bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms in ABCG2, ABCC3 and CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients
Authors: Müller Phillip J. , Dally Heike , Klappenecker Cornelia N. , Edler Lutz , Jäger Birgit , Gerst Martina , Spiegelhalder Bertold , Tuengerthal Siegfried , Fischer Jürgen R. , Drings Peter , Bartsch Helmut , Risch Angela
Published: August 2008

The prognosis of lung cancer patients treated with chemotherapy is poor, motivating the search for predictive factors. Single nucleotide polymorphisms (SNPs) in membrane transporter genes could influence the pharmacokinetics of cytostatic drugs and therefore affect treatment outcome. We examined 6 SNPs with known or suspected phenotypic effect: ABCG2 G34A, C421A; ABCC3 C−211T, G3890A, C3942T and CNT1 G565A. For 349 Caucasian patients with primary lung cancer [161 small cell lung cancer (SCLC), 187 nonsmall cell lung cancer (NSCLC) and 1 mixed] receiving first‐line chemotherapy 3 different endpoints were analyzed: response after the 2nd cycle (R), progression‐free survival (PFS) and overall survival (OS). The prognostic value of the SNPs was analyzed using multivariable logistic regression, calculating odds ratios (ORs) when comparing genotype frequencies in responders and nonresponders after the 2nd cycle. Hazard ratios (HRs) for PFS and for OS were calculated using Cox regression methods. In all lung cancer patients, none of the investigated polymorphisms modified response statistically significant. The only significant result in the histological subpopulations was in SCLC patients carrying the ABCC3 ‐211T allele who showed significantly worsened PFS (HR: 1.79; 95% confidence interval (CI) 1.13–2.82). In an exploratory subgroup analysis significantly worse OS was seen for carriers of the ABCG2 421A‐allele treated with platinum‐based drugs (HR: 1.60; 95% CI 1.04–2.47; n = 256). In conclusion, this study prioritizes ABCC3 C‐211T and ABCG2 C421A as candidate transporter SNPs to be further investigated as possible predictors of the clinical outcome of chemotherapy in lung cancer patients. © 2008 Wiley‐Liss, Inc.
Spatial fluorescence cross‐correlation spectroscopy by means of a spatial light modulator
Authors: Blancquaert Yoann , Gao Jie , Derouard Jacques , Delon Antoine
Published: August 2008

Spatial fluorescence cross‐correlation spectroscopy is a rarely investigated version of fluorescence correlation spectroscopy, in which the fluorescence signals from different observation volumes are cross‐correlated. In the reported experiments, two observation volumes, typically shifted by a few μm, are produced, with a spatial light modulator and two adjustable pinholes. We illustrated the feasibility and potentiality of this technique by: i) measuring molecular flows, in the range 0.2–1.5 μm/ms, of solutions seeded with fluorescent nanobeads or rhodamine molecules (simulating active transport phenomenons); ii) investigating the permeability of the phospholipidic membrane of giant unilamellar vesicles versus hydrophilic or hydrophobic molecules (in that case the laser spots were set on both sides of the membrane). Theoretical descriptions are proposed together with a discussion about fluorescence‐correlation‐spectroscopy‐based, alternative methods. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
New insights into cardiovascular and lipid metabolomics
Authors: Giovane Alfonso , Balestrieri Antonio , Napoli Claudio
Published: August 2008

Metabolomics is the study of metabolite profiles in biological samples, particularly urine, saliva, blood plasma and fat biopsies. The metabolome is now considered by some to be the most predictive phenotype: consequently, the comprehensive and quantitative study of metabolites is a desirable tool for diagnosing disease, identifying new therapeutic targets and enabling appropriate treatments. A wealth of information about metabolites has been accumulated with global profiling tools and several candidate technologies for metabolomic studies are now available. Many high‐throughput metabolomics methodologies are currently under development and have yet to be applied in clinical practice on a routine basis. In the cardiovascular field, few recent metabolomic studies have been reported so far. This minireview provides an updated overview of alternative technical approaches for metabolomics studies and reviews initial applications of metabolomics that relate to both cardiovascular disease and lipid metabolism research. J. Cell. Biochem. 105: 648–654, 2008. © 2008 Wiley‐Liss, Inc.
Changes in MicroRNA expression patterns in human fibroblasts after low‐LET radiation
Authors: Maes Olivier C. , An Jin , Sarojini Harshini , Wu Honglu , Wang Eugenia
Published: August 2008

Exposure to radiation provokes cellular responses controlled in part by gene expression networks. MicroRNAs (miRNAs) are small non‐coding RNAs which mostly regulate gene expression by degrading the messages or inhibiting translation. Here, we investigated changes in miRNA expression patterns after low (0.1 Gy) and high (2.0 Gy) doses of X‐ray in human fibroblasts. At early (0.5 h) and late (6 and 24 h) time points, irradiation caused qualitative and quantitative differences in the down‐regulation of miRNA levels, including miR‐92b, 137, 660, and 656. A transient up‐regulation of miRNAs was observed after 2 h post‐irradiation following high doses of radiation, including miR‐558 and 662. MicroRNA levels were inversely correlated with targets from mRNA and proteomic profiling after 2.0 Gy of radiation. MicroRNAs miR‐579, 608, 548‐3p, and 585 are noted for targeting genes involved in radioresponsive mechanisms, such as cell cycle checkpoint and apoptosis. We suggest here a model in which miRNAs may act as “hub” regulators of specific cellular responses, immediately down‐regulated so as to stimulate DNA repair mechanisms, followed by up‐regulation involved in suppressing apoptosis for cell survival. Taken together, miRNAs may mediate signaling pathways in sequential fashion in response to radiation, and may serve as biodosimetric markers of radiation exposure. J. Cell. Biochem. 105: 824–834, 2008. © 2008 Wiley‐Liss, Inc.
Ab initio calculations on halogen‐bonded complexes and comparison with density functional methods
Authors: Lu Yun‐Xiang , Zou Jian‐Wei , Fan Ji‐Cai , Zhao Wen‐Na , Jiang Yong‐Jun , Yu Qing‐Sen
Published: August 2008

