residues which are underutilised because, in their original form, produce large quantities of smoke, to cleaner burning charcoal. The conversion of agricultural residues to charcoal is also a viable alternative to anaerobic digestion in the Mid-hills.

Transport of Mechanically Ventilated Patients in the Prone Position.

OBJECTIVE: We present seven cases of patients with severe respiratory failure refractory to conventional ventilation who were safely transported in the prone position. METHODS: We describe all cases of patients transported by a regional critical care network in the prone position from January 2010-June 2015. All patients were mechanically ventilated for respiratory failure and transported by specialized nonphysician critical care teams. Utilizing direct medical oversight and real-time technical support from the clinical department, each patient underwent a thorough bedside evaluation, transport ventilator trial, and transfer to a transport stretcher either with the endotracheal tube secured by an anesthesia pillow or overhanging the stretcher. RESULTS: Seven patients with acute respiratory distress syndrome were transported in the prone position. Four were female (57%), with a median weight of 78 kg (range 58-131) and median age of 53 years (range 37-78). Initial vital signs demonstrated a median oxygen saturation of 94% (range 90-97%) supported with a FiO2 of 100% for all patients with a median positive end-expiratory pressure (PEEP) of 16 (range 14-20). Seven patients were transported, six by helicopter and one transported by ground ambulance. The median transport time was 36 minutes (IQR 19, 51). There were no deaths or major incidents (tube dislodgement or line displacement) during patient transport. CONCLUSION: The transport of mechanically ventilated patients with respiratory failure in the prone position is feasible and safe, with minimal complications identified in this case series.

Palmitic acid feeding increases ceramide supply in association with increased milk yield, circulating nonesterified fatty acids, and adipose tissue responsiveness to a glucose challenge.

Reduced insulin action is a key adaptation that facilitates glucose partitioning to the mammary gland for milk synthesis and enhances adipose tissue lipolysis during early lactation. The progressive recovery of insulin sensitivity as cows advance toward late lactation is accompanied by reductions in circulating nonesterified fatty acids (NEFA) and milk yield. Because palmitic acid can promote insulin resistance in monogastrics through sphingolipid ceramide-dependent mechanisms, palmitic acid (C16:0) feeding may enhance milk production by restoring homeorhetic responses. We hypothesized that feeding C16:0 to mid-lactation cows would enhance ceramide supply and ceramide would be positively associated with milk yield. Twenty multiparous mid-lactation Holstein cows were enrolled in a study consisting of a 5-d covariate, 49-d treatment, and 14-d posttreatment period. All cows were randomly assigned to a sorghum silage-based diet containing no supplemental fat (control; n=10; 138±45 d in milk) or C16:0 at 4% of ration dry matter (PALM; 98% C16:0; n=10; 136±44 d in milk). Blood and milk were collected at routine intervals. Liver and skeletal muscle tissue were biopsied at d 47 of treatment. Intravenous glucose tolerance tests (300mg/kg of body weight) were performed at d -1, 24, and 49 relative to start of treatment. The plasma and tissue concentrations of ceramide and glycosylated ceramide were determined using liquid chromatography coupled with tandem mass spectrometry. Data were analyzed as repeated measures using a mixed model with fixed effects of treatment and time, and milk yield served as a covariate. The PALM treatment increased milk yield, energy-corrected milk, and milk fat yield. The most abundant plasma and tissue sphingolipids detected were C24:0-ceramide, C24:0-monohexosylceramide (GlcCer), and C16:0-lactosylceramide. Plasma concentrations of total ceramide and GlcCer decreased as lactation advanced, and ceramide and GlcCer were elevated in cows fed PALM. Palmitic acid feeding increased hepatic ceramide levels, a response not observed in skeletal muscle tissue. Plasma ceramides (e.g., C24:0-ceramide) were positively correlated with plasma NEFA and milk yield, and positively correlated with NEFA levels following a glucose challenge. Our data demonstrate a remodeled plasma and hepatic sphingolipidome in mid-lactation dairy cows fed PALM. The potential involvement in ceramide in homeorhetic nutrient partitioning to support lactation requires further consideration.

