bluuebunny/crossref_metadata_2025 huggingface dataset:
A thermal dissociation–chemical ionization mass spectrometry (TD‐CIMS) technique for the simultaneous measurement of peroxyacyl nitrates and dinitrogen pentoxide
Authors: Slusher Darlene L. , Huey L. Gregory , Tanner David J. , Flocke Frank M. , Roberts James M.
Published: October 2004

We have developed a thermal dissociation–chemical ionization mass spectrometry (TD‐CIMS) technique for fast measurements of a series of peroxyacyl nitrates and dinitrogen pentoxide. Thermally generated acylperoxy radicals react with I− to produce a carboxylate ion that is unique for each parent species. NO3 resulting from the decomposition of N2O5 reacts with I− to form NO3−. The measurement technique was verified for PAN and PPN during an informal comparison with a gas chromatograph (GC) equipped with an electron capture detector (ECD) in Boulder, Colorado, during October 2002. Good agreement was obtained between the two instruments with R2 = 0.91 for PAN (n = 657) and R2 = 0.89 for PPN (n = 655). Detection limits of 7 pptv and 4 pptv were determined for PAN and PPN, respectively, for a 1 s integration period and a signal‐to‐noise ratio of 3. The TD‐CIMS simultaneously detected ambient PiBN and N2O5 + NO3 in addition to PAN and PPN during the intercomparison period. We estimate a detection limit of 3 pptv in 1 s for PiBN. PnBN would be detected at the same mass, so we cannot rule out a contribution from PnBN to our PiBN estimate. Sensitivity to MPAN was found to be lower than to PAN in laboratory experiments, but a detection limit of 10 pptv can still be achieved by integrating for 15 s. Assuming the same sensitivity as for PAN, the detection limit for the sum of N2O5 and NO3 was estimated to be 12 pptv in 1 s. The fast time response of the TD‐CIMS combined with a sensitivity and limit of detection comparable to the GC/ECD make this a promising technique for PAN flux measurements by eddy covariance. PAN uptake by different types of vegetation could be important input for global and regional ozone models, and PAN deposition to snow is of interest in polar regions.
Photochemistry of ozone over the western Pacific from winter to spring
Authors: Kondo Y. , Nakamura K. , Chen G. , Takegawa N. , Koike M. , Miyazaki Y. , Kita K. , Crawford J. , Ko M. , Blake D. R. , Kawakami S. , Shirai T. , Liley B. , Wang Y. , Ogawa T.
Published: October 2004

Aircraft measurements of ozone (O3) and its precursors, including NO, CO, H2O, and nonmethane hydrocarbons (NMHCs), were made over the western Pacific in the 20°– 45°N latitude range in January and April–May 2002 during the Pacific Exploration of Asian Continental Emission (PEACE)‐A and B campaigns. These measurements have provided data sets that, in combination with Transport and Chemical Evolution over the Pacific (TRACE‐P) data taken in March 2001, enable studies of O3 photochemistry from winter to late spring. A photochemical box model is used to calculate ozone formation (F(O3)) and destruction (D(O3)) rates constrained by the observed species concentrations. The values of F(O3) and D(O3) are controlled directly by NO, J(O1D) (O3 photolysis frequency), H2O, OH, and HO2. Changes in HO2 concentration cause corresponding changes in both F(O3) and D(O3), leading to their coupling. Concentrations of these species, which are strongly influenced by photochemistry and transport from the Asian continent, underwent large seasonal variations. In the boundary layer (0–3 km), NO was much higher in January than in April–May, because of stronger winds, lower convective activities, and lower oxidation rates by OH in winter. The net O3 formation rate, given by P(O3) = F(O3) − D(O3), was largely positive in the boundary layer at 30°–45°N (1.5 − 4 ppbv d−1) in January, mainly because of high NO and low H2O values. Net O3 formation continued from January to the end of March, demonstrating that the western Pacific is an important O3 source region during this season. Net O3 formation nearly ceased by late April/May because of the decrease in NO and the increase in H2O. In the latitude range of 20°–30°N, P(O3) in the boundary layer was positive in January and turned negative by March. The earlier transition was mainly due to lower NO and higher H2O concentrations, combined with weaker transport and higher temperatures than those at 30°–45°N. The upper troposphere (6–12 km) has been shown to be a region of net O3 formation throughout most of the year because of high NO and low H2O. The present study illustrates that a decrease in the net O3 formation rate at 20°–45°N latitude from winter to late spring is explained systematically by the increases in J(O1D), H2O, OH, and HO2 (primarily due to increases in temperature and solar radiation) and the decrease in NO (primarily due to decrease in transport from the Asian continent). Differences in the seasonal variation of O3 photochemistry observed over the North American continent are interpreted in terms of the differences in factors controlling O3 formation and destruction.
Shape control through molecular segregation in giant surfactant aggregates
Authors: Dubois Monique , Lizunov Vladimir , Meister Annette , Gulik-Krzywicki Thadeus , Verbavatz Jean Marc , Perez Emile , Zimmerberg Joshua , Zemb Thomas
Published: October 2004

