bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of load‐carrying in the evolution of modern body proportions
Authors: Wang W.‐J. , Crompton R. H.
Published: May 2004

The first unquestionably bipedal early human ancestors, the species Australopithecus afarensis, were markedly different to ourselves in body proportions, having a long trunk and short legs. Some have argued that ′chimpanzee‐like′ features such as these suggest a ‘bent‐hip, bent‐knee’ (BHBK) posture would have been adopted during gait. Computer modelling studies, however, indicate that this early human ancestor could have walked in a reasonably efficient upright posture, whereas BHBK posture would have nearly doubled the mechanical energy cost of locomotion, as it does the physiological cost of locomotion in ourselves. More modern body proportions first appear at around 1.8–1.5 Ma, with Homo ergaster (early African Homo erectus), represented by the Nariokotome skeleton KNM‐WT 15000, in which the legs were considerably longer in relation to the trunk than they are in human adults, although this skeleton represents an adolescent. Several authors have suggested that this morphology would have allowed faster, more endurant walking. But during the same period, the archaeological record indicates a sharp rise in distances over which stone tools or raw materials are transported. Is this coincidental, or can load‐carrying also be implicated in selection for a more modern morphology? Computer simulations of loaded walking, verified against kinetic data for humans, show that BHBK gait is even more ineffective while load‐carrying. However, walking erect, the Nariokotome individual could have carried loads of 10–15% body mass for less cost, relative to body size, than AL 288‐1 walking erect but unloaded. In fact, to the extent that our sample of humans is typical, KNM‐WT 15000 would have had better mechanical effectiveness in bearing light loads on the back than modern human adults. Thus, selection for effectiveness in load‐carrying, as well as in endurant walking, is indeed likely to have been implicated in the evolution of modern body proportions.
Quantitative optical microscope with enhanced resolution using a pixelated liquid crystal spatial light modulator
Authors: NG A. Y. M. , SEE C. W. , SOMEKH M. G.
Published: May 2004

This paper presents a brief account of a novel optical microscope, which combines the advantages of two well‐known techniques, namely phase contrast and phase stepping, to provide high contrast imaging and precision measurements. The inclusion of a programmable liquid crystal spatial light modulator provides for the phase stepping required, while also allowing flexibility for future improvements. The results shown reveal an important aspect of the system to facilitate quantitative sample measurements, with an enhancement of optical resolution compared with conventional optical imaging systems.
Off‐axis electron holography of electrostatic potentials in unbiased and reverse biased focused ion beam milled semiconductor devices
Authors: TWITCHETT A. C. , DUNIN‐BORKOWSKI R. E. , HALLIFAX R. J. , BROOM R. F. , MIDGLEY P. A.
Published: May 2004

Off‐axis electron holography in the transmission electron microscope (TEM) is used to measure two‐dimensional electrostatic potentials in both unbiased and reverse biased silicon specimens that each contain a single p–n junction. All the specimens are prepared for examination in the TEM using focused ion beam (FIB) milling. The in situ electrical biasing experiments make use of a novel specimen geometry, which is based on a combination of cleaving and FIB milling. The design and construction of an electrical biasing holder are described, and the effects of TEM specimen preparation on the electrostatic potential in the specimen, as well as on fringing fields beyond the specimen surface, are assessed.
Circuit editing of copper and low‐k dielectrics in nanotechnology devices
Authors: MOSSELVELD F. , MAKAROV V. V. , LUNDQUIST T. R. , GRIFFIS D. P. , RUSSELL P. E.
Published: May 2004

Circuit editing of integrated circuit (IC) devices fabricated in 100‐nm and smaller technologies has moved IC microsurgery into nanosurgery. Although the dimensions are challenging, an additional challenge is to mill the dielectric materials that are employed controllably. There are interesting biological similarities as carbon content and porosity increase in order to minimize the dielectric constant. These porous organic materials are extremely delicate and are readily carbonized under the ion beam. Besides minimizing carbonization, the etching of these materials must be minimized during the removal of a metallized area. A further challenge has been caused by the continuing tightening of fabrication specifications; the dielectric materials are dispersed (although not randomly) within the metallizations in order to reduce variations during a planarization process. In addition, to improve planarization tolerances, dummy metallizations are placed in regions where the need is only mechanical and not electrical. Neither of these ‘extra’ structures is readily available to assist in edit planning. To address these dielectrics and the structures in which they are found, several techniques – including chemistries – have been developed. Methods to increase the etching of metallization relative to the dielectric are reviewed, including chemistries that improve the selectivity of copper to dielectric.
Thermal stability of Ti and Pt nanowires manufactured by Ga+ focused ion beam
Authors: INKSON B. J. , DEHM G. , WAGNER T.
Published: May 2004

