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Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, these drugs can induce chronic neuropathic pain, leading to increased morbidity in HIV patients. This study examines the role of brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn (SDH) in development of mechanical allodynia in male C57BL/6J mice treated with the NRTI stavudine (d4T). After d4T administration, mice developed increased neuronal activity and BDNF expression in the SDH and hind paw mechanical allodynia that was exacerbated by intrathecal BDNF administration. Intrathecal BDNF alone also increased neuronal activity and caused mechanical allodynia. Because excess BDNF amplified d4T-induced mechanical allodynia and neuronal activity, the impact of decreasing BDNF in the SDH was investigated. After d4T, BDNF heterozygous mice were less allodynic than wild-type littermates, which was negated by intrathecal BDNF administration. Finally, pretreatment with intrathecal trkB-Fc chimera prior to d4T or administration of the tyrosine kinase inhibitor K252a 3 days after d4T blocked BDNF-mediated signaling, significantly attenuated the development of mechanical allodynia (trkB-Fc), and decreased neuronal activity (trkB-Fc and K252a). Taken together, these findings provide evidence that BDNF in the SDH contributes to the development of NRTI-induced painful peripheral neuropathy and may represent a new therapeutic opportunity.

Objective: We tested sex, race, and age differences in the patterning of visceral adipose tissue (VAT) and subcutaneous adipose tissue. Research Methods and Procedures: Contiguous 1-cm-thick magnetic resonance (MR) images of the abdomen were collected from 820 African-American and white adults. Repeated-measures ANOVA was used to examine the effects of image location, sex, race, and age (≥50 vs.

SUMMARY This paper describes the ARGUS prototype, a high-density, low-power supercomputer built from an IXIA network analyzer chassis and load modules. The prototype is configured as a diskless distributed system that is scalable to 128 processors in a single 9U chassis. The entire system has a footprint of 0.25 m 2 (2. 5f t 2 ), av olume of 0.09 m 3 (3. 3f t 3 ) and maximum power consumption of less than 2200 W. We compare and contrast the characteristics of ARGUS against various machines including our on-site 32-node Beowulf and LANL’s Green Destiny. Our results show that the computing density (Gflops ft −3 ) of ARGUS is about 30 times higher than that of the Beowulf and about three times higher than that of Green Destiny with a comparable performance. Copyright c � 2006 John Wiley & Sons, Ltd. Received 21 April 2005; Revised 8 September 2005; Accepted 24 September 2005

Aims To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening. Methods This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis. Results Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (Cmax) and concentration at the end of the dosing interval (C24 h) after am and pm dosing was, respectively, 143 (116–214) mg l−1 h, 12.8 (10.3–17.2) mg l−1, 1.34 (0.58–3.25) mg l−1, and 171 (120–232) mg l−1 h, 12.9 (8.22–16.3) mg l−1, 1.15 (0.59–1.98) mg l−1. The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), Cmax, and C24 h was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir Cmax after am and pm dosing was 1.05 and 0.90 mg l−1, respectively. The GMR (95% CI) of the RTV AUC(0,24 h), Cmax, and C24 h was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated. Conclusions No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.

A number of recent reports suggest that the average age at menarche of US girls has declined over the past 20 years. Because the putative declines in the age at menarche are concurrent with increases in childhood body mass index (BMI), it has been suggested that these two trends may be causally linked. We examined differences in mean age of menarche in Fels Longitudinal Study girls who were born in six 10-year birth cohorts (1930s, 1940s, 1950s, 1960s, 1970s, and 1980s) and simultaneous cohort changes in mean BMI measured cross-sectionally at selected ages from 3-35 years (n = 371). Girls born in the 1980s had a mean age at menarche of 12.34 years, which was approximately 3-6 months earlier than that of girls born previously (P < 0.001). While the mean BMI values at ages 25 and 35 generally increased from the 1930s to the 1970s, the mean BMI during childhood and adolescence remained constant across the six birth cohorts. In summary, we found no evidence that the recent decline in the age at menarche in the Fels Longitudinal Study girls was reflected in concurrent increases in BMI at any point in childhood or adolescence. Conversely, girls born in the 1960s and 1970s have subsequently become heavier in young and mid-adulthood than were girls from earlier birth cohorts, without any concurrent change in the mean age at menarche over that time period. These two findings suggest that population-level shifts in BMI and the timing of menarche are largely independent, although sometimes coincident, processes.