A systematic theoretical investigation on a series of dimeric complexes formed between some halocarbon molecules and electron donors has been carried out by employing both ab initio and density functional methods. Full geometry optimizations are performed at the Moller–Plesset second‐order perturbation (MP2) level of theory with the Dunning's correlation‐consistent basis set, aug‐cc‐pVDZ. Binding energies are extrapolated to the complete basis set (CBS) limit by means of two most commonly used extrapolation methods and the aug‐cc‐pVXZ (X = D, T, Q) basis sets series. The coupled cluster with single, double, and noniterative triple excitations [CCSD(T)] correction term, determined as a difference between CCSD(T) and MP2 binding energies, is estimated with the aug‐cc‐pVDZ basis set. In general, the inclusion of higher‐order electron correlation effects leads to a repulsive correction with respect to those predicted at the MP2 level. The calculations described herein have shown that the CCSD(T) CBS limits yield binding energies with a range of −0.89 to −4.38 kcal/mol for the halogen‐bonded complexes under study. The performance of several density functional theory (DFT) methods has been evaluated comparing the results with those obtained from MP2 and CCSD(T). It is shown that PBEKCIS, B97‐1, and MPWLYP functionals provide accuracies close to the computationally very expensive ab initio methods. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
QM/QM docking method based on the variational finite localized molecular orbital approximation
Authors: Anisimov Victor M. , Bugaenko Vladislav L.
Published: August 2008

We present a derivation of the semiempirical variational finite localized molecular orbital (VFL) approximation, which was introduced by Anikin et al. (J Chem Phys 2004, 121, 1266). On the basis of VFL approximation, we developed the novel semiempirical (quantum mechanical) QM/QM method in which a part of the system, including the ligand and protein active site, are treated self‐consistently, while the protein bulk is considered as carrying a frozen electronic density matrix. The developed method is applied toward the QM docking study for the p56 LCK SH2 domain. The virtual search has predicted 10 most potent inhibitors by searching through the database of 200,000 empirically docked poses of 20,000 drug‐like molecules. Energy score calculation of each complex roughly consisting of 1700 atoms took 14.54 s of single‐CPU time at the NDDO AM1 level. The entire computation performed on a 32‐CPU cluster would be accomplished in 1 day. Flexible ligand QM docking studies, performed on a subset of 10,000 poses, required 153.03 s of single‐CPU time per complex. The entire calculation performed on the 32‐CPU cluster would be finished in half‐day. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
Parallel Fock matrix construction program for molecular orbital calculation—Specific computer with a hierarchical network
Authors: Umeda Hiroaki , Inadomi Yuichi , Honda Hiroaki , Nagashima Umpei
Published: August 2008

A parallel Fock matrix construction program for a hierarchical network has been developed on the molecular orbital calculation‐specific EHPC system. To obtain high parallelization efficiency on the hierarchical network system, a multilevel dynamic load‐balancing scheme was adopted, which provides equal load balance and localization of communications on a tree‐structured hierarchical network. The parallelized Fock matrix construction routine was implemented into a GAMESS program on the EHPC system, which has a tree‐structured hierarchical network. Benchmark results on a 63‐processor system showed high parallelization efficiency even on the tree‐structured hierarchical network. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
Lactic acid fermentation of food waste using integrated glucoamylase production
Authors: Wang Xiao Qiang , Wang Qun Hui , Zhi Ma Hong , Yin Wei
Published: August 2008

Commercial enzyme is usually needed for the bioconversion of organic waste or biomass. The overall cost could be reduced very significantly if enzyme production could be integrated with its application, avoiding unnecessary steps in enzyme production (such as concentration, recovery and transportation). This investigation attempted to integrate crude glucoamylase production with lactic acid fermentation of food waste. A maximum glucoamylase activity of 1850 U g−1 was obtained with Aspergillus nigerduring solid‐state fermentation (SSF) of food waste, 14.8 times more than that obtained during submerged fermentation (SmF). The optimum pH for producing glucoamylase was 4.6, and glucoamylase retained 83.5% of peak activity at pH 3.0. Without any recovery treatment, the glucoamylase produced by SSF could be used directly for lactic acid fermentation of food waste. Lactic acid concentration reached 45.5 g L−1 with the addition of the crude enzyme, 72% higher than the control. No side‐effects were caused by the viable A. niger in the crude enzyme. This work successfully integrated glucoamylase production with lactic acid fermentation. The enzyme produced by SSF of food waste had sufficient activity to be used directly without any treatment. The integrated process proposed in this study was very economical and may be helpful to other bioconversions. Copyright © 2008 Society of Chemical Industry
Influence of carbohydrates on stability of papain in aqueous tetrahydrofuran mixture
Authors: Szabó András , Kotormán Márta , Laczkó Ilona , Simon L Mária
Published: August 2008

BACKGROUND: The use of enzymes in organic solvents has extended the scale of their practical applications. Papain has been widely used in chemical syntheses because of its broad substrate specificity. The aim of the present study was to improve the stability of papain in aqueous tetrahydrofuran (THF) by using different saccharides. The effects of these carbohydrates on the structure of papain were followed by means of circular dichroism (CD) and fluorescence spectroscopic measurements.