Ti and Pt nanowires have been produced by ultra high‐vacuum molecular beam epitaxy deposition of Ti thin films and focused ion beam (FIB) deposition of Pt thin films, followed by cross‐sectional FIB sputtering to form electron‐transparent nanowires. The thermal stability of the nanowires has been investigated by in situ thermal cycling in a transmission electron microscope. Epitaxial single crystal Ti nanowires on (0001)Al2O3 substrates are microstructurally stable up to 550–600 °C, above which limited dislocation motion is activated shortly before the Ti‐wires oxidize. The amorphous FIB‐deposited Pt wires are stable up to 580–650 °C where partial crystallization is observed in vacuum. Faceted nanoparticles grow on the wire surface, growing into free space by surface diffusion and minimizing contact area with the underlying wire. The particles are face‐centred cubic (fcc) Pt with some dissolved Ga. Continued heating results in particle spheroidization, coalescence and growth, retaining the fcc structure.
A quantitative, three‐dimensional depositional model of gravelly braided rivers
Authors: Lunt I. A. , Bridge J. S. , Tye R. S.
Published: May 2004

A quantitative, three‐dimensional depositional model of gravelly, braided rivers has been developed based largely on the deposits of the Sagavanirktok River in northern Alaska. These deposits were described using cores, wireline logs, trenches and ground‐penetrating radar profiles. The origin of the deposits was inferred from observations of: (1) channel and bar formation and migration and channel filling, interpreted from aerial photographs; (2) water flow during floods; and (3) the topography and texture of the river bed at low‐flow stage. This depositional model quantitatively represents the geometry of the different scales of strataset, the spatial relationships among them and their sediment texture distribution. Porosity and permeability in the model are related to sediment texture. The geometry of a particular type and scale of strataset is related to the geometry and migration of the bedform type (e.g. ripples, dunes, bedload sheets, bars) associated with deposition of the strataset. In particular, the length‐to‐thickness ratio of stratasets is similar to the wavelength‐to‐height ratio of associated bedforms. Furthermore, the wavelength and height of bedforms such as dunes and bars are related to channel depth and width. Therefore, the thickness of a particular scale of strataset (i.e. medium‐scale cross‐sets and large‐scale sets of inclined strata) will vary with river dimensions. These relationships between the dimensions of stratasets, bedforms and channels mean that this depositional model can be applied to other gravelly fluvial deposits. The depositional model can be used to interpret the origin of ancient gravelly fluvial deposits and to aid in the characterization of gravelly fluvial aquifers and hydrocarbon reservoirs.
Fluidization and injection in the deep‐water sandstones of the Eocene Alba Formation (UK North Sea)
Authors: Duranti Davide , Hurst Andrew
Published: May 2004

The Nauchlan Member of the Late Eocene Alba Formation (UK North Sea) consists of a deep‐water channel fill that was extensively modified by post‐depositional sand remobilization and injection. Sandstone textures, facies associations and the geometry of the channel fill were affected. A suite of sand‐rich facies was produced by large‐scale fluidization and injection within the channel fill and above it. These facies, termed here unstratified facies, are characterized by the absence of stratification surfaces and by discordant relationships with bedding in the adjacent succession. They reflect variable degrees of disruption of the primary sedimentary structures caused by escaping pore fluid, the velocity of which is estimated at least in the order of 0·1 ms−1. Adjacent mudstones were severely disrupted by hydraulic fracturing, and fragments of fractured mudstone were incorporated into the fluidized sand. Average porosity was decreased in the sandstones affected by fluidization. Two main phases of sand injection are inferred to occur at different burial depths. A shallow burial phase (below 100 m) produced thin dykes with ptygmatic folds. The second phase occurred at the boundary between Eocene and Oligocene (≈ 300 m burial depth) and resulted in large‐scale tabular wing‐like dykes that project from the edges of the channel fill. The significant pore‐fluid overpressure, which was required to hydraulically fracture the thick mudstone seal and to fluidize the large volume of sand, was likely to be built up by static liquefaction of the source sand and was possibly enhanced by hydrocarbon gas influx.
Implications of the fault scaling law for the growth of topography: mountain ranges in the broken foreland of north‐east Tibet
Authors: Hetzel Ralf , Tao Mingxin , Niedermann Samuel , Strecker Manfred R. , Ivy‐Ochs Susan , Kubik Peter W. , Gao Bo
Published: May 2004

A fault scaling law suggests that, over eight orders of magnitude, fault lengthLis linearly related to maximum displacementD. Individual faults may therefore retain a constant ratio ofD/Las they grow. If erosion is minor compared with tectonic uplift, the length and along‐strike relief of young mountain ranges should thus reflect fault growth. Topographic profiles along the crests of mountain ranges in the actively deforming foreland of north‐east Tibet exhibit a characteristic shape with maximum height near their centre and decreasing elevation toward the tips. We interpret the along‐strike relief of these ranges to reflect the slip distribution on high‐angle reverse faults. A geometric model illustrates that the lateral propagation rate of such mountain ranges may be deciphered if their length‐to‐height ratio has remained constant. As an application of the model, we reconstruct the growth of the Heli Shan using a long‐term uplift rate of ∼1.3 mm yr−1derived from21Ne and10Be exposure dating.
Initial reactions in sapwood of Norway spruce and Scots pine after wounding and infection by Heterobasidion parviporum and H. annosum
Authors: Johansson S. M. , Lundgren L. N. , Asiegbu F. O.
Published: May 2004