Using self-organizing maps to infill missing data in hydro-meteorological time series from the Logone catchment, Lake Chad basin.

Hydro-meteorological data is an important asset that can enhance management of water resources. But existing data often contains gaps, leading to uncertainties and so compromising their use. Although many methods exist for infilling data gaps in hydro-meteorological time series, many of these methods require inputs from neighbouring stations, which are often not available, while other methods are computationally demanding. Computing techniques such as artificial intelligence can be used to address this challenge. Self-organizing maps (SOMs), which are a type of artificial neural network, were used for infilling gaps in a hydro-meteorological time series in a Sudano-Sahel catchment. The coefficients of determination obtained were all above 0.75 and 0.65 while the average topographic error was 0.008 and 0.02 for rainfall and river discharge time series, respectively. These results further indicate that SOMs are a robust and efficient method for infilling missing gaps in hydro-meteorological time series.

Novel pulsatile cerebrospinal fluid model to assess pressure manometry and fluid sampling through spinal needles of different gauge: support for the use of a 22 G spinal needle with a tapered 27 G pencil-point tip.

BACKGROUND: Parallel-walled spinal needles ≤ 22 G are routinely used for lumbar puncture, despite a reported ≥ 32% incidence of post-dural puncture headache. A tapered spinal needle (22 G shaft, 27 G tip) is in use in our institution. We hypothesized that despite the smaller dural puncture hole, this needle has similar cerebrospinal fluid (CSF) pressure equilibration times and CSF sampling times to a standard 22 G needle and assessed a range of spinal needles using an experimental pulsatile CSF reservoir. METHODS: The pulsatile CSF reservoir had an oscillating pressure varying between 25 and 15 cm H(2)O at a cycle frequency of 80 s(-1). We tested seven parallel-walled spinal needles (18-27 G) and the tapered 22/27 G needle. CSF pressure was measured every 2 s by manometry. The time to collect 1 ml CSF samples was measured. Saline 0.9% and mannitol 20% were tested separately. One-way ANOVA with Bonferroni post-hoc test was used to compare 22G, 27G and 22/27G needles. RESULTS: The mean [standard deviation (sd)] CSF pressure equilibration time (saline) was 40.7 (6.4), 108.7 (6.1), and 51.3 (4.6) s for the 22, 27, and 22/27 G needles (P< 0.0001 for comparisons between 27 G and other needles). The mean (sd) CSF sampling time (saline) was 40.3 (3.1), 225.3 (10.0), and 63.0 (5.2) s for the 22, 27, and 22/27 G needles (P< 0.0001 for comparisons between 27 G and other needles, and P= 0.019 between 22 and 22/27 G needles). Saline was different from mannitol for both measurements and all needles (P< 0.0001). CONCLUSIONS: A 22/27 G tapered spinal needle has similar flow properties to the 22 G needle, despite a 27 G tip.

Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway.

Human immunodeficiency virus-type 1 (HIV-1) infection is characterized by a chronic state of immune hyperactivation in patients. Infection of human peripheral blood lymphocytes with HIV-1 in vitro resulted in increased interleukin-2 (IL-2) secretion in response to T cell activation via the CD3 and CD28 receptors. Expression of the HIV-1 transactivator Tat recapitulated this phenotype and was associated with increased IL-2 secretion in response to costimulation with CD3 plus CD28. IL-2 superinduction by Tat occurred at the transcriptional level, was mediated by the CD28-responsive element in the IL-2 promoter, and was exclusively dependent on the 29 amino acids encoded by the second exon of Tat.

Histological features of symptomatic carotid plaques in patients with impaired glucose tolerance and diabetes (oxford plaque study).