RESULTS: In contrast with most organic solvents, 60% (i.e. 600 mL L−1) THF practically inactivated the enzyme within 30 min. Sugars protected papain from THF‐induced inactivation in the sequence D‐ribose > D‐fructose > D‐glucose > D‐saccharose > D‐raffinose. Ribose at 1.6 mol L−1 proved the most effective stabiliser: in 60% THF in the presence of ribose, papain preserved about 55% of its initial activity after 2 h. Fluorescence and near‐UV CD spectroscopic measurements revealed local changes in the papain conformation. With decrease in the free amino group content of the enzyme, protein‐carbohydrate interactions (Schiff base formation) were detected.

CONCLUSION: These results demonstrate that the catalytic activity and stability of papain may be increased in aqueous THF by using different carbohydrates, when a more compact structure of the enzyme is formed. Copyright © 2008 Society of Chemical Industry
Dehydrogenation of 11α‐hydroxy‐16α, 17‐epoxyprogesterone by encapsulated Arthrobacter simplex cells in an aqueous/organic solvent two‐liquid‐phase system
Authors: Li Jiu‐Hong , Guan Yi‐Xin , Wang Hai‐Qing , Yao Shan‐Jing
Published: August 2008

BACKGROUND: Arthrobacter simplex cells immobilised in sodium cellulose sulfate/poly‐dimethyl‐diallyl‐ammonium chloride microcapsules were used for the microbial dehydrogenation of 11α‐hydroxy‐16α,17‐epoxyprogesterone to 11α‐hydroxy‐16α,17α‐epoxypregn‐1,4‐diene‐3,20‐dione in an aqueous/organic solvent two‐liquid‐phase system, which is a key reaction in the production of glucocorticoid pharmaceuticals. The aim of the study was to establish a suitable aqueous/organic solvent two‐liquid‐phase system for performing semi‐continuous production in an airlift loop reactor by encapsulated A. simplex cells with the addition of suitable surfactants to achieve a higher yield of the product.

RESULTS: n‐Hexane was selected as the most suitable organic solvent. In optimised Tween‐80 emulsion feed mode the conversion in the airlift loop reactor was as high as 97.54% when the time of reaction was 2 h, and the reaction time was greatly shortened. In semi‐continuous production the cultivation with immobilised cells was carried out for five batches in total. The conversion in each batch was above 95% and the enzymatic activity still remained quite high after five batches of biotransformation.

CONCLUSION: The results showed that performing the conversion by this method shortened the reaction time and increased the productivity, thus demonstrating the great potential of the method for the dehydrogenation of 11α‐hydroxy‐16α,17‐epoxyprogesterone. Copyright © 2008 Society of Chemical Industry
Angle‐distance image matching techniques for protein structure comparison
Authors: Chu Chia‐Han , Tang Chuan Yi , Tang Cheng‐Yin , Pai Tun‐Wen
Published: August 2008

Proteins that contain similar structural elements often have analogous functions regardless of the degree of sequence similarity or structure connectivity in space. In general, protein structure comparison (PSC) provides a straightforward methodology for biologists to determine critical aspects of structure and function. Here, we developed a novel PSC technique based on angle‐distance image (A‐D image) transformation and matching, which is independent of sequence similarity and connectivity of secondary structure elements (SSEs). An A‐D image is constructed by utilizing protein secondary structure information. According to various types of SSEs, the mutual SSE pairs of the query protein are classified into three different types of sub‐images. Subsequently, corresponding sub‐images between query and target protein structures are compared using modified cross‐correlation approaches to identify the similarity of various patterns. Structural relationships among proteins are displayed by hierarchical clustering trees, which facilitate the establishment of the evolutionary relationships between structure and function of various proteins.

Four standard testing datasets and one newly created dataset were used to evaluate the proposed method. The results demonstrate that proteins from these five datasets can be categorized in conformity with their spatial distribution of SSEs. Moreover, for proteins with low sequence identity that share high structure similarity, the proposed algorithms are an efficient and effective method for structural comparison. Copyright © 2008 John Wiley & Sons, Ltd.
Extracting statistical moments of output quantities from a small number of time‐domain simulations
Authors: de Menezes Leonardo , Ajayi Ajibola , Christopoulos Christos , Sewell Phillip , Borges Geovany A.
Published: August 2008

This work investigates the behavior of the time‐ and frequency‐domain approximations used in the combination of transmission line modeling (TLM) and the unscented transform (UT). The analysis of the accuracy of the approximation indicates that higher‐order schemes may be used as an indicator of the accuracy of the time‐domain results of the second‐order approximation. However, the frequency‐domain counterpart shows that the second‐order approximation is sufficiently accurate in the low‐frequency range. The UT+TLM technique is expanded for the estimation of the probability density function and two independent random variables. The UT+TLM combination is validated in both time and frequency domains using a 2D TLM program. The results are verified by comparison with Monte Carlo solutions. Copyright © 2008 John Wiley & Sons, Ltd.
Mixed‐mode analysis of the sensitivity of a radiofrequency oscillator disturbed by parasitic signals
Authors: Gontrand Christian , Bouhouche Manel , Nuñez Perez José‐Cruz , Valorge Olivier , Calmon Francis , Verdier Jacques , Latreche Saïda
Published: August 2008

The first step of this work is to study the susceptibility of a radiofrequency oscillator to deterministic disturbance sources.