The xylem surface of seedlings, stem material and roots of Norway spruce (Picea abies) and Scots pine (Pinus sylvestris) were inoculated with strains of Heterobasidion annosum s. str. and H. parviporum s. str. The depth of necrosis in wounded spruce increased at a linear rate for at least seven weeks of incubation, but the rate of necrotic spread was significantly faster in infected wounds. In wounded pine the necrosis was maintained at a more superficial level for several weeks. Both spruce and pine sapwood were initially infected by hyphae of both species. In spruce, the hyphae advanced at a constant rate behind the necrotic front. On the contrary, after 1–2 weeks living H. parviporum hyphae were rare in pine rays. Heterobasidion annosum hyphae survived in pine rays, phloem and tracheids, despite a heavy accumulation of phenolics and resins and were able to penetrate into the sapwood at a linear rate although slower than infections in spruce. Histochemistry and quantitative estimates demonstrated that peroxidase activity was initially higher in spruce sapwood than in pine. Within three days of incubation, the activity in spruce sapwood disappeared concurrently with deepening necrosis. However, in pine, in both control and infected samples, there was a significant increase in peroxidase activity in the area surrounding the superficial necrosis, up to the wound surface and in the cambium and phloem around the wound. After wounding and infection, the content of soluble protein increased significantly in wood of older trees but not in seedlings. Infection resulted in an increased formation of lipophilic extractives in both spruce and pine but to a significantly greater degree in the latter, whereas the amount of hydrophilic compounds decreased in both. High‐performance liquid chromatography (HPLC) analyses of lipophilic extracts showed that inoculation of pine with the two species of Heterobasidion increased the amounts of pinosylvin, its monomethylether and several other phenolics as also resinous compounds. The results obtained may be relevant in explaining the known higher resistance of Scots pine to H. parviporum.
Mercury Inactivates Transcription and the Generalized Transcription Factor TFB in the Archaeon
Sulfolobus solfataricus
Authors: Dixit Vidula , Bini Elisabetta , Drozda Melissa , Blum Paul
Published: May 2004

Mercury has a long history as an antimicrobial agent effective against eukaryotic and prokaryotic organisms. Despite its prolonged use, the basis for mercury toxicity in prokaryotes is not well understood. Archaea, like bacteria, are prokaryotes but they use a simplified version of the eukaryotic transcription apparatus. This study examined the mechanism of mercury toxicity to the archaeal prokaryote
Sulfolobus solfataricus
. In vivo challenge with mercuric chloride instantaneously blocked cell division, eliciting a cytostatic response at submicromolar concentrations and a cytocidal response at micromolar concentrations. The cytostatic response was accompanied by a 70% reduction in bulk RNA synthesis and elevated rates of degradation of several transcripts, including
tfb-1
,
tfb-2
, and
lacS
. Whole-cell extracts prepared from mercuric chloride-treated cells or from cell extracts treated in vitro failed to support in vitro transcription of 16S rRNAp and
lacSp
promoters. Extract-mixing experiments with treated and untreated extracts excluded the occurrence of negative-acting factors in the mercury-treated cell extracts. Addition of transcription factor B (TFB), a general transcription factor homolog of eukaryotic TFIIB, to mercury-treated cell extracts restored >50% of in vitro transcription activity. Consistent with this finding, mercuric ion treatment of TFB in vitro inactivated its ability to restore the in vitro transcription activity of TFB-immunodepleted cell extracts. These findings indicate that the toxicity of mercuric ion in
S. solfataricus
is in part the consequence of transcription inhibition due to TFB-1 inactivation.
α-Galactosylceramide and Novel Synthetic Glycolipids Directly Induce the Innate Host Defense Pathway and Have Direct Activity against Hepatitis B and C Viruses
Authors: Mehta Anand S. , Gu Baohua , Conyers Bertha , Ouzounov Serguey , Wang Lijuan , Moriarty Robert M. , Dwek Raymond A. , Block Timothy M.
Published: May 2004

α-Galactosylceramide is a glycolipid derived from marine sponges that is currently in human clinical trials as an anticancer agent. It has also been shown to be effective in reducing the amount of hepatitis B virus (HBV) DNA detected in mice that produce HBV constitutively from a transgene. It was assumed that all of the antiviral and antitumor activities associated with α-galactosylceramide were mediated through the activation of NK T cells. However, we report here an additional unpredicted activity of α-galactosylceramide as a direct antiviral agent and inducer of the innate host defense pathway. To exploit this activity, we have developed a new class of smaller, orally available glycolipids that also induce the innate host defense pathway and have direct activity against HBV and hepatitis C virus.
Application of Real-Time Quantitative PCR to Molecular Analysis of
Candida albicans
Strains Exhibiting Reduced Susceptibility to Azoles
Authors: Chau Andrew S. , Mendrick Cara A. , Sabatelli Frank J. , Loebenberg David , McNicholas Paul M.
Published: May 2004