BACKGROUND: Diabetes is associated with an increased risk of incident stroke and both early and late recurrent stroke after transient ischaemic attack. Some small studies have suggested that atherosclerotic plaques from diabetics have a higher prevalence of unstable features than plaques from non-diabetics but results have been inconsistent. METHOD: We made detailed histological assessments of 526 plaques from consecutive patients undergoing carotid endarterectomy for recently symptomatic stenosis and related these to the presence of diabetes and impaired glucose tolerance (IGT). RESULTS: 53 (10.1%) patients had diabetes, 26 (5%) had IGT and 447 (84.9%) had normal glucose tolerance (NGT). The overall prevalence of unstable plaque features was similar across these groups. However, whereas plaques removed >60 days after last symptoms in patients with NGT had less surface thrombus (OR = 0.61, 95% CI = 0.40-0.92, p = 0.02), fewer plaque macrophages (OR = 0.78, 95% CI = 0.51-1.19, p < 0.001) and less marked overall instability (OR = 0.57, 95% CI = 0.35-0.88, p = 0.009) than plaques removed more acutely, these features tended to be more persistent in patients with diabetes/IGT (OR = 1.08, 95% CI = 0.42-2.77, OR = 1.16, 95% CI = 0.46-2.96 and OR = 1.51, 95% CI = 0.60-3.77, respectively). CONCLUSION: Overall, the prevalence of unstable histology features in recently symptomatic carotid plaques is similar in patients with diabetes, IGT and NGT. However, surface thrombus and plaque macrophages appear to persist for longer after ischaemic symptoms in plaques from patients with diabetes/IGT compared to plaques from patients with NGT. This may contribute to the increased risk of recurrent stroke that is associated with diabetes/IGT.

Synthesis of Well-Defined Pyrrolidone-Based Homopolymers and Stimulus-Responsive Diblock Copolymers via RAFT Aqueous Solution Polymerization of 2-(N-Acryloyloxy)ethylpyrrolidone.

Poly(N-vinylpyrrolidone) (PNVP) is a well-known, highly polar, nonionic water-soluble polymer. However, N-vinylpyrrolidone (NVP) usually exhibits strongly non-ideal behavior when copolymerized with methacrylic or styrenic monomers. Moreover, NVP is not particularly well-controlled under living radical polymerization conditions. For these reasons, alternative pyrrolidone-based monomers have been investigated. For example, the reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(N-methacryloyloxy)ethylpyrrolidone (NMEP) has been recently investigated using various polymerization formulations. However, PNMEP homopolymers are significantly less hydrophilic than PNVP and exhibit inverse temperature solubility in aqueous solution. In the present work, we studied the RAFT aqueous solution polymerization of 2-(N-acryloyloxy)ethylpyrrolidone (NAEP) using either AIBN at 70 °C or a low-temperature redox initiator at 30 °C. PNAEP homopolymers are obtained in high yield (>99%) with good control (M w/M n < 1.20) for target degrees of polymerization (DP) of up to 400 using the latter initiator, which produced relatively fast rates of polymerization. However, targeting DPs above 400 led to lower NAEP conversions and broader molecular weight distributions. 2-Hydroxyethyl acrylate (HEA) and oligo(ethylene glycol) methyl ether acrylate (OEGA) were chain-extended using a PNAEP x macro-CTA via RAFT aqueous solution polymerization, yielding double-hydrophilic acrylic diblock copolymers with high conversions (>99%) and good control (M w/M n < 1.31). In addition, a PNAEP95 macro-CTA was chain-extended via RAFT aqueous solution polymerization of N-isopropylacrylamide (NIPAM) at 22 °C. Dynamic light scattering (DLS) analysis indicated that heating above the lower critical solution temperature of PNIPAM led to so-called "anomalous micellization" at 35 °C and the formation of near-monodisperse spherical micelles at 40 °C. Finally, 2-(diethylamino)ethyl methacrylate (DEA) was polymerized using an N-morpholine-functionalized trithiocarbonate-based RAFT chain transfer agent and subsequently chain-extended using NAEP to form a novel pH-responsive diblock copolymer. Above the pK a of PDEA (∼7.3), DLS and 1H NMR studies indicated the formation of well-defined PDEA-core spherical micelles.

Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford plaque study.

BACKGROUND: Atherosclerotic plaque at the carotid bifurcation is often associated with transient ischemic attack (TIA) and ischemic stroke, but the mechanisms are not completely understood. Previous histological studies have been too small or insufficiently detailed to reliably determine the temporal course of features of plaque instability or to stratify analyses by the nature of presenting symptoms. METHODS AND RESULTS: We performed the largest-ever histological study of symptomatic carotid plaques from consecutive patients (n=526) undergoing endarterectomy and related detailed reproducible histological assessments to the nature and timing of presenting symptoms. There was a high prevalence of many features of coronary-type plaque instability. Dense plaque inflammation (especially infiltration with macrophages) was the feature most strongly associated with both cap rupture (odds ratio 3.39, 95% confidence interval 2.31 to 4.98, P<0.001) and time since stroke (P=0.001). Strong negative associations with time since stroke were also seen for cap rupture (P=0.02), overall plaque inflammation (P=0.003), and "unstable plaque" (P=0.001). Although plaques removed < or =60 days after the most recent event were more unstable after a stroke than after a TIA, the instability persisted after a TIA, and plaques removed >180 days after most recent event were less unstable after a stroke than after a TIA (plaque inflammation: < or =60 days, odds ratio 2.33 [95% confidence interval 0.76 to 7.19]; >180 days, 0.36 [0.16 to 0.84]; P=0.008; unstable plaque: odds ratio 3.27 [95% confidence interval 0.93 to 11.50] versus 0.74 [0.33 to 1.69], P=0.05). CONCLUSIONS: Pathology of recently symptomatic carotid plaques is similar to that of culprit coronary plaques, with strong correlations between macrophage infiltration and plaque instability. The tendency for plaque inflammation and overall instability to persist with time after a TIA but to decrease with time after a stroke suggests that the nature of the underlying pathology may differ.

A Robust Cross-Linking Strategy for Block Copolymer Worms Prepared via Polymerization-Induced Self-Assembly.

A poly(glycerol monomethacrylate) (PGMA) chain transfer agent is chain-extended by reversible addition-fragmentation chain transfer (RAFT) statistical copolymerization of 2-hydroxypropyl methacrylate (HPMA) with glycidyl methacrylate (GlyMA) in concentrated aqueous solution via polymerization-induced self-assembly (PISA). A series of five free-standing worm gels is prepared by fixing the overall degree of polymerization of the core-forming block at 144 while varying its GlyMA content from 0 to 20 mol %. 1H NMR kinetics indicated that GlyMA is consumed much faster than HPMA, producing a GlyMA-rich sequence close to the PGMA stabilizer block. Temperature-dependent oscillatory rheological studies indicate that increasing the GlyMA content leads to progressively less thermoresponsive worm gels, with no degelation on cooling being observed for worms containing 20 mol % GlyMA. The epoxy groups in the GlyMA residues can be ring-opened using 3-aminopropyltriethoxysilane (APTES) in order to prepare core cross-linked worms via hydrolysis-condensation with the siloxane groups and/or hydroxyl groups on the HPMA residues. Perhaps surprisingly, 1H NMR analysis indicates that the epoxy-amine reaction and the intermolecular cross-linking occur on similar time scales. Cross-linking leads to stiffer worm gels that do not undergo degelation upon cooling. Dynamic light scattering studies and TEM analyses conducted on linear worms exposed to either methanol (a good solvent for both blocks) or anionic surfactant result in immediate worm dissociation. In contrast, cross-linked worms remain intact under such conditions, provided that the worm cores comprise at least 10 mol % GlyMA.

Histological correlates of carotid plaque surface morphology on lumen contrast imaging.