A Colpitts oscillator, working around a 4 GHz frequency, contains a heterojunction bipolar transistor with a silicon–germanium base as an active device. A mixed‐mode analysis is involved, applying a microscopic drift diffusion model to the device, whereas the rest of the circuit used is governed by Kirchhoff's laws.

We assume that this tool is very relevant to grasp the influence of intrinsic or extrinsic noisy sources of the oscillator. Our first simulation raw results motivate us to discuss, and perhaps extend, via some analytical models, the so‐called impulse sensitivity function model.

In this paper, we try to develop quantitative predictions about the phase noise of such oscillators, and to give some new tracks on this field. Copyright © 2008 John Wiley & Sons, Ltd.
Revisiting the maximum intensity of recurving tropical cyclones
Authors: Knaff John A.
Published: August 2008

Previous studies have indicated that recurving western North Pacific tropical cyclones, initially westward moving tropical cyclones that turn toward the east, often reach their maximum intensity close to the time of recurvature. Those results have often been cited in the literature and sometimes inferred to be valid in other tropical cyclone basins. This study revisits this topic in the western North Pacific, North Atlantic and Southern Hemisphere tropical cyclone basins. The timing of lifetime maximum intensity associated with recurving tropical cyclones is examined using best track datasets from the United States' Joint Typhoon Warning Center and the National Hurricane Center, Miami during the period 1980–2006. Results reveal that tropical cyclones are less likely to experience peak intensity within ± 12 h and ± 24 h of recurvature than has been previously reported in the western North Pacific. Furthermore, it is shown that tropical cyclones that become most intense (i.e. intensities greater than 52 m s−1) have a greater tendency to reach peak intensity before recurvature than weaker storms save for in the South Pacific where the most intense storms have a slightly greater probability of reaching their maximum intensity following recurvature. It also appears that weak tropical cyclones (i.e. lifetime peak intensities less than 33 m s−1) often reach peak intensity prior to or close to recurvature in all tropical cyclone basins as others have reported. However, findings suggest that the cumulative distributions of maximum intensity with respect to the time of recurvature can be quite different for other intensity ranges suggesting that a universal relationship between peak intensity and time of recurvature does not exist. Copyright © 2008 Royal Meteorological Society
Ages and inferred causes of Late Pleistocene glaciations on Mauna Kea, Hawai'i
Authors: Pigati Jeffrey S. , Zreda Marek , Zweck Chris , Almasi Peter F. , Elmore David , Sharp Warren D.
Published: August 2008

Glacial landforms on Mauna Kea, Hawai'i, show that the summit area of the volcano was covered intermittently by ice caps during the Late Pleistocene. Cosmogenic 36Cl dating of terminal moraines and other glacial landforms indicates that the last two ice caps, called Older Makanaka and Younger Makanaka, retreated from their maximum positions approximately 23 ka and 13 ka, respectively. The margins and equilibrium line altitudes of these ice caps on the remote, tropical Pacific island were nearly identical, which would seem to imply the same mechanism for ice growth. But modelling of glacier mass balance, combined with palaeotemperature proxy data from the subtropical North Pacific, suggests that the causes of the two glacial expansions may have been different. Older Makanaka air atop Mauna Kea was likely wetter than today and cold, whereas Younger Makanaka times were slightly warmer but significantly wetter than the previous glaciation. The modelled increase in precipitation rates atop Mauna Kea during the Late Pleistocene is consistent with that near sea level inferred from pollen data, which suggests that the additional precipitation was due to more frequent and/or intense tropical storms associated with eastward‐moving cold fronts. These conditions were similar to modern La Niña (weak ENSO) conditions, but persisted for millennia rather than years. Increased precipitation rates and the resulting steeper temperature lapse rates created glacial conditions atop Mauna Kea in the absence of sufficient cooling at sea level, suggesting that if similar correlations existed elsewhere in the tropics, the precipitation‐dependent lapse rates could reconcile the apparent difference between glacial‐time cooling of the tropics at low and high altitudes. Copyright © 2008 John Wiley & Sons, Ltd.
Late Pleistocene mountain glaciation in Alaska: key chronologies
Authors: Briner Jason P. , Kaufman Darrell S.
Published: August 2008