Real-time quantitative PCR was used to measure expression levels of genes encoding efflux pumps,
ERG11
and two control genes,
ACT1
and
PMA1
, in a collection of 14 fluconazole-susceptible
Candida albicans
isolates. For each gene, average expression levels and variations within the population were determined. These values were then used as reference points to make predictions about the molecular basis of resistance in 38 clinical isolates (the majority of which were resistant to fluconazole) obtained from 18 patients treated with posaconazole for refractory oropharyngeal candidiasis. For each of the 38 isolates, the expression levels of genes encoding efflux pumps,
ERG11
and the control genes, were measured as above. Comparison of the two data sets revealed that expression of
ACT1
and
PMA1
did not vary significantly between the two sets of isolates. In contrast,
MDR1, ERG11
,
CDR1
, and
CDR2
were overexpressed in 3, 4, 14, and 35, respectively, of the isolates from patients treated with azoles. In addition to these changes, the patient isolates all had at least one and often multiple missense mutations in
ERG11
. Select
ERG11
alleles were expressed in
Saccharomyces cerevisiae
; all of the alleles tested conferred reduced susceptibility to fluconazole. Despite both the increases in pump expression and the
ERG11
mutations, only one of the patient isolates exhibited a large decrease in posaconazole susceptibility.
Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir
Authors: Grossman Zehava , Paxinos Ellen E. , Averbuch Diana , Maayan Shlomo , Parkin Neil T. , Engelhard Dan , Lorber Margalit , Istomin Valery , Shaked Yael , Mendelson Ella , Ram Daniela , Petropoulos Chris J. , Schapiro Jonathan M.
Published: May 2004

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as “subtype-C-infected patients”) versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%;
P
= 0.03) while L90M was similar (
P
< 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 <
P
< 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC
50
) change in susceptibility to nelfinavir only. Other mutations increased IC
50
correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ± 22% to 22% ± 15% (
P
= 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.
Pyruvate Decarboxylase, the Target for Omeprazole in Metronidazole-Resistant and Iron-Restricted
Tritrichomonas foetus
Authors: Sutak Róbert , Tachezy Jan , Kulda Jaroslav , Hrdý Ivan
Published: May 2004

The substituted benzimidazole omeprazole, used for the treatment of human peptic ulcer disease, inhibits the growth of the metronidazole-resistant bovine pathogen
Tritrichomonas foetus
in vitro (MIC at which the growth of parasite cultures is inhibited by 50%, 22 μg/ml [63 μM]). The antitrichomonad activity appears to be due to the inhibition of pyruvate decarboxylase (PDC), which is the key enzyme responsible for ethanol production and which is strongly upregulated in metronidazole-resistant trichomonads. PDC was purified to homogeneity from the cytosol of metronidazole-resistant strain. The tetrameric enzyme of 60-kDa subunits is inhibited by omeprazole (50% inhibitory concentration, 16 μg/ml). Metronidazole-susceptible
T. foetus
, which expresses very little PDC, is only slightly affected. Omeprazole has the same inhibitory effect on
T. foetus
cells grown under iron-limited conditions. Similarly to metronidazole-resistant cells,
T. foetus
cells grown under iron-limited conditions have nonfunctional hydrogenosomal metabolism and rely on cytosolic PDC-mediated ethanol fermentation.
Mutations Conferring Resistance to a Potent Hepatitis C Virus Serine Protease Inhibitor In Vitro
Authors: Lu Liangjun , Pilot-Matias Tami J. , Stewart Kent D. , Randolph John T. , Pithawalla Ron , He Wenping , Huang Peggy P. , Klein Larry L. , Mo Hongmei , Molla Akhteruzzaman
Published: May 2004

BILN 2061 is a novel, specific hepatitis C virus (HCV) NS3 serine protease inhibitor discovered by Boehringer Ingelheim that has shown potent activity against HCV replicons in tissue culture and is currently under clinical investigation for the treatment of HCV infection. The poor fidelity of the HCV RNA-dependent RNA polymerase will likely lead to the development of drug-resistant viruses in treated patients. The development of resistance to BILN 2061 was studied by the in vitro passage of HCV genotype 1b replicon cells in the presence of a fixed concentration of the drug. Three weeks posttreatment, four colonies were expanded for genotypic and phenotypic characterization. The 50% inhibitory concentrations of BILN 2061 for these colonies were 72- to 1,228-fold higher than that for the wild-type replicon. Sequencing of the individual colonies identified several mutations in the NS3 serine protease gene. Molecular clones containing the single amino acid substitution A156T, R155Q, or D168V resulted in 357-fold, 24-fold, and 144-fold reductions in susceptibility to BILN 2061, respectively, compared to the level of susceptibility shown by the wild-type replicon. Modeling studies indicate that all three of these residues are located in close proximity to the inhibitor binding site. These findings, in addition to the three-dimensional structure analysis of the NS3/NS4A serine protease inhibitor complex, provide a strategic guide for the development of next-generation inhibitors of HCV NS3/NS4A serine protease.
Anti-Hepatitis B Virus Activity of ORI-9020, a Novel Phosphorothioate Dinucleotide, in a Transgenic Mouse Model
Authors: Iyer Radhakrishnan P. , Roland Arlene , Jin Yi , Mounir Samir , Korba Brent , Julander Justin G. , Morrey John D.
Published: May 2004