Mixtures of cationic and anionic surfactants crystallized at various ratios in the absence of added salt form micrometer-sized colloids. Here, we propose and test a general mechanism explaining how this ratio controls the shape of the resulting colloidal structure, which can vary from nanodiscs to punctured planes; during cocrystallization, excess (nonstoichiometric) surfactant accumulates on edges or pores rather than being incorporated into crystalline bilayers. Molecular segregation then produces a sequence of shapes controlled by the initial mole ratio only. Using freeze-fracture electron microscopy, we identified three of these states and their corresponding coexistence regimes. Fluorescence confocal microscopy directly showed the segregation of anionic and cationic components within the aggregate. The observed shapes are consistently reproduced upon thermal cycling, demonstrating that the icosahedral shape corresponds to the existence of a local minimum of bending energy for facetted icosahedra when the optimal amount of excess segregated material is present.
Ringwoodite lamellae in olivine: Clues to olivine–ringwoodite phase transition mechanisms in shocked meteorites and subducting slabs
Authors: Chen Ming , Goresy Ahmed El , Gillet Philippe
Published: October 2004

The first natural occurrence of ringwoodite lamellae was found in the olivine grains inside and in areas adjacent to the shock veins of a chondritic meteorite, and these lamellae show distinct growth mechanism. Inside the veins where pressure and temperature were higher than elsewhere, ringwoodite lamellae formed parallel to the {101} planes of olivine, whereas outside they lie parallel to the (100) plane of olivine. The lamellae replaced the host olivine from a few percent to complete. Formation of these lamellae relates to a diffusion-controlled growth of ringwoodite along shear-induced planar defects in olivine. The planar defects and ringwoodite lamellae parallel to the {101} planes of olivine should have been produced in higher shear stress and temperature region than that parallel to the (100) plane of olivine. This study suggests that the time duration of high pressure and temperature for the growth of ringwoodite lamellae might have lasted at least for several seconds, and that an intracrystalline transformation mechanism of ringwoodite in olivine could favorably operate in the subducting lithospheric slabs in the deep Earth.
Traditional Mediterranean diet and longevity in the elderly: a review
Authors: Trichopoulou Antonia
Published: October 2004

Objective:

To review the evidence that the traditional Mediterranean diet is associated with longevity.

Setting:

Elderly persons of both genders in Greece, Spain, Denmark and Australia studied by different groups of investigators.

Methods:

Adherence to the principles of the Mediterranean diet was operationalised through a score devised a priori, and study participants were followed up until death or the end of the study. Proportional hazard models were used.

Results:

Closer adherence to the Mediterranean diet was associated with a significant decrease in general mortality among the elderly persons studied.

Conclusion:

The Mediterranean diet is positively associated with longevity among the elderly. If the assumption holds that there is no interaction between age and diet with respect to general mortality, it can be inferred that the traditional Mediterranean diet represents a healthy nutritional pattern.
Mediterranean diet and overall mortality differences in the European Union
Authors: Trichopoulos Dimitrios , Lagiou Pagona
Published: October 2004

Objective:

To assess whether the Mediterranean diet contributes to overall mortality differences and trends between Mediterranean and non-Mediterranean European Union (EU) countries.

Design:

Routinely recorded adjusted overall mortality and food availability data in Mediterranean and non-Mediterranean EU countries. A Mediterranean diet score designed a priori was used as instrument.

Setting:

Fifteen EU countries in the 1960s and the 1990s.

Subjects:

The general population in the 15 EU countries.

Results:

The difference between Mediterranean and non-Mediterranean EU countries in a 7-point Mediterranean diet score was reduced from 2.9 in the 1960s to 1.6 in the 1990s. This reduction may underlie the reduction in the difference in general mortality between these countries, from about 100 deaths per 100 000 person-years in the early 1970s to about 50 deaths per 100 000 person-years in the 1990s.

Conclusions:

The decline in overall mortality in the 15 EU countries over the last 25 years is probably unrelated to diet. However, the gradual loss of the survival advantage of Mediterranean EU citizens, compared with other EU citizens, may be linked to the gradual abandonment by the former of their dietary traditions.
Mediterranean diet and cancer
Authors: La Vecchia Carlo
Published: October 2004

Objective:

To analyse the role of various aspects of the Mediterranean diet in several common epithelial cancers, including digestive and selected non-digestive tract neoplasms.

Design:

Systematic analysis of data from a series of case-control studies.

Setting:

Northern Italy, between 1983 and 1998.

Subjects:

Over 12 000 cases of 20 cancer sites and 10 000 controls.

Results:

For most epithelial cancers, the risk decreased with increasing vegetable and fruit consumption, with relative risk (RR) between 0.3 and 0.7 for the highest versus the lowest tertile. For digestive tract cancers, population-attributable risks for low intake of vegetables and fruit ranged between 15 and 40%. A protective effect was observed also for breast, female genital tract, urinary tract and a few other epithelial neoplasms. A number of antioxidants and other micronutrients showed an inverse relationship with cancer risk, but the main components responsible for the favourable effect of a diet rich in vegetables and fruit remain undefined. Fish tended to be another favourable diet indicator. In contrast, subjects reporting frequent red meat intake showed RRs above unity for several common neoplasms. Intake of whole-grain foods was related to a reduced risk of several types of cancer, particularly of the upper digestive tract. This may be due to a favourable role of fibre, but the issue is still open to discussion. In contrast, refined grain intake and, consequently, glycaemic load and glycaemic index were associated with increased risk of different types of cancer including, among others, breast and colorectal.