Moraine sequences of mountain glaciers can be used to infer spatial and temporal patterns of climate change across the globe. Alaska is an accessible high‐latitude location in the Northern Hemisphere and contains a rich record of alpine glaciation. Here, we highlight the key chronologies from three mountain ranges in Alaska that reveal the timing and spatial extent of Late Pleistocene glaciation, and pay particular attention to age of the penultimate glaciation. The most extensive glacier advance of the last glaciation occurred prior to the last global glacial maximum. Cosmogenic exposure ages from moraine boulders in three sites spanning 800 km indicate that this penultimate advance most likely culminated during marine isotope stage (MIS) 4 or early MIS 3. During MIS 2, more limited glacier expansion generated multiple moraines that span from prior to the global Last Glacial Maximum (LGM) through the Lateglacial period. Glaciers retreated from their terminal positions ca. 27–25 ka in arctic Alaska and ca. 22–19 ka in southern Alaska. Moraines in at least two ranges date to 12–11 ka, indicating a glacial advance during the Younger Dryas period. Reconstructed equilibrium‐line altitudes of both penultimate and MIS 2 glaciers were lowered only 300–600 m – much less than elsewhere in the Americas. Alaska is documented to have been more arid during MIS 2, perhaps due in large part to the exposure of the Bering–Chukchi platform during eustatic sea‐level lowering. The restricted ice extent is also consistent with the output of climate models that simulate a lack of significant summer cooling. Copyright © 2008 John Wiley & Sons, Ltd.
Chronology of the last glacial cycle in the European Alps
Authors: Ivy‐Ochs Susan , Kerschner Hanns , Reuther Anne , Preusser Frank , Heine Klaus , Maisch Max , Kubik Peter W. , Schlüchter Christian
Published: August 2008

Chronological data for glacier advances in the European Alps between the Last Interglacial (Eemian) and the Holocene are summarised (115 to 11 ka). During this time glaciers were most extensive, extending tens of kilometres out onto the forelands, between 30 and 18 ka, that is, synchronous with the global ice volume maximum of Marine Isotope Stage (MIS) 2. Evidence for ice expanding to just past the mountain front for an earlier major glacier advance comes from Swiss sites, where advances have been luminescence dated to MIS 5d (100 ka) and MIS 4 (70 ka). Up to now no such evidence has been found in the Eastern Alps. By 18 ka, more than 80% of the Late Würmian ice volume had gone. Subsequently glaciers readvanced, reaching into the upper reaches of the main valleys during the Lateglacial Gschnitz stadial, which likely occurred around 17 ka, with final moraine stabilisation no later than 15.4 ka. The link of the Egesen stadial with the Younger Dryas climate deterioration is supported by exposure ages from four sites as well as minimum‐limiting radiocarbon dates from bogs within former glacier tongue areas. Key questions on the spatial and temporal variability of ice extents throughout the last glacial cycle have yet to be answered. Copyright © 2008 John Wiley & Sons, Ltd.
Quaternary glaciation of the Himalayan–Tibetan orogen
Authors: Owen Lewis A. , Caffee Marc W. , Finkel Robert C. , Seong Yeong Bae
Published: August 2008

Glacial geological evidence from throughout the Himalayan–Tibetan orogen is examined to determine the timing and extent of late Quaternary glaciation in this region and its relation to similar changes on a global scale. The evidence summarised here supports the existence of expanded ice caps and extensive valley glacier systems throughout the region during the late Quaternary. However, it cannot yet be determined whether the timing of the extent of maximum glaciation was synchronous throughout the entire region or whether the response was more varied. The lack of organic material needed for radiocarbon dating has hindered past progress in glacial reconstruction; however, application of optically stimulated luminescence and terrestrial cosmogenic radionuclide methods has recently expanded the number of chronologies throughout the region. Limits to the precision and accuracy available with these methods and, more importantly, geological uncertainty imposed by processes of moraine formation and alteration both conspire to limit the time resolution on which correlations can be made to Milankovitch timescales (several ka). In order to put all studies on a common scale, well‐dated sites have been re‐evaluated and all the published terrestrial cosmogenic nuclide ages for moraine boulders and glacially eroded surfaces in the Himalayan–Tibetan orogen have been recalculated. Locally detailed studies indicate that there are considerable variations in the extent of glaciation from one region to the next during a glaciation. Glaciers throughout monsoon‐influenced Tibet, the Himalaya and the Transhimalaya are likely synchronous both with climate change resulting from oscillations in the South Asian monsoon and with Northern Hemisphere cooling cycles. In contrast, glaciers in Pamir in the far western regions of the Himalayan–Tibet orogen advanced asynchronously relative to the other regions that are monsoon‐influenced regions and appear to be mainly in phase with the Northern Hemisphere cooling cycles. Broad patterns of local and regional variability based on equilibrium‐line altitudes have yet to be fully assessed, but have the potential to help define changes in climatic gradients over time. Copyright © 2008 John Wiley & Sons, Ltd.
The timing and magnitude of mountain glaciation in the tropical Andes
Authors: Smith Jacqueline A. , Mark Bryan G. , Rodbell Donald T.
Published: August 2008

The Andes of Ecuador, Peru and Bolivia host the majority of the world's tropical glaciers. In the tropical Andes, glaciers accumulate during the wet season (austral summer) and ablate year‐round. Precipitation is delivered mainly by easterlies, and decreases both N–S and E–W. Chronological control for the timing of glacial advances in the tropical Andes varies. In Ecuador, six to seven advances have been identified; dating is based on radiocarbon ages. Timing of the local Last Glacial Maximum (LGM) and the existence of Younger Dryas advances remain controversial. In Peru, local variability in glaciation patterns is apparent. Surface exposure dating in the Cordillera Blanca and Junin Plain suggests that the local LGM may have been early (∼30 ka), although uncertainties in age calculations remain; the local LGM was followed by a Lateglacial readvance/stillstand and preceded by larger glaciations. In contrast, preliminary data from an intervening massif indicate that the largest moraines are Lateglacial. Chronologies from Bolivia also suggest local variability. In leeward Milluni and San Francisco Valleys, local LGM moraines descend to ∼4300 m above sea level (a.s.l.), whereas in windward Zongo Valley Lateglacial moraines reach ∼3400 m a.s.l. Atlantic and Pacific sea surface temperatures, El Niño–Southern Oscillation and insolation changes all likely play roles in mediating tropical Andean glacial cycles. Copyright © 2008 John Wiley & Sons, Ltd.
Timing and nature of late Quaternary mountain glaciation
Authors: Thackray Glenn D. , Owen Lewis A. , Yi Chaolu
Published: August 2008