ORI-9020, a novel dinucleotide, evaluated in transgenic mice expressing hepatitis B virus (HBV), significantly reduced liver HBV DNA (
P
≤ 0.001). Levels of HBeAg and HBsAg in serum and of HBcAg in liver were not affected by treatment. A minimal effective dosage was determined to be between 1.6 and 0.5 mg/kg of body weight/day, which was similar to that observed for adefovir dipivoxil.
Lack of Effect of Recombinant Human Growth Hormone on the In Vitro Activities of Antiretroviral Drugs against Human Immunodeficiency Virus Type 1
Authors: Wainberg Mark A , Brenner Bluma G. , Daar Eric , Gertner Joseph M. , Olivier Clement , Kenley Susan
Published: May 2004

We studied the effects of recombinant human growth hormone (r-hGH) on human immunodeficiency virus type 1 replication by growing both wild-type and drug-resistant variants of virus in the presence of various concentrations of eight different antiretroviral drugs. r-hGH had no significant effect on either viral replication or the 50% inhibitory concentrations of these compounds.
Validity of Queen’s College step test for use with young Indian men
Authors: Chatterjee S , Chatterjee P , Mukherjee P S , Bandyopadhyay A
Published: May 2004

Objectives:To assess the suitability of the Queen’s College step test (QCT) to predict maximum oxygen uptake in Indian men.

Methods:Thirty sedentary male university students from West Bengal, India, with the same socioeconomic background and mean (SD) age, height, and weight of 22.6 (0.2) years, 166.4 (0.5) cm, and 53.8 (0.2) kg, respectively, were randomly sampled from University of Calcutta. VO2max of each participant was determined by direct procedure involving incremental bicycle exercise and also by applying indirect QCT method with a gap of 4 days between the tests.

Results:The difference between the mean (SD) VO2max values directly measured (VO2max = 39.8 (1.03) ml/min/kg body mass) and indirectly predicted (PVO2max = 39.3 (1.07) ml/min/kg body mass) was statistically insignificant (p>0.10). PVO2max and VO2max values expressed as ml/min/kg body mass corroborated with previous studies in the same laboratory involving the same population, and also exhibited significant statistical correlation (r = 0.95, p<0.001) between them.

Conclusion:The results suggest that QCT can be applied in the studied population to produce a good estimation of maximum oxygen uptake, especially in the field where large numbers of participants are to be evaluated without a well equipped laboratory.
Extreme risk taker who wants to continue taking part in high risk sports after serious injury
Authors: Pain M , Kerr J H
Published: May 2004

The case is reported of a 40 year old male high risk sport athlete who had seriously injured himself several times and as a result was partially physically disabled and had trouble with mental tasks requiring concentration such as spelling, reading numbers, and writing. The athlete was referred to a sports psychologist. In consultations, it became clear that he was having difficulty reconciling the difference between his life as it used to be and as it would be in the future. Part of his difficulty was dealing with the frustration and anger “outbursts” which resulted from not being able to perform straightforward everyday motor skills. In spite of his injuries and disability, the patient badly wanted to continue participating in extreme sports. Reversal theory is used in the discussion to provide theoretical explanations of the motivation for his extreme risk taking behaviour.
Epidemiology of injuries in adventure racing athletes
Authors: Fordham S , Garbutt G , Lopes P
Published: May 2004

Objectives:To assess the demographics and training characteristics of adventure racing athletes in the United Kingdom, the prevalence and anatomical distribution of hazardous encounter, and overuse injury in this population, and the effects these injuries have on training.

Methods:A retrospective training and injury questionnaire for the previous 18 months was distributed to 300 adventure racing athletes at two national race meetings. The definition of an injury was “any musculoskeletal problem causing a stop in training for at least one day, reduction in training mileage, taking of medicine, or seeking of medical aid.”

Results:The data were derived from the responses of 223 athletes. Advanced level athletes did 11 (4) sessions and 17 (8) hours of training a week (mean (SD)). An injury was reported in the previous 18 months by 73% of the respondents. The most common site of acute injury was the ankle (23%) and of chronic/overuse injury, the knee (30%), followed by the lower back, shin, and Achilles tendon (12% each). There were significant correlations (p<0.01) between the hours spent cycling per week and number of acute injuries, and between the number of days off per week and number of chronic/overuse injuries. Injuries resulted in an average of 23 days training cessation or reduction.

Conclusions:Acute injuries were sustained mainly as a result of the nature of the terrain over which athletes train and compete. In overuse injuries lack of adequate rest days was a significant contributing factor. Only a small proportion of training time was spent developing flexibility and core stability.
Effects of 20 days of bed rest on the viscoelastic properties of tendon structures in lower limb muscles
Authors: Kubo K , Akima H , Ushiyama J , Tabata I , Fukuoka H , Kanehisa H , Fukunaga T
Published: May 2004

Objectives:The purpose of this study was to investigate the effects of 20 days’ bed rest on the viscoelastic properties of human tendon structures in knee extensor and plantar flexor muscles in vivo.

Methods:Eight healthy men (age: 24±4 years, height: 172±9 m, body mass: 69±13 kg) carried out a 6° head-down bed rest for 20 days. Before and after bed rest, elongation (L) of the tendon and aponeurosis of vastus lateralis (VL) and medial gastrocnemius muscles (MG) during isometric knee extension and plantar flexion, respectively, were determined using real-time ultrasonic apparatus, while the subjects performed ramp isometric contraction up to the voluntary maximum, followed by ramp relaxation. The relationship between estimated muscle force (Fm) and tendon elongation (L) was fitted to a linear regression, the slope of which was defined as stiffness. The hysteresis was calculated as the ratio of the area within the Fm-L loop to the area beneath the load portion of the curve.