Conclusions:

A low-risk diet for cancer in the Mediterranean would imply increasing the consumption of fruit and vegetables, as well as avoiding increasing the intakes of meat and refined carbohydrates. Further, olive oil and other unsaturated fats, which are also typical aspects of the Mediterranean diet, should be preferred to saturated ones.
Assessment of Turkish women's knowledge concerning folic acid and prevention of birth defects
Authors: Unusan Nurhan
Published: October 2004

Objectives:

In Turkey, the incidence of neural tube defects (NTDs) is 30.1 per 10 000 births. For this reason it seems an important problem for women of childbearing age. Adequate periconceptional consumption of folic acid could prevent NTDs. Most women are unaware of this recommendation. The objectives of this study were to evaluate women' knowledge and beliefs with regard to folic acid, and to estimate the consumption frequency of vitamin supplements periconceptionally and during the first trimester of pregnancy.

Design:

Eight hundred and eighteen married women who had delivered a live-born infant within the previous 12 months completed the questionnaire. Each subject participated in a 20-minute interview, with the questionnaire comprising multiple-choice statements. A random sample of 10 public health centres was drawn from 27 in three districts in Konya where about 50% of the population lives.

Results:

Only 22% of subjects had heard or read about folic acid. Thirteen per cent of women indicated knowledge of the direct link between folic acid supplementation and NTD prevention. The knowledge was greatest among 26- to 35-year-olds. Women with a university degree were more likely to have heard about folic acid than were less-educated women.

Conclusion:

The results indicate that further government efforts are needed to inform the population and promote the optimal use of folic acid supplements and folate-enriched foods. It is the responsibility of national authorities to increase health education concerning folic acid and the prevention of NTDs in their countries.
Analysis of herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids
Authors: Oberlies Nicholas H , Kim Nam-Cheol , Brine Dolores R , Collins Bradley J , Handy Robert W , Sparacino Charles M , Wani Mansukh C , Wall Monroe E
Published: October 2004

Objectives:

To determine the relative quantities of two hepatotoxic pyrrolizidine alkaloids, symphytine and echimidine, in teas prepared from comfrey leaves (Symphytum officinale), and to determine the potential contribution of theN-oxide forms of these alkaloids to levels of the parent alkaloids.

Design:

Comfrey leaves were purchased from three commercial sources and used to prepare tea in a manner consistent with the methods used by consumers. An extraction scheme was devised for extraction of the alkaloids, and a gas chromatographic method was developed to quantify the two major alkaloids, symphytine and echimidine. Recognising that theN-oxide derivatives of these alkaloids have also been identified in comfrey preparations, chemical reduction was applied to determine the total quantities of the alkaloids as free bases and asN-oxide derivatives.

Results:

The concentration of symphytine and echimidine varied considerably between teas prepared from leaves purchased from the different vendors of plant material. Moreover, a much higher concentration of symphytine was found in the tea when steps were included to reduceN-oxides prior to analysis. The treatment of pure symphytine with hot water did not generate theN-oxide derivativede novo.

Conclusions:

Since the pyrrolizidine alkaloids are known to be hepatotoxic, consumption of herbal teas made from comfrey leaves may be ill-advised. The concentration of pyrrolizidine alkaloids in such teas may be underestimated substantially unless the concentration ofN-oxides is taken into consideration.
Effects of revision of Japanese food composition tables on estimation of nutrient intakes, with reference to age-dependent differences
Authors: Matsuda-Inoguchi Naoko , Shimbo Shinichiro , Nakatsuka Haruo , Watanabe Takao , Higashikawa Kae , Ikeda Masayuki
Published: October 2004

Objective:

To identify effects of revision of the Japanese food composition tables from the fourth version to the fifth version on nutrient intake estimation.

Design:

A database on 783 samples of 24-hour food duplicate portions was re-visited. Nutrients in the duplicate portions were estimated by use of the fourth and fifth versions of the Japanese food composition tables in parallel, together with supplemental use of other databases. The two sets of estimates were subjected to comparison.

Setting:

The sample collection was conducted at 31 sites all over Japan.

Subjects:

The sample donors were 783 women aged 20–78 years.

Results:

Compared with the estimates by use of the fourth version of the tables, the estimates by the fifth version were substantially higher for intakes of energy, carbohydrate, dietary fibre, vitamin A and niacin, and lower for iron intake. The increase in carbohydrate intake estimates was more evident in older women than in young women, whereas the decrease in the intake estimation of iron and the increase in that of dietary fibre were more marked in young women than in older women.

Conclusion:

The recent revision of food composition tables in Japan induced substantial changes in the estimation of nutrient intakes, i.e. an increase in energy, carbohydrate, dietary fibre, vitamin A and niacin, and a decrease in iron. The extent of the changes varied depending on age.
Low compliance with recommendations on folic acid use in relation to pregnancy: is there a need for fortification?
Authors: Knudsen Vibeke K , Orozova-Bekkevold Ivanka , Rasmussen Lone B , Mikkelsen Tina B , Michaelsen Kim F , Olsen Sjúrður F
Published: October 2004

Objective:

As a means to prevent neural tube defects (NTDs), women planning pregnancy in Denmark are recommended to take a dietary supplement of 400 μg folic acid daily during the periconceptional period. We examined compliance with this recommendation in a national survey.

Design:

Cohort study on pregnant women in Denmark.

Setting:

The Danish National Birth Cohort (DNBC).

Subjects:

From November 2000 to February 2002, 22 000 pregnant women were recruited for DNBC. Use of dietary supplements was recorded at enrolment. Compliance with the recommendation was related to an information campaign that took place during the second half of 2001, and to lifestyle factors provided in a telephone interview by the end of the first trimester of pregnancy.