‘Life’ is manifest in autonomous being in a contingent world and ‘natural life’ is life that has developed autonomously in that its becoming has not depended on prior agency. Autonomous being requires the capacity of autopoiesis and the maintenance of autonomous being in a contingent world requires the capacity of intentional agency. Also, autonomous and diverse becoming requires the capacities of accidental creation and reproductive evolution in an environment of contingent events. These capacities may be explained in theories of functional organization, each of which may be variously realized in the physical domain. Copyright © 2001 John Wiley & Sons, Ltd.

— This paper reports the current status of my smoothed particle hydrodynamic (SPH) simulations of the formation of the Moon. Since the Moon has recently been found to have been formed approximately 50 Ma after the solar nebula itself was formed, I have placed the lunar formation problem in the entire context of the formation and early evolution of the solar nebula. This set of processes remains controversial, and I have outlined what I believe to be the essential physical processes involved. These start with the formation of short-lived (now extinct) radioactive nuclides in a massive supernova. Then follows the probable role of the supernova ejecta in triggering the collapse of a core in a molecular cloud to form the solar nebula, and the injection of the radioactivities into the collapsing cloud core. Most of the solar nebula dissipates to form the Sun, and what remains becomes relatively quiescent. Gas drag acting on interstellar grains and the dustballs formed from them, due both to vertical descent to midplane and inward spiralling in midplane, quickly causes growth of the solid materials to form planetesimals. When these bodies reach the kilometer size range and beyond, gravitational forces dominate the accumulation process. The accumulation of the Earth requires of the order of 108 years. About half-way through that process the giant impact occurs with the next largest accumulating body near the protoearth. I have been simulating the giant impact using SPH with 100 000 particles. The simulations of three of these runs are depicted in detail with a series of color images. It is shown that conventional accumulation simulations that assume Keplerian orbits and that merge bodies upon collision are misleading because they cannot take account of tidal stripping nor of loss and gain of particles during the accumulation. In addition, the large rotational flattening of the protoearth renders the orbital motions nonkeplerian. The simulations that are shown in detail have been followed for just over a week of real time, and in that time the largest accumulating clump has reached about half or more of the mass of the Moon and additional clumps have accumulated into bodies in the range of 1 to 20% of a lunar mass. It is important to note that although these runs have given very promising results, the parameter space that could plausibly be associated with the giant impact is not yet adequately explored.

In conversations with six community college presidents, issue editor Rosemary Gillet-Karam asks about the definitions, roles, essential skills, and accomplishments of midlevel managers at their respective institutions.