Results:L values above 100 N were significantly greater after bed rest for VL, while there were no significant differences in L values between before and after for MG. The stiffness decreased after bed rest for VL (70.3±27.4v50.1±24.8 N/mm, before and after bed rest, respectively; p = 0.003) and MG (29.4±7.5v25.6±7.8 N/mm, before and after bed rest, respectively; p = 0.054). In addition, hysteresis increased after bed rest for VL (16.5±7.1%v28.2±12.9%, before and after bed rest, respectively; p = 0.017), but not for MG (17.4±4.4%v17.7±6.1%, before and after bed rest, respectively; p = 0.925).

Conclusions:These results suggested that bed rest decreased the stiffness of human tendon structures and increased their hysteresis, and that these changes were found in knee extensors, but not the plantar flexors.
Physiology of sport rock climbing
Authors: Sheel A W
Published: May 2004

Rock climbing has increased in popularity as both a recreational physical activity and a competitive sport. Climbing is physiologically unique in requiring sustained and intermittent isometric forearm muscle contractions for upward propulsion. The determinants of climbing performance are not clear but may be attributed to trainable variables rather than specific anthropometric characteristics.
Transgenic Tagging Defining Pancreatic Pedigrees
Authors: MERINO PEDRO LUIS HERRERA
Published: May 2004

Abstract: In this review, analyses of the ontogenetic relations between the different pancreatic cell types are summarized. Lineage analyses allow identification of progenitor cells from which mature cell types differentiate. This knowledge is highly relevant for future cell replacement therapies in diabetic patients, helping to define the identity of putative pancreatic stem cells.
REST and Peace for the Neuronal‐Specific Transcriptional Program
Authors: LUNYAK VICTORIA V. , PREFONTAINE GRATIEN G. , ROSENFELD MICHAEL G.
Published: May 2004

Abstract: Despite a genetic homogeneity, cells in multicellular organisms are structurally and functionally heterogeneous. The diversity of cell phenotypes exists due to differential transcriptional programs precisely regulated by specific nuclear factors and induced upon differentiation. The differences in gene expression programs arise during development and become heritable during cell proliferation. Over the last few years, research has focused on three molecular mechanisms that mediate epigenetic phenomena: DNA methylation, histone modification, and formation of specialized nuclear domains or territories. All of these processes are dynamic and tightly linked to the organism's development. Here we review advances in understanding the significance of epigenetic mechanisms in the establishment and maintenance of the specialized transcriptional program. We project the accumulated knowledge onto the delineation of the molecular mechanisms by which central nervous system‐specific genes are expressed in the nervous system and repressed in other tissues.
Immunohistochemical Localization of Somatostatin Receptor sst2A in Human Gut and Lung Tissue: Possible Implications for Physiology and Carcinogenesis
Authors: Gugger M , Waser B , Kappeler A , Schonbrunn A , Reubi JC
Published: May 2004

Abstract: Many neuroendocrine gastrointestinal and lung tumors express sst2A somatostatin receptors. Because the cellular location of sst2A in the corresponding non‐neoplastic tissue is unknown, we searched for sst2A immuno‐reactive cells and characterized their type in these tissues using a highly specific sst2A antibody (R2–88). Epithelial sst2A cells, identified as neuroendocrine, gastrin‐producing cells, were found in large numbers in the antrum and the duodenum, but not in the gastric corpus. They were also present in the proximal jejunum, rarely noted in the distal jejunum and ileum, and absent in the large intestine and the appendix vermiformis. Moreover, sst2A cells were found abundantly in the neural plexus. sst2A receptors on antral gastrin cells could mediate somatostatin inhibition on gastrin secretion, whereas those in the neural plexus could mediate somatostatin effects on motility and ion transport in the lower gastrointestinal tract. Rare sst2A cells in bronchi and bronchioles located basally and parabasally in the gastrointestinal epithelium were detected that could represent stem/progenitor cells. It is currently not clear whether and which of the identified sst2A cells are at the origin of sst2A‐positive neuroendocrine gut or lung tumors.
Peptide Receptor Radionuclide Therapy
Authors: KRENNING ERIC P. , KWEKKEBOOM DIK J. , VALKEMA ROELF , PAUWELS STANISLAS , KVOLS LARRY K. , DE JONG MARION
Published: May 2004

Abstract: On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, for example, overexpression in many tumors, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualization of receptor‐positive tumors were radiolabeled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicenter studies already have shown an effective therapeutic response when using radiolabeled somatostatin analogues to treat receptor‐positive tumors. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK‐B receptor‐positive tumors, such as medullary thyroid carcinoma, radiolabeled minigastrin analogues currently are being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabeled peptides. The combination of different radionuclides, such as 177Lu‐ and 90Y‐labeled somatostatin analogues, to reach a wider tumor region of high curability, has been described. A variety of other peptide‐based radioligands, such as bombesin and NPY(Y1) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multireceptor tumor targeting using the combination of bombesin and NPY(Y1) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases.
Heterogeneous Expression of Neuroendocrine Marker Proteins in Human Undifferentiated Carcinoma of the Colon and Rectum
Authors: GRABOWSKI PATRICIA , SCHÖNFELDER JULIA , AHNERT‐HILGER GUDRUN , FOSS HANS‐DIETER , STEIN HARALD , BERGER GERD , ZEITZ MARTIN , SCHERÜBL HANS
Published: May 2004