Compilations of regional‐ to subcontinental‐scale mountain glacier chronologies from five continents, plus Hawaii, examine the temporal and spatial patterns of mountain glaciation. The compilations yield key insights into the nature of past fluctuations in temperature and precipitation in mountains and adjacent regions, and provide baseline data for examining the dynamics of glacier responses to climate change. Key insights from these compilations include the wide variability of glacier responses to fluctuations in insolation, temperature and precipitation and the regionally specific variations in climatic variables through late Quaternary time. The compilations highlight the need to improve the density and quality of geochronological data and to enhance the understanding of the links between climate and glaciation. Copyright © 2008 John Wiley & Sons, Ltd.
Experimental and theoretical study of the structure and vibrational spectra of valpromide, C7H15CONH2
Authors: Comelli Nieves C. , Massa Nestor E. , Castro Eduardo A. , Blanch Luis Bruno , Jubert Alicia H.
Published: August 2008

In this work, we present results of the conformational and vibrational properties of valpromide (Vpd), an amide with antiepileptic activity, studied by IR and Raman spectroscopy at 300 and 77 K, and 300 K, respectively. Experimental data are compared against ab initio calculations performed at B3LYP level with the inclusion of solvatation effects.

Experimental results, reinforced by theoretical calculations, point out that Vpd has three conformers on the potential energy surface, with different structures that can be identified in the CO and NH spectral regions. These conformers are defined by different angular arrays of the dihedral angles formed with the CO, CN and C〈H, CC of the aliphatic chain bonds.

The existence of different conformations and structures are discussed on the basis of results derived from electronic localization function (ELF) and natural orbital bond (NBO) analysis. Copyright © 2008 John Wiley & Sons, Ltd.
Large‐scale submerged fermentation of Antrodia cinnamomea for anti‐hepatoma activity
Authors: Pan Jih‐Hung , Chen Yi‐Song , Sheen Lee‐Yen , Chiang Been‐Huang
Published: August 2008

BACKGROUND: Submerged cultivation of Antrodia cinnamomea was carried out for manufacturing the fermentation product with anti‐hepatoma activity. The fermentation process was optimized for different parameters at shake flask level to obtain products with high inhibition potency against Hep G2 hepatoma cells. Scale‐up of the fermentation process was then achieved from 250 mL shake flask to 5 L, 500 L and 5‐ton fermenters.

RESULTS: Glucose and malt extract were found to be the best carbon and nitrogen sources, respectively. The initial pH of 5.0 and an operating temperature of 22 °C were the best for a product with lowest IC50 value. A shorter cultivation time was required when the scale of fermentation increased from 5 L to 5 tons. The reducing sugar and solids contents of the broth filtrate were correlated exponentially with the IC50 of the ethanolic extract of mycelium for hepatoma cells, and the level of ergosterol in the mycelium extract follows the same profile as the increase in Hep G2 cells inhibition.

CONCLUSION: When Antrodia cinnamomea is cultured in a 5‐ton fermenter, 4 weeks are required for the fermentation product to reach the highest anti‐hepatoma activity. The solid and reducing sugar contents of the broth filtrate as well as the ergosterol content in the ethanol extract of mycelium can serve as the marker during fermentation for manufacturing product with anti‐hepatoma activity. Copyright © 2008 Society of Chemical Industry
Application of a trigonometric approach to the regionalization of precipitation for a complex small‐scale terrain in a GIS environment
Authors: Franke Johannes , Häntzschel Janet , Goldberg Valeri , Bernhofer Christian
Published: August 2008

To regionalize precipitation on a small‐scale, complex, low mountain range terrain, trigonometric relationships were constructed in a geographical information system (GIS) environment using a digital elevation model (DEM). The large‐scale orographic effect and small‐scale windward and leeward effects on precipitation were recorded and quantified using a grid‐based combination of a terrain vector (slope angle, aspect) with a wind vector (wind direction, speed). This was based on the parameterization of a longer‐term wind‐precipitation distribution. Both effects were mapped for the meso‐scale Weißeritz River catchment in the Ore Mountains of Germany, using an estimate of spatially distributed slope precipitation. It was shown that the small‐scale windward and leeward effects modify the larger‐scale orographic effect spatially. It was determined that both the amount and the phase of the small‐scale windward and leeward effect correlates with the height above sea level. During the 1971–2003 growing seasons the amount of precipitation increased by 4% per 100 m, and for the 1971–2000 statistically heavy precipitation (SHP) (duration: 24 h, return period: 100 years) the increase was 1% per 100 m. The phase shift occurred because the main wind veered south‐west to west to north‐west with elevation increase, and it was more pronounced for mean than for heavy precipitation. Spatial slope precipitation was estimated to be within the 390–715 mm range for mean adjusted precipitation and 100–140 mm for SHP. The maximum of the windward and leeward effect on precipitation amounts to ± 25% of fallen precipitation. Copyright © 2008 Royal Meteorological Society
Clinical outcomes from a physiotherapist‐led intra‐articular hyaluronic acid injection clinic
Authors: Birchall Dolina , Ismail A. Mobeen , Peat George
Published: August 2008

Objectives: To describe the clinical course of knee osteoarthritis following a single course of intra‐articular hyaluronic acid (HA) injection clinic, and specifically to explore treatment withdrawal.