— The 26Al/27Al ratio in a large number of calcium-aluminum inclusions (CAIs) is a rather uniform 5 × 10−5, whereas in chondrules the ratio is either undetectable or has a much lower value; the simplest interpretation of this is that there was an interval of a few million years between the times that these two meteoritic constituents formed stable solids. The present investigation was undertaken as an exploration of the physics of the processes in the solar nebula during and after the accumulation of the Sun. Understanding the time scales of events in this nebular model, to see if this would cast light on this apparent CAI to chondrule time interval, was the major motivation for the exploration. There were four stages in the history of the solar nebula; in stage 1, a fragment of an interstellar molecular cloud collapsed to form the Sun and solar nebula; in stage 2, the nebula was in approximate steady state balance between infall from the cloud and accretion onto the Sun and was in its FU Orionis accumulation stage; in stage 3, the Sun had been mainly accumulated and there was a slow residual mass flow into the Sun while it was in its classical T Tauri stage; and in stage 4, the nebula had finished accreting material onto the Sun (now a weak-lined T Tauri star) and was in a static condition with no significant dissipation or motions, other than removal at the inner edge due to the T Tauri solar wind and photoevaporation beyond 9 astronomical units (AU). It is found that the energy source keeping the nebula warm during stages 3 and 4 is recombination of ionized H in the ionized bipolar jets and the T Tauri coronal expansion solar wind. The parameters of the heating model were adjusted to locate the ice sublimation line at 5.2 AU. In this work, a nebular model is used with a surface density of 4.25 × 103 gm/cm2 at 1 AU and a variation with radial distance as the inverse first power. Under normal conditions in the nebula, there is a negative pressure gradient that provides partial radial support for the gas, which thus circles the Sun more slowly than large solid objects do. Large objects undergo a slow inward spiral due to the gas drag; very small objects move essentially with the gas but have a slow inward drift; and intermediate objects (e.g., 1 m) have a fairly large inward drift velocity that traverses the full radial extent of the nebula in considerably less than the CAI to chondrule time interval. Such objects are thus lost unless they can grow rapidly to larger sizes. Near the inner edge (bow) of the nebula during stage 4, the pressure gradient becomes positive, creating a narrow zone of zero gas drag toward which solids drift from both directions, facilitating planetesimal formation in the inner solar nebula. Recent theoretical and experimental results on sticking probabilities of solids show that icy surfaces have the best sticking properties, but icy interstellar grains can only stick together when subjected to impact velocities of less than 2000 cm/sec. However, if the solid objects are very underdense, then a collision leads to interpenetration and many points at which the small constituent grains can adhere to one another, and thus coagulation becomes possible for such underdense objects. Simulations were made of such coagulation in the outer solar nebula, and it was found that the central plane of the nebula quickly becomes filled with meter-sized and larger bodies that rapidly accumulated near the top of the nebula and rapidly descended; in a few thousand years this quickly leads to gravitational instabilities that can form planetesimals. These processes led to the rapid formation of Jupiter in the nebula (and the slightly less rapid formation of the other giant planets). The early formation of Jupiter opens an annular gap in the nebula, and thus a second region is created in the nebula with zero gas drag. It is concluded that CAIs were formed at the end of stage 2 of the nebula history and moved out into the nebula for long-term storage, and that most chondrules were formed by magnetic reconnection flares in the bow region of the nebula during stage 4, several million years later. Carbonaceous meteorites should be formed on the far side of the Jovian gap, with the chondrules being heated by flares on the early Jupiter irradiating materials in the nearby zone of zero gas drag, and they should have essentially the same 26Al ages as the CAIs (this will be very hard to confirm owing to scarcity of Al mineral phases in these chondrules).

The purpose of this study was to compare estimates of body composition in two ethnic groups, 31 black and 38 white girls 10 through 16 years of age, to establish accurate and precise laboratory standards for field measures of body composition in the NHLBI Growth and Health Study HC 55025. The dual energy X-ray absorptiometry (DXA) measures of fat free mass (FFM) and % body fat (%BF) were made using Hologic QDR-1000/W. Corresponding values of FFM and %BF from underwater weighing (UWW) were determined using the two-component model of Siri, and these were corrected using the model of Lohman for white girls only. In the comparison of the different models and methods, the two-component model overestimated FFM compared to estimates from DXA for black girls, as did the corrected Lohman model for white girls. The two-component model significantly overestimated %BF in both white and black girls compared to corresponding estimates from DXA. The ratio of bone mineral content (BMC)/FFM affected the degree of %BF differences in black girls but not in white girls. Also, as the density of FFM increased or approached adult status in black girls (BMC/FFM increased), differences between the two-component model and estimates from DXA decreased. In both groups of girls, the relationship of %BF from UWW and DXA are a function of the level of body fatness. DXA values of %BF are greater than those from UWW under about 24% body fat, but the converse occurs above 25% body fat. The inability of UWW using the two-component model to account for the body composition in these girls can be corrected in part by measuring the variables for a multicomponent model or more easily by using DXA estimates of body composition. © 1994 Wiley-Liss, Inc.