Results:

An increase was seen in the proportion of women complying with the recommendation in the study period and this coincided with the information campaign events. However, even at the end of the period, only 22.3% of the women who had planned their pregnancy fully complied with the recommendation. No increase at all was seen in periconceptional folic acid use among women with unplanned pregnancies. Young age, low education and smoking were identified as factors that determined non-compliance.

Conclusions:

Alternative and more effective strategies are needed if the Danish population is to benefit fully from the knowledge that folic acid prevents NTDs. Future strategies should not only target vulnerable groups, such as the less educated and the young, but also women who get pregnant without planning this. The only possible way to reach the last group may be through fortification of foods with folic acid.
Do childhood growth indicators in developing countries cluster? Implications for intervention strategies
Authors: Fenn Bridget , Morris Saul S , Frost Chris
Published: October 2004

Objective:

The effectiveness of geographic targeting in nutrition programmes depends largely on the degree to which malnutrition clusters within particular areas. This study investigates the extent to which the childhood nutrition indicators, stunting (height-for-age Z-score <−2) and wasting (weight-for-height Z-score <−2), are spatially clustered; this information is used to determine the implications of spatial clustering for the effectiveness of geographic targeting.

Design:

Analysis of data from Demographic and Health Survey (DHS) results. Clustering is assessed by calculating intra-cluster correlation coefficients (ICCs). Estimating the proportion of malnourished children covered by a programme successfully targeting 10% of clusters with the highest malnutrition prevalences allows an assessment of the effectiveness of geographic targeting.

Setting:

Fifty-eight DHS III (1992–1997) and DHS IV (1998–2001) reports from 46 developing countries.

Subjects:

Pre-school children of mothers interviewed by DHS.

Main results: The extent of clustering of nutritional status was surprisingly low (median ICC for national samples: stunting=0.054, wasting=0.032) and most countries were characterised by having an ICC <0.1 – i.e. low clustering – for childhood undernutrition (91% of countries for wasting and 78% for stunting). Our assessment of the effectiveness of geographic targeting showed that coverage was better for wasting than for stunting; for wasting, 23% of countries would achieve less than 20% coverage, compared with 76% of countries achieving less than 20% coverage for stunting. Coverage is dependent on the overall prevalence of malnutrition and the ICC.

Conclusions:

Childhood nutritional status is determined at the household, or even individual, level; nutrition programmes that are geographically targeted may result in high levels of under-coverage and leakage, thereby compromising their cost-effectiveness; the lack of clustering questions the appropriateness of current nutrition interventions.
Underreporting of energy intake among Japanese women aged 18–20 years and its association with reported nutrient and food group intakes
Authors: Okubo Hitomi , Sasaki Satoshi
Published: October 2004

Objectives:

To evaluate the ratio of energy intake to basal metabolic rate (EI/BMR) among young female Japanese adults, and to compare the lifestyle and dietary characteristics between relatively low and high reporters.

Design:

Dietary intakes were assessed over a 1-month period with a validated, self-administered, diet history questionnaire, and lifestyle variables were assessed by a second questionnaire designed for this survey. The ratio of EI/BMR was calculated from reported energy intake and estimated basal metabolic rate.

Subjects:

In total, 1889 female Japanese university students aged 18–20 years who were enrolled in dietetics courses.

Results:

Ninety-five per cent of the subjects were classified into a non-obese group (body mass index (BMI) <25 kg m−2; mean±standard deviation (SD): 20.8±2.6 kg m−2). EI/BMR was 1.43±0.40 (mean±SD). Sixty-eight per cent of the subjects showed an EI/BMR level below the possibly balanced value of 1.56, 37% showed EI/BMR below the minimum survival value of 1.27 and 2% of the subjects showed EI/BMR exceeding the maximum value for a sustainable lifestyle of 2.4. BMI, body weight and BMR decreased significantly with the increase in EI/BMR (P<0.001). The percentage of energy from carbohydrate was significantly higher, whereas those from fat and protein were significantly lower, among the lower EI/BMR groups. As for food groups, a significantly declining trend from the lowest to the highest EI/BMR groups was observed for cereals.

Conclusion:

Underreporting, rather than overreporting, of energy intake was predominant in this relatively lean Japanese female population. BMI was the most important factor affecting the reporting accuracy of energy intake.
Award Article: Microcirculatory Society Award for Excellence in Lymphatic Research
Authors: COX CHARLES S. , FISCHER UWE M. , ALLEN STEVEN J. , LAINE GLEN A.
Published: October 2004

Objective: Mesenteric ischemia/reperfusion (I/R) is associated with cardiac dysfunction. Mesenteric lymph primes polymorphonuclear leukocytes (PMNs) for increased superoxide release following I/R. We hypothesized that mesenteric I/R causes myocardial edema resulting in myocardial dysfunction, and that diverting mesenteric lymph would preserve myocardial function.

Methods: Two canine groups were studied: lymphatic diversion (LD) and no lymphatic diversion (No LD). Preload recruitable stroke work, ±dp/dtmax, isovolumic relaxation (tau), cardiac output, and myocardial water content (MWC) were determined. I/R consisted of 60 min of ischemia followed by 180 min of reperfusion. Myocardial myeloperoxidase (MPO) was measured as an index of PMN leukosequestration. In addition, mesenteric lymph harvested after I/R was infused into normal canines and all variables measured.