Design: Prospective consecutive case series with follow‐up, set in an innovative physiotherapist‐led clinic, based in a hospital orthopaedic surgery department.

Participants: A total of 100 patients with knee osteoarthritis referred to the clinic received a single course of five injections of Hyalgan®. Patients were followed up in clinic at five, 13, 26 and 52 weeks. The primary outcome measures were Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) Likert 3.0 pain (0–20) and physical function (0–68) scores. In addition, at 13 and 26 weeks, patients were reviewed independently by an orthopaedic surgeon, with the option of withdrawing for alternative management those patients who had not responded.

Results: Ninety (90%) patients were successfully followed to study endpoint. Improvements were seen at five weeks and, to a lesser extent, at 13 weeks (mean reduction in WOMAC pain at 13 weeks = 1.3; 95% confidence interval [CI] 0.5, 2.0; mean reduction in WOMAC Physical Function at 13 weeks = 5.6; 95% CI 3.0, 8.1). Of 34 treatment withdrawals, most had returned to baseline levels by 13 weeks. The remaining 56 patients maintained improvements up to 52 weeks, although the pattern of outcome was highly variable between individuals. Withdrawals and non‐responders had higher initial pain severity.

Conclusions: Physiotherapist‐led intra‐articular HA clinics are feasible. Clinical outcomes for individual patients are highly heterogeneous up to one year after injections. Patients with initially high levels of pain may be less likely to benefit. Copyright © 2008 John Wiley & Sons, Ltd.
Anxiety disorders: a comprehensive review of pharmacotherapies
Authors: Hoffman Ellen J. , Mathew Sanjay J.
Published: August 2008

This article reviews the evidence from randomized, placebo‐controlled trials and meta‐analyses of pharmacological treatments of the following anxiety disorders: generalized anxiety disorder, panic disorder, social anxiety disorder, and post–traumatic stress disorder. There is evidence from multiple randomized, placebo‐controlled trials to support the use of selective serotonin reuptake inhibitors as first‐line pharmacotherapy in these disorders, and a number of the selective serotonin reuptake inhibitors have received US Food and Drug Administration approval for these indications. Serotonin‐norepinephrine reuptake inhibitors are now emerging as first‐line treatments for these anxiety disorders alongside the selective serotonin reuptake inhibitors and have been US Food and Drug Administration–approved for some of these indications as well. Benzodiazepines are also effective treatments for anxiety disorders, and although this medication class has the advantage of a rapid onset of action, their use is limited by their potential for abuse and lack of antidepressant properties. In addition to reviewing the clinical trials that have investigated the anxiolytic effects of these commonly used medications, we review the evidence for novel uses of other agents, including anticonvulsants and atypical antipsychotics, in anxiety disorders. Mt Sinai J Med 75:247–262, 2008. © 2008 Mount Sinai School of Medicine
Major depression: emerging therapeutics
Authors: Sen Srijan , Sanacora Gerard
Published: August 2008

The first effective antidepressants, monoamine oxidase inhibitors and tricyclic antidepressants, were identified 50 years ago, largely through serendipity. These medications were found to improve mood in a little more than half of depressed patients after a few weeks of chronic use. Almost all antidepressants prescribed today were developed through minor modifications of these original antidepressants and, like monoamine oxidase inhibitors and tricyclic antidepressants, act primarily through monoaminergic mechanisms. Although there have been improvements in side‐effect profiles and overdose toxicity, these newer medications have not provided substantial advances in the efficacy and speed of the antidepressant effect for patients. Over the last 2 decades, our understanding of the neurobiology underlying depression has expanded exponentially. Given this expansion, we may be nearing an inflection point in antidepressant drug development, at which useful medicines will be designed through a rational understanding of the biological systems. In this review, we discuss the biological basis and preclinical and clinical evidence for a series of promising classes of antidepressants developed primarily out of a pathophysiologically informed approach. Mt Sinai J Med 75:203–224, 2008. © 2008 Mount Sinai School of Medicine
Neurostimulatory therapeutics in management of treatment‐resistant depression with focus on deep brain stimulation
Authors: Dumitriu Dani , Collins Kate , Alterman Ron , Mathew Sanjay J.
Published: August 2008