Abstract: The expression of neuroendocrine marker proteins in undifferentiated colorectal cancers has not yet been studied in great detail. Therefore, the survival of 20 patients with small cell undifferentiated colorectal cancers treated at our institution between 1982 and 1997 (0.8% of all operated colorectal carcinomas) was correlated with the extent of neuroendocrine differentiation. Chromogranin A, synaptophysin, syntaxin1, VAMP2, SNAP25, and α/β‐SNAP were used as neuroendocrine markers. Based on the degree of immunoreactivity for these marker proteins, tumors were divided into group 0 (<2% cells stained positive for neuroendocrine markers) and group 1 (>2% cells stained positive). Patients were followed up for at least 5 years or until death. Nine of twenty (45%) undifferentiated colorectal tumors expressed neuroendocrine markers (group 1). Only one patient of this group survived 2 years (11%), whereas the 2‐year survival rate was 45.4% in group 0. Nine of eleven patients of group 0 were diagnosed in UICC stage I‐III, whereas eight of nine tumors with expression of neuroendocrine markers were diagnosed in UICC stage IV (P= 0.002). Our results show that neuroendocrine differentiation is often seen in small cell undifferentiated colorectal cancer. It correlates with a more aggressive course of the disease.
Implication of the INK4a/ARF Locus in Gastroenteropancreatic Neuroendocrine Tumorigenesis
Authors: SIMON BABETTE , LUBOMIERSKI NIKOLAUS
Published: May 2004

Abstract: The INK4a/ARF locus on chromosome 9p21 is one of the important defenses against tumor development and engages both the Rb and the p53 tumor suppressor pathways through its capacity to encode two distinct proteins, p16INK4a and p14ARF. Despite controversial reports, the body of present data suggests that tumor suppressors p16INK4a and p14ARF are targets of in‐activation in GEP‐NETs. Moreover, tumor type‐specific aberrant p16INK4a silencing appears to be associated with advanced tumor stage and may function as a predictor of patients' outcome after surgical resection. Since conventional histological and biochemical assessment are limited with respect to predicting GEP‐NET behavior or outcome, methylation profiles including INK4a/ARF might offer a tool to refine future diagnosis and therapeutic management of GEP‐NET patients.
From the Editor
Authors: Kelton W. David
Published: May 2004

The very name of JOC suggests that we should be on the cutting edge of technology when it comes to disseminating research, as well as in the content of the work itself. One aspect of this is our growing repository of Online Supplements housed permanently on our website. As I write this, there are some 17 supplements supporting 18 papers, and several more are in development. I invite you to peruse them for a flavor of the kinds of things that we’re able to do in JOC. They include voluminous material for which we don’t have room in the papers themselves, as well as a wide variety of other information in forms not amenable to inclusion in the papers, like downloadable code, data sets, and links to other sites. And as a purely practical budgetary matter, the Online Supplements allow us to shorten some papers, thus making room for more research to appear closer to the completion of the actual work, without impeding access. (It’s hard to imagine any JOC readers at all without ready Internet access.) If you’re an author, you might also think about creative ways to enhance your papers via this medium . . . we’re certainly game to try out new ideas.

The Summer 2004 and Fall 2004 issues will focus our attention on the growing and critically important field of biology and on what our community has to offer the exciting prospects there. The Summer 2004 issue will begin with a state-ofthe- art survey on the topic, and the Fall 2004 issue will be a Special Issue devoted entirely to biology. Founding Editor-in-Chief Harvey Greenberg has been the driving force behind both of these efforts.

Also in development is a special issue on OR in electrical and computer engineering, guest-edited by John Chinneck. And a special cluster of papers on computation in music will be guest-edited by Elaine Chew. So, running the gamut from electrical engineering to biology to music, we are definitely charting new directions in OR and CS, as our tag line claims.

After many years of service as an Associate Editor working primarily in the Telecommunications & Electronic Commerce Area, Rita Vachani has decided to rotate off at this time, and we thank her very much for her fine work for JOC. We welcome Edmund K. Burke of the University of Nottingham as a new Associate Editor, serving primarily in the Heuristic Search and Learning Area, especially on metaheuristics. And we are also happy to have Leyuan Shi of the University of Wisconsin-Madison as a new Associate Editor for our Simulation Area.
Association Between Acetaminophen or Nonsteroidal Antiinflammatory Drugs and Risk of Developing Ovarian, Breast, or Colon Cancer
Authors: Meier Christoph R. , Schmitz Stephen , Jick Hershel
Published: May 2004

Study Objective. To explore the association between exposure to acetaminophen (paracetamol) or nonsteroidal antiinflammatory drugs (NSAIDs) and risk of developing ovarian, breast, or colon cancer.

Design. Retrospective case‐control study.

Setting. General practice offices.