BACKGROUND: Carotid angiographic plaque surface morphology is a powerful risk factor for stroke and systemic vascular risk. However, the underlying pathology is unclear, and a better understanding is required both to evaluate other forms of carotid imaging and to develop new treatments. Previous studies comparing angiographic plaque surface morphology with pathology have been small and unblinded, and the vast majority assessed only the crude macroscopic appearance of the plaque. We performed the first large study comparing angiographic surface morphology with detailed histology. METHODS AND RESULTS: Carotid plaque surface morphology was classified as ulcerated, irregular, or smooth on 128 conventional selective carotid artery angiograms from consecutive patients undergoing endarterectomy for severe symptomatic stenosis. Blinded angiographic assessments were compared with 10 histological features recorded on detailed microscopy of the plaque using reproducible semiquantitative scales. Angiographic ulceration was associated with plaque rupture (P=0.001), intraplaque hemorrhage (P=0.001), large lipid core (P=0.005), less fibrous tissue (P=0.003), and increased instability overall (P=0.001). For example, angiographically ulcerated plaques were much more likely than smooth plaques to be ruptured (OR=15.4, 95% CI=2.7 to 87.3, P<0.001), show a large lipid core (OR=26.7, 95% CI=2.6 to 270, P<0.001) or a large hemorrhage (OR=17.0, 95% CI=2.0 to 147, P=0.02). The equivalent odds ratios for angiographically irregular versus smooth plaque were 6.3 (1.3 to 31, P=0.02), 6.7 (1.5 to 30, P=0.008), and 9.2 (1.1 to 77, P=0.02), respectively. CONCLUSIONS: In contrast to previous studies based on macroscopic assessment, we found very strong associations between detailed histology and carotid angiographic plaque surface morphology. Plaque surface morphology on carotid angiography is a highly sensitive marker of plaque instability. Studies of the predictive value of MR- and CT-based lumen contrast plaque surface imaging are required.

A critical appraisal of the performance, reporting, and interpretation of studies comparing carotid plaque imaging with histology.

BACKGROUND AND PURPOSE: Carotid plaque instability is an important determinant of stroke risk. There are now a number of different imaging techniques that provide information on carotid plaque morphology. However, it is unclear how they compare with one another or whether they can reliably assess plaque instability. Studies comparing imaging with pathology have shown highly variable results, even for similar imaging techniques. This may be because of variable pathology techniques rather than differences in imaging. METHODS: We performed a systematic review of studies that compared carotid imaging with histology of the excised plaque published between January 1995 and September 2004. We assessed the quality and comparability of these studies. In particular, we determined which histology methods were used and whether observer reproducibility of the histology assessment was reported. RESULTS: Among 73 eligible studies, histological methods were poorly reported and highly variable; 23% reported reproducibility data for imaging and only 12% reported reproducibility data for histology. Of 29 studies that reported quantitative results of blinded comparisons, there were methodological deficiencies and the results were highly variable. No study considered the extent to which the lack of reproducibility influenced the imaging-pathological correlations reported. CONCLUSIONS: Pathological correlation in studies of carotid plaque imaging cannot be reliably interpreted or compared because of incomparable and poorly reported histology methods. We make recommendations for the performance, reporting, and interpretation of imaging-pathological correlation studies and highlight the need for consensus guidelines.

Very early risk of stroke after a first transient ischemic attack.

BACKGROUND AND PURPOSE: The commonly quoted early risks of stroke after a first transient ischemic attack (TIA)-1% to 2% at 7 days and 2% to 4% at 1 month-are likely to be underestimates because of the delay before inclusion into previous studies and the exclusion of patients who had a stroke during this time. Therefore, it is uncertain how urgently TIA patients should be assessed. We used data from the Oxford Community Stroke Project (OCSP) to estimate the very early stroke risk after a TIA and investigated the potential effects of the delays before specialist assessment. METHODS: All OCSP patients who had a first-ever definite TIA during the study period (n=209) were included. Three analyses were used to estimate the early stroke risk after a first TIA starting from 3 different dates: assessment by a neurologist, referral to the TIA service, and onset of first TIA. RESULTS: The stroke risk from assessment by a neurologist was 1.9% [95% confidence interval (CI), 0.1 to 3.8] at 7 days and 4.4% (95% CI, 1.6 to 7.2) at 30 days. The 7- and 30-day stroke risks from referral were 2.4% (95% CI, 0.3 to 4.5) and 4.9% (95% CI, 1.9 to 7.8), respectively, and from onset of first-ever TIA were 8.6% (95% CI, 4.8 to 12.4) and 12.0% (95% CI, 7.6 to 16.4), respectively. CONCLUSIONS: The early risk of stroke from date of first-ever TIA is likely to be higher than commonly quoted. Public education about the symptoms of TIA is needed so that medical attention is sought more urgently and stroke prevention strategies are implemented sooner.