Treatment‐resistant depression continues to pose a major medical challenge, as up to one‐third of patients with major depressive disorder fail to have an adequate response to standard pharmacotherapies. An improved understanding of the complex circuitry underlying depressive disorders has fostered an explosion in the development of new, nonpharmacological approaches. Each of these treatments seeks to restore normal brain activity via electrical or magnetic stimulation. In this article, the authors discuss the ongoing evolution of neurostimulatory treatments for treatment‐resistant depression, reviewing the methods, efficacy, and current research on electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, focal electrically administered stimulated seizure therapy, transcranial direct current stimulation, chronic epidural cortical stimulation, and vagus nerve stimulation. Special attention is given to deep brain stimulation, the most focally targeted approach. The history, purported mechanisms of action, and current research are outlined in detail. Although deep brain stimulation is the most invasive of the neurostimulatory treatments developed to date, it may hold significant promise in alleviating symptoms and improving the quality of life for patients with the most severe and disabling mood disorders. Mt Sinai J Med 75:263–275, 2008. © 2008 Mount Sinai School of Medicine
Type 1 diabetes mellitus: primary, secondary, and tertiary prevention
Authors: Bollyky Jennifer , Sanda Srinath , Greenbaum Carla J.
Published: August 2008

We have entered the era of clinical trials to prevent type 1 diabetes mellitus (T1DM). Before 1922, when insulin was first given to a patient with diabetes, a diagnosis of T1DM was considered a death sentence. Advances in treatment for subjects with diabetes are not yet sufficient to prevent the deleterious impact of diabetes on both day‐to‐day activities and the early morbidity and mortality still associated with the disease. We now understand a great deal about blood glucose regulation and potential health complications associated with long‐term T1DM, but the mystery of why, or the pathogenesis of this devastating disease, remains elusive. Great strides toward unraveling this mystery have been made over the past several decades. Even without definitive answers, we are moving from the period of discovery and animal research to the era of clinical trials. In this review, we wish to convey the palpable excitement in the field. It is time to determine if we can safely change the course of T1DM. Mt Sinai J Med 75:385–397, 2008. © 2008 Mount Sinai School of Medicine
Toward a cell‐based cure for diabetes: advances in production and transplant of beta cells
Authors: Claiborn Kathryn C. , Stoffers Doris A.
Published: August 2008

Type 1 diabetes results from autoimmune destruction of the insulin‐producing beta cells of the pancreatic islets of Langerhans. Although developments in exogenous insulin therapy have greatly improved clinical outcomes in patients with diabetes, the ability of the pancreatic beta cell to exquisitely regulate the delivery of insulin and maintain normal levels of blood glucose is still far superior to what can be achieved by external delivery of insulin. As a result, the majority of patients with type 1 diabetes still experience the complications of chronic hyperglycemia or serious and potentially life‐threatening hypoglycemia. The shortcomings of medical therapy have driven research toward more direct approaches of beta cell replacement. Indeed, the specificity of beta cell loss in type 1 diabetes makes this disease a particularly attractive candidate for cell‐based therapies. In order for significant progress to be made, however, a thorough understanding of beta cell biology and more broadly islet biology is necessary. This review addresses recent advances in developmental biology that have expanded our understanding of islet cell differentiation, assesses the promise and limitations of islet transplantation, and discusses the future of alternative sources of beta cells, including directed differentiation of stem cells, replication of adult beta cells, and transdifferentiation of nonislet cells to a beta cell fate. Mt Sinai J Med 75:362–371, 2008. © 2008 Mount Sinai School of Medicine
Dynamic capacity reservation and due date quoting in a make‐to‐order system
Authors: Pibernik Richard , Yadav Prashant
Published: August 2008

We consider a make‐to‐order manufacturer facing random demand from two classes of customers. We develop an integrated model for reserving capacity in anticipation of future order arrivals from high priority customers and setting due dates for incoming orders. Our research exhibits two distinct features: (1) we explicitly model the manufacturer's uncertainty about the customers' due date preferences for future orders; and (2) we utilize a service level measure for reserving capacity rather than estimating short and long term implications of due date quoting with a penalty cost function.

We identify an interesting effect (“t‐pooling”) that arises when the (partial) knowledge of customer due date preferences is utilized in making capacity reservation and order allocation decisions. We characterize the relationship between the customer due date preferences and the required reservation quantities and show that not considering the t‐pooling effect (as done in traditional capacity and inventory rationing literature) leads to excessive capacity reservations. Numerical analyses are conducted to investigate the behavior and performance of our capacity reservation and due date quoting approach in a dynamic setting with multiple planning horizons and roll‐overs. One interesting and seemingly counterintuitive finding of our analyses is that under certain conditions reserving capacity for high priority customers not only improves high priority fulfillment, but also increases the overall system fill rate. © 2008 Wiley Periodicals, Inc. Naval Research Logistics, 2008
An optimal critical level policy for inventory systems with two demand classes
Authors: Möllering Karin T. , Thonemann Ulrich W.
Published: August 2008

Traditional inventory systems treat all demands of a given item equally. This approach is optimal if the penalty costs of all customers are the same, but it is not optimal if the penalty costs are different for different customer classes. Then, demands of customers with high penalty costs must be filled before demands of customers with low penalty costs. A commonly used inventory policy for dealing with demands with different penalty costs is the critical level inventory policy. Under this policy demands with low penalty costs are filled as long as inventory is above a certain critical level. If the inventory reaches the critical level, only demands with high penalty costs are filled and demands with low penalty costs are backordered. In this article, we consider a critical level policy for a periodic review inventory system with two demand classes. Because traditional approaches cannot be used to find the optimal parameters of the policy, we use a multidimensional Markov chain to model the inventory system. We use a sample path approach to prove several properties of this inventory system. Although the cost function is not convex, we can build on these properties to develop an optimization approach that finds the optimal solution. We also present some numerical results. © 2008 Wiley Periodicals, Inc. Naval Research Logistics, 2008