Results: MWC increased from baseline in No LD. Tau and −dp/dtmax were significantly affected in No LD, but not in LD. After mesenteric I/R, mesenteric lymph primed PMNs for increased superoxide production. Lymph diversion resulted in significantly lower myocardial MPO. With reinfusion of I/R lymph, MWC and tau increased. MPO was also increased post I/R mesenteric lymph reinfusion.

Conclusions: Our data indicate that myocardial dysfunction after mesenteric I/R is due to lymph‐induced, PMN‐mediated microvascular alterations and myocardial edema.
Gender‐Specific Regulation of Cardiovascular Function: Estrogen as Key Player
Authors: HUANG AN , KALEY GABOR
Published: October 2004

This review provides an overview of gender‐specific differences in the incidence and development of cardiovascular diseases, including hypertension, atherosclerosis, heart failure and the corresponding myocardial remodeling. The review discusses the possible mechanisms by which estrogen affords a beneficial effect on cardiovascular function via genomic vs non genomic regulation; estrogen receptor‐dependent vs estrogen receptor‐independent pathways, specific signal transduction cascades, especially those involving protein kinase B (Akt) and mitogen activated protein kinase (MAPK), as well as their downstream targets, such as nitric oxide synthase, cyclooxygenase, cytochrome P450 (CYP), NADPH oxidase and superoxide dismutase. Having considered the essential role of the microcirculation in the control of vascular resistance in vivo, estrogen‐related regulation of microvascular function and blood pressure is highlighted. Attention is focused on the effects of estrogen on pressure (myogenic)‐dependent and flow/shear stress‐dependent mechanisms of arterioles, which contribute significantly to the control of local blood flow and peripheral resistance via alterations in the release of endothelial mediators, such as nitric oxide, prostaglandins and endothelium‐derived hyperpolarizing factor.
Regulation of Leukocyte Recruitment by Local Wall Shear Rate and Leukocyte Delivery
Authors: KIM MICHAEL B. , SARELIUS INGRID H.
Published: October 2004

Objective: To determine the influence of wall shear rate and leukocyte delivery on leukocyte margination, rolling, and adhesion in post‐capillary venules.

Methods: Leukocyte–endothelial cell interactions were characterized in cremaster muscle venules of anesthetized mice with video microscopy under control conditions and after 3 h exposure to TNF‐α. Hemodynamic parameters were measured with fluorescent particle tracking using confocal microscopy.

Results: Leukocyte recruitment to the vessel wall and leukocyte rolling increased as a function of wall shear rate (P < 0.05) over the range observed (0–200 s−1) in intact post capillary venules. Leukocyte delivery affected recruitment and rolling flux only in activated vessels (P < 0.05). In addition, leukocyte firm adhesion was independent of both wall shear rate and leukocyte delivery, but showed an overall increase in TNF‐α stimulated tissues (0.9 ± 0.2 vs. 2.7 ± 0.6 cells/50 μm).

Conclusions: Leukocytes are delivered to venules in excess of the capacity of the local endothelium to support interactions. Elevated shear forces increase leukocyte recruitment to the vessel wall, which correlates to elevated rolling flux. In contrast, leukocyte firm adhesion is primarily affected by the activation state of the tissue and not by hemodynamic factors. Overall, the capacity of endothelial cells to support leukocyte interactions primarily regulates leukocyte recruitment and is not limited by leukocyte supply.
Glycoprotein IIB/IIIA‐Inhibition and Microcirculatory Alterations During Experimental Endotoxemia—An Intravital Microscopic Study in the Rat
Authors: WALTHER ANDREAS , CZABANKA MARCUS , GEBHARD MARTHA MARIA , MARTIN EIKE
Published: October 2004

Objective: Endothelial damage during early endotoxemia has been shown to be leukocyte‐independent. Platelet‐activating factor (PAF) and serotonin‐receptor antagonism are known to reduce leukocyte‐independent macromolecular leakage significantly, thereby focusing the field of interest to the platelets. We hypothesized that inhibition of the GP IIb/IIIa receptor, using the unspecific GP IIb/IIIa inhibitor abciximab, would reduce leukocyte‐independent endothelial damage during early endotoxemia, and furthermore, that inhibition of the GP IIb/IIIa receptor with abciximab might improve microcirculatory disturbances, seen in a leukocyte‐dependent animal model during endotoxemia.

Methods: In male Wistar rats, venular wall shear rate, macromolecular efflux, and leukocyte‐endothelial interaction were determined in mesenteric postcapillary venules using intravital microscopy at baseline, 60, and 120 min after the start of the experiment. The experiment was divided into two parts. In the first part, we investigated the effects of the GP IIb/IIIa inhibitor abciximab on leukocyte‐independent endothelial permeability during endotoxemia. In the second part of the experiment, we focused on the effects of the GP IIb/IIIa inhibitor abciximab on microcirculatory disturbances during endotoxemic states, without a modification of the leukocyte‐endothelial interaction, putting the main emphasis again on endothelial permeability.

Results: GP IIb/IIIa inhibition with abciximab resulted in a significant reduction of macromolecular efflux during leukocyte‐independent endotoxemia. Both pretreatment with abciximab and post‐treatment with abciximab reduced macromolecular leakage during leukocyte‐dependent endotoxemia to values comparable to control values, and prevented an increase in leukocyte adherence, that has been reduced to values comparable to control values, too.