Multimodality therapy of favorable prognosis non-Hodgkin's lymphoma.

Twenty-seven previously untreated patients with favorable prognosis non-Hodgkin's lymphoma were treated with a combination of total body irradiation followed by cyclophosphamide - vincristine - prednisone (CVP). The dose of total body irradiation was planned to be 150 rad followed by 6 cycles of chemotherapy. The complete response rate was 59%; the complete plus partial response rate, 93%. The 50% disease-free survival was 8 months. The actuarial projected 5 year survival was 60% and the disease-free survival at 5 years was 27%. The program was well tolerated by the majority of patients. It is possible for some patients with favorable non-Hodgkin's lymphomas to achieve prolonged periods of disease-free survival when treated with combinations of irradiation plus chemotherapy.

Molecular characterization of a thrombospondin-related anonymous protein homologue in Neospora caninum.

Thrombospondin-related anonymous protein (TRAP) family members participate in attachment and invasion of host cells by apicomplexan parasites. A TRAP homologue in Neospora caninum strain Nc-1 (NcMIC2) was cloned, sequenced and found to be 61% identical (75% similar) at the amino acid level to Toxoplasma gondii MIC2 (TgMIC2). Similar to TgMIC2, the predicted amino acid sequence of NcMIC2 contains one integrin-like domain (I or A domain), five thrombospondin (TSP) repeats, a putative transmembrane spanning region and intracellular C-terminus, and was localized to micronemes by cryo-immunoelectron microscopy. The secretion of NcMIC2 was temperature dependent and was induced at or above 25 degrees C. The secreted form of NcMIC2 released into the medium was found to be proteolytically processed such that it lacked the C-terminal domain. Secretion of NcMIC2 was regulated by calcium, since several agents which raise intracellular calcium levels were shown to promote NcMIC2 secretion and chelation of [Ca(2+)](i) abrogated release. As a member of the growing family of apicomplexan TRAP proteins, NcMIC2 may play an important role in attachment and invasion by N. caninum into host cells.

N,N-dialkylated leucine enkephalins as potential delta opioid receptor antagonists.

A series of N,N-dialkylated leucine enkephalins were prepared in order to study the effect of substitution on antagonist activity at the delta opioid receptor. The target peptides 1-7 were evaluated in the mouse vas deferens (MVD) and guinea pig ileum (GPI) at 1 microM. All of the compounds except [N,N-di-2-phenethyl,Leu5]enkephalin (7) showed antagonist activity in the MVD against the delta receptor agonist [D-Ala2,D-Leu5]enkephalin. The most potent congener, [N,N-dibenzyl,Leu5]enkephalin (3), was 2.5-fold more potent than [N,N-diallyl,Leu5]enkephalin (1). None of the compounds at 1 microM showed any antagonist activity against agonists for other receptor types. The N,N-di-2-phenethyl (7) and N,N-dioctyl (6) analogues showed significant agonist activity at 1 microM in the MVD.

Synthesis and evaluation of melphalan-containing N,N-dialkylenkephalin analogues as irreversible antagonists of the delta opioid receptor.