A known precursor (1) of the naphthopyran antibiotics has been synthesised from the napthoquinones (11) and (12) by reaction with the diene (5) and subsequent elaboration.

Carminomycinone (1) has efficiently been synthesised in a five-stage sequence based on cycloaddition of a 1,3-dioxybutadiene to the 1,4-anthraquinone (3); (1) was then converted into daunomycinone (2), an established source of daunomycin, adriamycin and related antiturmour anthracyclines.

Acylation of the aryl nitromethane (35) with (9) gave the enone (45), which underwent cyclization to the tricyclic system (50). Thermally induced aromatization to the naphthopyran (51) and oxidation gave ventiloquinone E (3). On selective demethylation this gave ventiloquinone G methyl ether (54). Analogous chemistry based on the aryl nitromethane (57) gave tricyclic nitro compound (60). On thermally induced aromatization this gave karwinaphthol B (5), while application of the Nef reaction and concomitant oxidation gave 7-methoxyeleutherin (2).

Synthesis of ventilagone (4) from the naphthol (5) was complicated by oxidation involving the central ring and by extensive epimerization to the trans series in the course of Lewis-acid-mediated demethylation . These complications were avoided by prior protection as the acetate (23). Oxidative demethylation and subsequent hydrolysis converted the latter into the dihydroxy quinone (6), which was also accessible from the nitro compound (26). Spectroscopic procedures for determining relative stereochemistry of such systems are discussed. Compound (6) underwent radical C-methylation to give ventilagone (4).

The tetracycle SS-228R ( 2 ) has been synthesised by a short regioselective based on cycloaddition and novel deoxygenation of an intermediate naphthacenequinone.

C -Alkylation of 1,4,5-trihydroxyanthraquinone with nitroalkanes in alkali gives regioselective 3-substitution contrary to literature; this is applied to a two-step synthesis of the anthracyclinone 9 .

The non-steroidal androgen-receptor antagonists WS9761 A (1,6,10-trihydroxy-2,8,10-trimethylanthrone) and WS9761 B (1,6,10-trihydroxy-2-hydroxymethyl-8,10-dimethylanthrone) were synthesized for the first time in racemic form by using Diels-Alder methodology followed by regioselective Grignard addition.

The two isomeric structures (2) and (3) proposed for the photodynamic pigment stentorin have both been synthesized for the first time, thereby allowing unambiguous identification of the natural material as (2). Synthesis of these highly condensed aromatic systems involved controlled oxidative couplings of the new anthrones (7) and (8), each synthesized by regiocontrolled cycloaddition.

Four isomeric anthraquinones (2)–(5) have been synthesized for the first time, by cycloaddition involving the new dienes (8) and (9). Their spectroscopic properties have been compared together and with data for two natural anthraquinones reported from Chamaecrista greggii. The assigned structure (2) was thereby supported for one of the natural isomers. The other isomer, previously formulated as (3), did not correspond to any of the synthesized compounds [(2)–(5)].

The 2,3-dioxy-1,4-anthraquinones (6) and (7) have been synthesized from the 9,10-anthraquinone (19), through the anthrone (18). Quinones (6) and (7) respectively possess substituents appropriate for three of the four rings of tetracenomycins C (2) and X (3) but they did not show dienophilic properties towards the reactive diene (5). Interaction with the diene was complicated by transsilylation, as was also observed for the model quinone (25).

Reaction of 2-acetoxy-3-chloro naphthoquinones towards the 1,3-dioxy diene (2) and the 1,1,3-trioxy diene (9) was examined. The competing influence of the acetoxy and chloro substituents was assessed from the regiochemistry of the resulting Diels–Alder chemistry, as was competition between that process and Michael addition/elimination. Reaction of the same dienes towards the less reactive 2,3-diacetoxy naphthoquinone (25) was also investigated.