Conclusion: GP IIb/IIIa inhibition, using abciximab, protects against endothelial dysfunction and an increase in leukocyte adherence to the vascular wall during experimental endotoxemia. The protective properties of abciximab on microcirculation seemed to be leukocyte‐independent
Expression of Cytochrome P450‐4A Isoforms in the Rat Cremaster Muscle Microcirculation
Authors: WANG JINGLI , MAIER KRISTOPHER G. , ROMAN RICHARD J. , DE LA CRUZ LOURDES , ZHU JIAXUAN , HENDERSON LISA , LOMBARD JULIAN H.
Published: October 2004

Objective: This study sought to identify any specific cytochrome P450 (CYP450) ‐4A enzyme isoforms expressed in arterioles and/or the surrounding parenchymal tissue of the rat cremaster muscle.

Methods: RT‐PCR was used to detect the presence of specific CYP450‐4A isoforms in isolated muscle fibers and arterioles from the cremaster muscle of Sprague‐Dawley rats; CYP450‐4A protein expression was determined by Western blotting.

Results: CYP450‐4A3 mRNA was expressed in isolated muscle fibers and in cremasteric arterioles, while CYP450‐4A8 mRNA was expressed only in cremasteric arterioles. CYP450‐4A1 and CYP450‐4A2 mRNA were not expressed in arterioles and skeletal muscle cells, although all four isoforms were strongly expressed in the liver. CYP450‐4A protein was detected in both the isolated muscle fibers and in the isolated arterioles.

Conclusions: The present study identifies the specific pattern of cytochrome P450‐4A isoform expression in arterioles and parenchymal cells of the skeletal muscle microcirculation, and supports the hypothesis that the cytochrome P‐450 enzymes may play a role in the regulation of microvascular function in the skeletal muscle microcirculation.
Anti‐Insulin Receptor Autoantibodies Are Not Required for Type 2 Diabetes Pathogenesis in NZL/Lt Mice, a New Zealand Obese (NZO)‐Derived Mouse Strain
Authors: McInerney Marcia F. , Najjar Sonia M. , Brickley Deanna , Lutzke Mary , Abou-Rjaily George A. , Reifsnyder Peter , Haskell Bradford D. , Flurkey Kevin , Zhang Ying-Jian , Pietropaolo Susan L. , Pietropaolo Massimo , Byers James P. , Leiter Edward H.
Published: October 2004

The New Zealand obese (NZO) mouse strain shares with
the related New Zealand black (NZB) strain a number of
immunophenotypic traits. Among these is a high proportion
of B‐1 B lymphocytes, a subset associated with autoantibody
production. Approximately 50% of NZO/HlLt
males develop a chronic insulin‐resistant type 2 diabetes
syndrome associated with 2 unusual features: the presence
of B lymphocyte–enriched peri‐insular infiltrates and
the development of anti‐insulin receptor autoantibodies
(AIRAs). To establish the potential pathogenic contributions
ofBlymphocytes and AIRAs in this model, a disrupted immunoglobulin heavy chain gene (Igh-6) congenic on the
NZB/BlJ background was backcrossed 4 generations into
the NZO/HlLt background and was then intercrossed to
produce mice that initially segregated for wild‐type versus
the mutant Igh-6 allele and thus permitted comparison
of syndrome development. A new flow cytometric assay
(AIRA binding to transfected Chinese hamster ovary
cells stably expressing mouse insulin receptor) showed IgM
and IgG subclass AIRAs in serum from Igh-6 intact males,
but not in Igh‐6null male serum. However, the absence of
B lymphocytes and antibodies distinguishing mutant from
wild‐type males failed to significantly affect diabetes‐free
survival. The Igh‐6nullmales gained weight less rapidly than
wild‐type males, probably accounting for a retardation, but
not prevention, of hyperglycemia. Thus, AIRA and the Blymphocyte
component of the peri‐insulitis in chronic diabetics
were not essential either to development of insulin
resistance or to eventual pancreatic beta cell failure and
loss. A new substrain, designated NZL, was generated by
inbreeding Igh-6 wild‐type segregants. Currently at the F10
generation, NZL mice exhibit the same juvenile‐onset obesity
as NZO/HlLt males, but develop type 2 diabetes at a
higher frequency (> 80%). Also, unlike NZO/HlLt mice that
are difficult to breed, the NZL/Lt strain breeds well and thus
offers clear advantages to obesity/diabetes researchers.
Sensory Nerve Innervation of Epineurial Arterioles of the Sciatic Nerve Containing Calcitonin Gene–Related Peptide: Effect of Streptozotocin‐Induced Diabetes
Authors: Yorek M. A. , Coppey L. J. , Gellett J. S. , Davidson E. P.
Published: October 2004

The authors have determined that epineurial arterioles of the sciatic nerve are innervated by nonadrenergic, noncholinergic nerves that contribute to the regulation of vasodilation. Using immunohistochemistry, the authors determined that nerves innervating epineurial arterioles contain the neuropeptide calcitonin gene–related peptide (CGRP). Using streptozotocin‐induced diabetic rats, the authors demonstrated that CGRP content in sensory nerves innervating epineurial arterioles and vasodilation in response to exogenous CGRP was decreased. In summary, epineurial arterioles of the sciatic nerve are innervated by sensory nerves containing the neuropeptide CGRP. The diabetes‐like condition induced by streptozotocin reduces the content of CGRP in these nerves and exogenous CGRPmediated vasodilation. CGRP is likely an important regulator of vascular tone and compromising its function could contribute to nerve ischemia and diabetic neuropathy.
Effect of α‐Lipoic Acid on Lipid Profile in Rats Fed a High‐Fructose Diet
Authors: Thirunavukkarasu V. , Nandhini A. T. Anitha , Anuradha C. V.
Published: October 2004