Subjects. Four hundred eighty‐three women with ovarian cancer and 1877 women matched for age, years of medical history in computer record, general practice attended, and calendar time; 3706 women with breast cancer and 14,155 matched control subjects; and 635 women with colon cancer and 2434 matched control subjects.

Intervention. United Kingdom‐based General Practice Research Database was searched for women aged 50–89 years with a first‐time diagnosis of ovarian, breast, or colon cancer and for matched controls to assess prescription analgesic exposure.

Measurements and Main Results. Regular acetaminophen exposure (30 prescriptions) was associated with a slightly decreased risk of developing breast (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.7–1.0) but not ovarian (OR 1.0, 95% CI 0.6–1.5) or colon (OR 1.0, 95% CI 0.7–1.4) cancer. Regular NSAID exposure was associated with a reduced risk of colon (OR 0.5, 95% CI 0.3–0.9) but not ovarian or breast cancer.

Conclusion. We found no evidence for a decreased ovarian cancer risk for women with regular acetaminophen or NSAID exposure.
Possible Mesalamine‐Induced Pericarditis: Case Report and Literature Review
Authors: Waite Robert A. , Malinowski Jennifer M.
Published: May 2004

Pericarditis should be considered in any patient complaining of chest pain and/or dyspnea who is taking a product that contains mesalamine or sulfasalazine. A 41‐year‐old woman was taking mesalamine 800 mg 3 times/day for 3 weeks before hospital admission. She complained of sharp, pleuritic chest pain that radiated down both arms and increased in intensity when lying down. She was diagnosed with pericarditis based on clinical presentation and electrocardiogram findings. Differential diagnoses for myocardial infarction, systemic lupus erythematosus, and viral or bacterial causes were ruled out based on subjective and objective data. Mesalamine‐induced pericarditis was considered on hospital day 2, and the drug was discontinued at discharge on day 3. Clinicians should be aware of this potential drug‐related complication, as the relationship between mesalamine or sulfasalazine and pericarditis has been reported rarely in the literature.
Venlafaxine‐Associated Vaginal Bleeding
Authors: Linnebur Sunny A. , Saseen Joseph J. , Pace Wilson D.
Published: May 2004

A 41‐year‐old amenorrheic woman started taking venlafaxine 37.5 mg/day for treatment of depression; 7 days later, she experienced vaginal bleeding, which ceased 1 day after she stopped taking the drug. On rechallenge with venlafaxine, she again experienced vaginal bleeding that resolved after discontinuation. We found no published reports describing vaginal bleeding associated with venlafaxine. However, premarketing and postmarketing data report similar adverse effects in patients taking the agent. In addition, several cases of menstrual irregularities have occurred with two other anti‐depressants: fluoxetine and bupropion. This case report supports previous surveillance data indicating that venlafaxine may cause vaginal bleeding.
Apraxia of Lid Opening: Dose‐Dependent Response to Carbidopa‐Levodopa
Authors: Lee Kelly C. , Finley Ron , Miller Bruce
Published: May 2004

A 67‐year‐old woman with an 8‐year history of Parkinson's disease and Lewy body dementia experienced difficulty in opening her eyelids (apraxia of lid opening [ALO]); she could close them without difficulty. This problem emerged 2 weeks after the patient's dosage of carbidopa 50 mg–levodopa 200 mg 3 times/day was decreased to twice/day. Two weeks after the onset of ALO the patient visited her physician, who suspected carbidopa‐levodopa of causing the problem; the drug was discontinued. When the patient's condition worsened rather than improved, she was referred to a neuroophthalmologist, who confirmed the diagnosis of ALO. However, the neuroophthalmologist noted that this may not have been a true apraxia but rather a form of sustained blepharospasm that prevented the eyelid from opening. Carbidopa‐levodopa was restarted, and her condition improved dramatically when her dosage was increased gradually to carbidopa 50 mg–levodopa 200 mg in the morning and at noon, and carbidopa 25 mg–levodopa 100 mg in the evening. Clinicians should be aware of adverse reactions, such as AOL, in patients taking carbidopa‐levodopa who have dementia of the Lewy body type.
Prolonged Cardiac Repolarization After Tacrolimus and Haloperidol Administration in the Critically Ill Patient
Authors: Akers Wendell S. , Flynn Jeremy D. , Davis George A. , Green Amy E. , Winstead P. Shane , Strobel Gunnar
Published: May 2004

A 42‐year‐old woman who underwent single lung transplantation who received tacrolimus and a 58‐year‐old woman with pneumonia and multiple comorbidities who received haloperidol both experienced drug‐induced prolongation of cardiac repolarization. The second woman also developed torsade de pointes. Critically ill patients are particularly susceptible to developing torsade de pointes due to various comorbidities, electrolyte disturbances, and receipt of numerous drugs. These two case reports illustrate the increased risk for drug‐induced cardiotoxicity in the critically ill patient. They also indicate the need for current knowledge derived from basic research and retrospective case reports on drug‐induced torsade de pointes to be integrated into the existing body of knowledge. Guidelines can then be developed to help prospectively reduce the frequency of adverse effects in intensive care patients. Research is necessary regarding identification of high‐risk patients before drugs are administered, and clarification of the proper role of therapeutic QT monitoring in clinical practice.