Many drug candidates contain a basic functional group that results in lysosomotropism--the accumulation of drug in the acidic lysosomes of a cell. When evaluating inhibitors of lysosomal enzymes, such as the cathepsins, this physical property can have a dramatic impact on the functional selectivity of the test compounds. A basic P3 substituent in cathepsin K inhibitors provides a means of achieving potent and selective enzyme inhibition. To evaluate the whole-cell selectivity of the basic cathepsin K inhibitor L-006235, we identified the irreversible pan-selective cathepsin probe BIL-DMK and used it to design whole-cell enzyme-occupancy assays. These cell-based assays showed a dramatic reduction in selectivity against cathepsins B, L, and S relative to the selectivities observed in enzyme assays. Two-photon confocal fluorescence microscopy showed punctated subcellular localization of L-006235, which colocalized with BODIPY-labelled Lysotracker, consistent with compound lysosomotropism. To address this potential problem, a series of potent cathepsin K inhibitors was developed by replacing the P2--P3 amide bond with a metabolically stable trifluoroethylamine moiety. X-ray crystallography has identified the binding of this functional group to active-site residues in cathepsin K. This modification resulted in increased potency and selectivity that allowed the removal of the basic P3 substituent. The resulting nonbasic inhibitor L-873724 is a 0.2 nM inhibitor of cathepsin K with cathepsin B, L, and S potencies that were not shifted between purified enzyme and whole-cell assays; thus indicating that this compound is not lysosomotropic. L-873724 exhibits excellent pharmacokinetics and is orally active in a monkey model of osteoporosis at 3 mg kg(-1) q.d.

2,3-Dichloro quinonoid dienophiles react with 1,3-dioxy butadienes to give cycloadducts, which aromatise with uptake of external nucleophile to give 1,2-disubstitution in the newly formed aromatic ring. With oxy nucleophiles this has led to synthesis of natural alizarin derivatives.

The aim of the study was to evaluate the health of children with cerebral palsy (CP) using a global assessment of quality of life, condition-specific measures, and assessments of health care use. A multicenter population-based cross-sectional survey of 235 children, aged 2 to 18 years, with moderate to severe impairment, was carried out using Gross Motor Function Classification System (GMFCS) levels III (n = 56), IV (n = 55), and V (n = 122). This study group scored significantly below the mean on the Child Health Questionnaire (CHQ) for Pain, General Health, Physical Functioning, and Impact on Parents. These children used more medications than children without CP from a national sample. Fifty-nine children used feeding tubes. Children in GMFCS level V who used a feeding tube had the lowest estimate of mental age, required the most health care resources, used the most medications, had the most respiratory problems, and had the lowest Global Health scores. Children with the most severe motor disability who have feeding tubes are an especially frail group who require numerous health-related resources and treatments. Also, there is a relationship among measures of health status such as the CHQ, functional abilities, use of resources, and mental age, but each appears to measure different aspects of health and well-being and should be used in combination to reflect children's overall health status.

Twelve chemicals from diverse structural classes were tested under code for their capacity to enhance the transformation of Syrian hamster embryo cells by simian adenovirus SA7 in two independent laboratories. Pretreatment of hamster cells with eight of those chemicals (reserpine, dichlorvos, methapyrilene hydrochloride, benzidine dihydrochloride, diphenylhydantoin, cinnamyl anthranilate, 11-aminoundecanoic acid, and 4,4'-oxydianiline) produced repeatable enhancement of SA7 transformation at two or more consecutive dose levels, which constitutes clear evidence of enhancing activity in this assay. Both toxic and nontoxic doses of each of these chemicals caused enhancement of virus transformation. Two chemicals (2,6-dichloro-p-phenylenediamine and cinnamaldehyde) produced some evidence of enhancing activity (repeatable transformation enhancement at one dose). Dose ranges for cytotoxicity and enhancement of SA7 transformation were similar in both laboratories for all chemicals producing activity. The final two chemicals, chloramphenicol sodium succinate and ethylene thiourea, failed to reproducibly demonstrate either significant cytotoxicity or enhancement of SA7 transformation at concentrations up to 10-20 mM. The test results for these 12 chemicals were combined with the test results for 9 known carcinogens and noncarcinogens in order to evaluate relationships between activity, dose response, and lowest effective enhancing concentration for these compounds, as well as to correlate them with rodent carcinogenesis classifications. The Syrian hamster embryo cell-SA7 system demonstrated reproducible test responses in both intra- and interlaboratory studies and detected 13 out of 15 known rodent carcinogens.