This study investigated the effect of administration of
α‐lipoic acid (LA) on lipid metabolism in high fructose–fed insulin‐resistant rats. High‐fructose feeding (60 g/100 g
diet) to normal rats resulted in a significant increase in
the concentrations of cholesterol, triglycerides (TGs), free
fatty acids (FFAs), and phospholipids in plasma, liver, kidney,
and skeletal muscle. Reduced activities of lipoprotein
lipase (LPL) and lecithin cholesterol acyl transferase
(LCAT) and increased activity of the lipogenic enzyme
hydroxymethylglutaryl–coenzyme A (HMG‐CoA) reductase
were observed in plasma and liver. High‐density
lipoprotein cholesterol (HDL‐C) was significantly lowered
and very low‐density lipoprotein cholesterol (VLDL‐C) and
low‐density lipoprotein cholesterol (LDL‐C) were significantly
elevated. Treatment with LA (35 mg/kg body weight
intraperitoneal) reduced the effects of fructose. The rats
showed near‐normal levels of lipid components on plasma
and tissues. Activities of key enzymes of lipid metabolism
were also restored to normal values. Cholesterol distribution
in the plasma lipoproteins was normalized, resulting in
a favorable lipid profile. This study demonstrates that LA
can alter lipid metabolism in fructose‐fed insulin‐resistant
rats and may have implications in the treatment of insulin
resistance.
Improved Experimental Procedures for Achieving Efficient Germ Line Transmission of Nonobese Diabetic (NOD)‐Derived Embryonic Stem Cells
Authors: Arai Satoko , Minjares Christina , Nagafuchi Seiho , Miyazaki Toru
Published: October 2004

The manipulation of a specific gene in NOD mice, the
best animal model for insulin‐dependent diabetes mellitus
(IDDM), must allow for the precise characterization of the
functional involvement of its encoded molecule in the pathogenesis
of the disease. Although this has been attempted by
the cross‐breeding of NOD mice with many gene knockout
mice originally created on the 129 or C57BL/6 strain background,
the interpretation of the resulting phenotype(s) has
often been confusing due to the possibility of a known or
unknown disease susceptibility locus (e.g., Idd locus) cosegregating
with the targeted gene from the diabetes‐resistant
strain. Therefore, it is important to generate mutant mice
on a pure NOD background by using NOD‐derived embryonic
stem (ES) cells. By using the NOD ES cell line established
by Nagafuchi and colleagues in 1999 (FEBSLett., 455,
101–104), the authors reexamined various conditions in the
context of cell culture, DNA transfection, and blastocyst injection,
and achieved a markedly improved transmission
efficiency of these NOD ES cells into the mouse germ line.
These modifications will enable gene targeting on a “pure” NOD background with high efficiency, and contribute to
clarifying the physiological roles of a variety of genes in the
disease course of IDDM.
Circular genome visualization and exploration using CGView
Authors: Stothard Paul , Wishart David S.
Published: October 2004

Summary: CGView (Circular Genome Viewer) is a Java application and library for generating high-quality, zoomable maps of circular genomes. It converts XML or tab-delimited input into a graphical map (PNG, JPG or Scalable Vector Graphics format), complete with sequence features, labels, legends and footnotes. In addition to the default full view map, the program can generate a series of hyperlinked maps showing expanded views. The linked maps can be explored using any Web browser, allowing rapid genome browsing and facilitating data sharing.

Availability: CGView (the standalone application, library or applet), sample input, sample maps and documentation can be obtained from http://wishart.biology.ualberta.ca/cgview/

Contact:  david.wishart@ualberta.ca
Improving conformational searches by geometric screening
Authors: Zhang Ming , White R. Allen , Wang Liqun , Goldman Ronald , Kavraki Lydia , Hassett Brendan
Published: October 2004

Motivation: Conformational searches in molecular docking are a time-consuming process with wide range of applications. Favorable conformations of the ligands that successfully bind with receptors are sought to form stable ligand–receptor complexes. Usually a large number of conformations are generated and their binding energies are examined. We propose adding a geometric screening phase before an energy minimization procedure so that only conformations that geometrically fit in the binding site will be prompted for energy calculation.

Results: Geometric screening can drastically reduce the number of conformations to be examined from millions (or higher) to thousands (or lower). The method can also handle cases when there are more variables than geometric constraints. An early-stage implementation is able to finish the geometric filtering of conformations for molecules with up to nine variables in 1 min. To the best of our knowledge, this is the first time such results are reported deterministically.

Contact:  mzhang@mdanderson.org
Bayesian analysis of signaling networks governing embryonic stem cell fate decisions
Authors: Woolf Peter J. , Prudhomme Wendy , Daheron Laurence , Daley George Q. , Lauffenburger Douglas A.
Published: October 2004

Motivation: Signaling events that direct mouse embryonic stem (ES) cell self-renewal and differentiation are complex and accordingly difficult to understand in an integrated manner. We address this problem by adapting a Bayesian network learning algorithm to model proteomic signaling data for ES cell fate responses to external cues. Using this model we were able to characterize the signaling pathway influences as quantitative, logic-circuit type interactions. Our experimental dataset includes measurements for 28 signaling protein phosphorylation states across 16 different factorial combinations of cytokine and matrix stimuli as reported previously.