N,N-Dialkylated leucine enkephalin analogues containing melphalan (Mel) in place of Phe4 were synthesized as potentially irreversible antagonists of the delta opioid receptor. These compounds, along with the corresponding Phe4 peptides, were tested for both agonist and antagonist activity in the GPI and MVD smooth muscle preparations. All but two of the eight compounds showed antagonist activity at 1 microM against [D-Ala2,D-Leu5]enkephalin (DADLE) in the MVD when tested under reversible conditions; in all cases the Mel4 peptide had lower activity against DADLE than did the corresponding Phe4 peptide. At higher concentrations (10 microM) the two active Mel4 analogues, (benzyl)2Tyr-Gly-Gly-Mel-Leu (2a) and (allyl)2Tyr-Aib-Aib-Mel-Leu (3a), both showed weak irreversible antagonism at the delta receptor. Compound 2a was a selective irreversible delta opioid antagonist while 3a was an irreversible antagonist at both the mu and delta opioid receptors.

Synthesis and evaluation of 19-aza- and 19-aminoandrostenedione analogues as potential aromatase inhibitors.

Derivatives of 19- azaandrostenedione (10 beta-amino-4- estrene -3,17-dione, 2) and 19-amino-4-androstene-3,17-dione (3) were synthesized as potential inhibitors of aromtase (estrogen synthetase). Compound 2 and its derivatives were synthesized from 3,17-dioxo-4-androsten-19-oic acid (5) via a Curtius rearrangement. Derivatives of 3 were synthesized from the intermediate 3,17-bis(ethylenedioxy)-5-androsten-19-al oxime (14), which was reduced to the corresponding amine (16) with Raney nickel. However, attempts to synthesize the parent compound, 3, from 16 by several different methods were unsuccessful. The compounds obtained were tested for inhibitory activity in the tritiated water assay for aromatase, with human placental microsomes as the enzyme source and [1-3H]-androst-4-ene-3,17-dione (83% 3H 1 beta) as the substrate. All of the compounds caused less than 20% inhibition of enzyme activity when tested at one and five times the substrate concentration (0.25 microM, 1.25 microM) and were poorer inhibitors than two known inhibitors, 7 alpha-[(p-aminophenyl)thio] androstenedione (7- APTA ) and 4-hydroxy-4-androstene-3,17-dione (4-OHA).

7 alpha-substituted derivatives of androstenedione as inhibitors of estrogen biosynthesis.

In an effort to obtain more information on the structure-activity relationship among the 7 alpha-(phenylthio)androstenedione inhibitors of the enzyme aromatase, a series of compounds containing both electron-donating and electron-withdrawing ring substituents was synthesized and tested for aromatase inhibitory activity. No linear correlation between substituent electronic effects and inhibitory activity was observed. The halogen-containing compounds, particularly 8, appeared to be quite potent inhibitors. The 125I analogue of 8 was synthesized in order to evaluate the possibility of side-chain elimination under the assay conditions. Approximately 90% of [125I]-8 remained intact for up to 1 h under assay conditions.

Growth and development of full-term nonasphyxiated small-for-gestational-age newborns: follow-up through adolescence.

Previous studies of growth and development in small-for-gestational-age (SGA) infants have been plagued by several methodologic defects, including a lack of control for socioeconomic status and parental height and an inability to distinguish among the effects of prematurity, neonatal asphyxia, and intrauterine growth retardation. An attempt has been made to overcome these defects in a study of 33 full-term, nonasphyxiated small-for-gestational-age neonates born between 1960 and 1966 and 33 matched control infants of normal birth weight. The infants were followed up and compared for physical growth and sexual, neurologic, and cognitive development at ages 13 to 19 years. Significant deficits in height, weight, and head circumference were found among the SGA cohort, even after statistical adjustment for differences in socioeconomic status and parental height. Sexual development and bone age were not delayed in the SGA group, however, indicating that the deficits in growth are permanent. On neurologic and cognitive testing, the SGA group had trends toward lower scores but scores were well within the normal range. It is concluded that full-term nonasphyxiated SGA infants have an impaired potential for physical growth, but a good prognosis for neurologic and cognitive development. Previous findings of more severe cognitive deficits are attributed to a failure to distinguish the effects of isolated intrauterine growth retardation from effects due to asphyxia.