The intralaboratory and interlaboratory reproducibility of a DNA virus (SA7) transformation enhancement assay was investigated using nine carcinogenic and noncarcinogenic compounds representing a variety of chemical classes. By the use of standardized procedures designed to limit assay variables, replicate assay data were collected in two independent laboratories and analyzed for concurrence. The carcinogens, 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene, and N-methyl-N'-nitro-N-nitrosoguanidine yielded reproducible dose-dependent cytotoxicity and positive transformation effects (defined as statistically significant [p less than or equal to 0.05] enhancement of virus transformation at two or more consecutive dose levels) in all experiments in both laboratories. The carcinogens lead chromate, diethylnitrosamine, 4-nitroquinoline-N-oxide, and 2-acetylaminofluorene demonstrated enhancement of SA7 transformation at two or more dose levels in 40-50% of the assays. The noncarcinogenic structural analogs anthracene and pyrene consistently did not produce positive assay responses when tested at dose levels up to the limits of solubility. Good interlaboratory concurrence was demonstrated for these model compounds in the Syrian hamster embryo cell-SA7 assay.

Repeated measures of periosteal and endosteal widths of the left second metacarpal from two samples of radiographs were made independently with either a dial caliper or an electronic digitizer connected to a microcomputer. In addition, periosteal and endosteal bone widths of a common sample of radiographs were measured with dial calipers and the electronic digitizer. Dial calipers and an electronic digitizer are both very reliable, but intraobserver errors produced with the use of the digitizer are significantly less than those produced with the use of dial calipers. However, measurements made with the electronic digitizer are systematically larger than corresponding widths measured with dial calipers, but this difference is very small.

Rind oil components (excluding terpenes) of diploid and tetraploid selections of seven Citrus varieties comprising four species were compared by gas chromatography. The tetraploids were autotetraploid, asexual derivatives of the diploids. Percentages of the oil constituents were markedly similar between diploids and their respective tetraploids. Those significant differences which were found tended to occur at the same peaks among different varieties; the direction of the differences between diploids and tetraploids also tended to be the same for a given peak. 'Royal' grapefruit which may be a natural hybrid, showed several conspicuous differences between its diploid and tetraploid forms, and showed many differences from a more typical grapefruit, the 'Hall'. The diploid and tetraploid forms of 'Lisbon' lemon both had high percentages of oil in the regions of geranyl acetate, geranial, and nerol. The components ocatanal, linalool, nonanol, and a-terpineol were present in substantial quantities in most of the varieties. Each variety could be distinguished from the others by the overall percentages of its various oil components.

A B S T R A C T Tree characters of 13 sets of twin and triplet hybrids from single seeds of crosses of Citrus X Poncirus and characters of three other Citrus twin sets are described. Evidence from tree size and habit, leaf size, shape, and thickness, and time of leafing and leaf fall indicates that these twins and triplets are probably all genetically identical within sets. Recent cytological evidence is cited which indicates that supernumerary sexual embryos can occur in Citrus by a process of budding from the primary embryo. The twin and triplet hybrids are clearly of separate origin from multiple asexual seedlings, also normally genetically identical, which arise fram cells of the nucellus in many Citrus varieties. MVANY MEMBERS of the genus Citrus and some closely related genera reproduce asexually by

Virtually all published accounts of territorial behaviour in the Grey seal apply to breeding males only. Long-range field studies reveal, however, that lactating cows also maintain territories for a period of several weeks. During the summer months, adults and sub-adults have specific resting places to which they return each day at low water and which they defend against other individuals of their own species.