Results: The Bayesian network modeling approach allows us to uncover previously reported signaling activities related to mouse ES cell self-renewal, such as the roles of LIF and STAT3 in maintaining undifferentiated ES cell populations. Furthermore, the network predicts novel influences such as between ERK phosphorylation and differentiation, or RAF phosphorylation and differentiated cell proliferation. Visualization of the influences detected by the Bayesian network provides intuition about the underlying physiology of the signaling pathways. We demonstrate that the Bayesian networks can capture the linear, nonlinear and multistate logic interactions that connect extracellular cues, intracellular signals and consequent cell functional responses.

Availability: Datasets and software are available online from http://sysbio.engin.umich.edu/~pwoolf/mouseES/

Contact:  pwoolf@umich.edu

Supplementary information:  http://sysbio.engin.umich.edu/~pwoolf/mouseES/
Understanding protein dispensability through machine-learning analysis of high-throughput data
Authors: Chen Yu , Xu Dong
Published: October 2004

Motivation: Protein dispensability is fundamental to the understanding of gene function and evolution. Recent advances in generating high-throughput data such as genomic sequence data, protein–protein interaction data, gene-expression data and growth-rate data of mutants allow us to investigate protein dispensability systematically at the genome scale.

Results: In our studies, protein dispensability is represented as a fitness score that is measured by the growth rate of gene-deletion mutants. By the analyses of high-throughput data in yeast Saccharomyces cerevisiae, we found that a protein's dispensability had significant correlations with its evolutionary rate and duplication rate, as well as its connectivity in protein–protein interaction network and gene-expression correlation network. Neural network and support vector machine were applied to predict protein dispensability through high-throughput data. Our studies shed some lights on global characteristics of protein dispensability and evolution.

Availability: The original datasets for protein dispensability analysis and prediction, together with related scripts, are available at http://digbio.missouri.edu/~ychen/ProDispen/

Contact:  xudong@missouri.edu
TRbase: a database relating tandem repeats to disease genes for the human genome
Authors: Boby T. , Patch A.-M. , Aves S. J.
Published: October 2004

Motivation: Tandem repeats are associated with disease genes, play an important role in evolution and are important in genomic organization and function. Although much research has been done on short perfect patterns of repeats, there has been less focus on imperfect repeats. Thus, there is an acute need for a tandem repeats database that provides reliable and up to date information on both perfect and imperfect tandem repeats in the human genome and relates these to disease genes.

Results: This paper presents a web-accessible relational tandem repeats database that relates tandem repeats to gene locations and disease genes of the human genome. In contrast to other available databases, this database identifies both perfect and imperfect repeats of 1–2000 bp unit lengths. The utility of this database has been illustrated by analysing these repeats for their distribution and frequencies across chromosomes and genomic locations and between protein-coding and non-coding regions. The applicability of this database to identify diseases associated with previously uncharacterized tandem repeats is demonstrated.

Availability: TRbase is available at http://trbase.ex.ac.uk/

Contact:  S.J.Aves@exeter.ac.uk
ParIS Genome Rearrangement server
Authors: Miklós I. , Ittzés P. , Hein J.
Published: October 2004

Summary: ParIS Genome Rearrangement is a web server for a Bayesian analysis of unichromosomal genome pairs. The underlying model allows inversions, transpositions and inverted transpositions. The server generates a Markov chain using a Partial Importance Sampler technique, and samples trajectories of mutations from this chain. The user can specify several marginalizations to the posterior: the posterior distribution of number of mutations needed to transform one genome into another, length distribution of mutations, number of mutations that have occurred at a given site. Both text and graphical outputs are available. We provide a limited server, a downloadable unlimited server that can be installed locally on any linux/Unix operating system, and a database of mitochondrial gene orders.

Availability:  http://www.colbud.hu:8765/paris.html and http://doob.stats.ox.ac.uk/~miklos/paris.html

Contact:  miklosi@ramet.elte.hu
An empirical Bayes approach to inferring large-scale gene association networks
Authors: Schäfer Juliane , Strimmer Korbinian
Published: October 2004

Motivation: Genetic networks are often described statistically using graphical models (e.g. Bayesian networks). However, inferring the network structure offers a serious challenge in microarray analysis where the sample size is small compared to the number of considered genes. This renders many standard algorithms for graphical models inapplicable, and inferring genetic networks an ‘ill-posed’ inverse problem.

Methods: We introduce a novel framework for small-sample inference of graphical models from gene expression data. Specifically, we focus on the so-called graphical Gaussian models (GGMs) that are now frequently used to describe gene association networks and to detect conditionally dependent genes. Our new approach is based on (1) improved (regularized) small-sample point estimates of partial correlation, (2) an exact test of edge inclusion with adaptive estimation of the degree of freedom and (3) a heuristic network search based on false discovery rate multiple testing. Steps (2) and (3) correspond to an empirical Bayes estimate of the network topology.

Results: Using computer simulations, we investigate the sensitivity (power) and specificity (true negative rate) of the proposed framework to estimate GGMs from microarray data. This shows that it is possible to recover the true network topology with high accuracy even for small-sample datasets. Subsequently, we analyze gene expression data from a breast cancer tumor study and illustrate our approach by inferring a corresponding large-scale gene association network for 3883 genes.

Availability: The authors have implemented the approach in the R package ‘GeneTS’ that is freely available from http://www.stat.uni-muenchen.de/~strimmer/genets/, from the R archive (CRAN) and from the Bioconductor website.

Contact:  korbinian.strimmer@lmu.de