bluuebunny/crossref_metadata_2025 huggingface dataset:
MyD88S, a splice variant of MyD88, differentially modulates NF‐κB‐ and AP‐1‐dependent gene expression
Authors: Janssens Sophie , Burns Kim , Vercammen Elisabeth , Tschopp Jurg , Beyaert Rudi
Published: July 2003

MyD88 is an adapter protein that is involved in Toll‐like receptor (TLR)‐ and interleukin‐1 receptor (IL‐1R)‐induced activation of nuclear factor‐κB (NF‐κB) and c‐Jun N‐terminal kinase (JNK). By directly binding IL‐1R‐associated kinase (IRAK)‐1 and IRAK‐4, MyD88 serves as a bridging protein, enabling IRAK‐4‐induced IRAK‐1 phosphorylation. We previously identified a lipopolysaccharide‐inducible splice variant of MyD88, MyD88S, which specifically prevents the recruitment of IRAK‐4 into the IL‐1R complex and thus inhibits IRAK‐4‐mediated IRAK‐1 phosphorylation. MyD88S is not able to activate NF‐κB, and in contrast functions as a dominant negative inhibitor of TLR/IL‐1R‐induced NF‐κB activation. Unexpectedly, we here demonstrate that MyD88S still allows JNK phosphorylation and activator protein (AP)‐1‐dependent reporter gene induction upon overexpression in HEK293T cells. These observations indicate that NF‐κB and JNK activation pathways can already diverge at the level of MyD88. Moreover, the regulated expression of a MyD88 splice variant which specifically interferes with NF‐κB‐ but not AP‐1‐dependent gene expression implies an important role for alternative splicing in the fine‐tuning of TLR/IL‐1R responses.
The ribosomal A site‐bound sense and stop codons are similarly positioned towards the A1823–A1824 dinucleotide of the 18S ribosomal RNA
Authors: Bulygin Konstantin N , A. Demeshkina Natalia , Frolova Ludmila Yu , Graifer Dmitri M , Ven'yaminova Aliya G , Kisselev Lev L , Karpova Galina G
Published: July 2003

Positioning of the mRNA codon towards the 18S ribosomal RNA in the A site of human 80S ribosomes has been studied applying short mRNA analogs containing either the stop codon UAA or the sense codon UCA with a perfluoroaryl azide group at the uridine residue. Bound to the ribosomal A site, a modified codon crosslinks exclusively to the 40S subunits under mild UV irradiation. This result is inconsistent with the hypothesis [Ivanov et al. (2001) RNA 7, 1683–1692] which requires direct contact between the large rRNA and the stop codon of the mRNA as recognition step at translation termination. Both sense and stop codons crosslink to the same A1823/A1824 invariant dinucleotide in helix 44 of 18S rRNA. The data point to the resemblance between the ternary complexes formed at elongation (sense codon·aminoacyl‐tRNA·AA dinucleotide of 18S rRNA) and termination (stop codon·eRF1·AA dinucleotide of 18S rRNA) steps of protein synthesis and support the view that eRF1 may be considered as a functional mimic of aminoacyl‐tRNA.
Stratigraphy and timing of eolianite deposition on Rottnest Island, Western Australia
Authors: Hearty Paul J.
Published: July 2003

Over 100 whole-rock amino acid racemization (AAR) ratios from outcrops around Rottnest Island (32.0° S Latitude near Perth) indicate distinct pulses of eolian deposition during the late Quaternary. Whole-rock d-alloisoleucine/l-isoleucine (A/I) ratios from bioclastic carbonate deposits fall into three distinct modal classes or “aminozones.” The oldest, Aminozone E, averages 0.33 ± 0.04 (n= 21). Red palaeosol and thick calcrete generally cap the Aminozone E deposits. A younger Aminozone C averages 0.22 ± 0.03 (n= 63); comprising two submodes at 0.26 ± 0.01 (n= 14) and 0.21 ± 0.02 (n= 49). Multiple dune sets of this interval are interrupted by relatively weak, brown to tan “protosols.” A dense, dark brown rendzina palaeosol caps the Aminozone C succession. Ratios from Holocene dune and marine deposits (“Aminozone A”) center on 0.11 ± 0.02 (n= 15), comprising submodes of 0.13 ± 0.01 (9) and 0.09 ± 0.01 (6). Calibration ofA/Iaverages from Aminozones E and A are provided by U/Th and14C radiometric ages of 125,000 yr (marine oxygen isotope stage (MIS) 5e and 2000–600014C yr B.P. (MIS 1), respectively. The whole-rock A/I results support periodic deposition initiated during MIS 5e, continuing through MIS 5c, and then peaking at the end of MIS 5a, about 70,000–80,000 yr ago. Oceanographic evidence indicates the area was subjected to much colder conditions during MIS 2–4 (10,000 to 70,000 yr ago), greatly slowing the epimerization rate. Eolianite deposition resumed in the mid Holocene (∼6000 yr ago) up to the present. The A/I epimerization pathway constructed from Rottnest Island shows remarkable similarity to that of Bermuda in the North Atlantic (32° N Latitude). These findings suggest that, like Bermuda, the eolian activity on Rottnest occurred primarily during or shortly after interglacial highstands when the shoreline was near the present datum, rather than during glacial lowstands when the coastline was positioned 10–20 km to the west.
Parent–child interaction and children's depression: the relationships between Parent–Child interaction and children's depressive symptoms in Taiwan
Authors: Liu Yih‐Lan
Published: July 2003

This study examines how perceptions of parenting and family messages are associated with the depressive symptoms of early adolescents (N=454, boys=224; girls=210; age,M=12,s.d.=1.01) from East Taiwan. Results show that higher levels of parental care and low levels of parental indifference were associated with lower depression scores. Moreover, perceptions of positive messages regarding children themselves, their world, and their future were found to negatively associate with depression, whereas negative messages had an opposite effect. Basically, girls’ depressive symptoms were more related to maternal messages, and boys’ were more related to paternal messages.
The social distribution of explanations of health and illness among adolescents in São Paulo, Brazil
Authors: De Moura Sérgio Luiz , Harpham Trudy , Lyons Michal
Published: July 2003

The present paper reports on a study, which investigated explanations of health and illness among adolescents from three socio‐economic backgrounds in São Paulo, Brazil. Interviews and group discussions were used to elicit definitions of health and illness, explanations of illness causality and prevention and maintenance of health among 31 deprived adolescents with recent experience of living on the streets, 20 adolescents from poor families and 20 adolescents from privileged families. The findings showed that adolescents from different socio‐economic conditions draw upon similar explanatory models to make sense of health and illness. There were also clear distinctions between the groups. Health and illness were presented as being dependent upon multiple factors such as resistance of the body and socio‐economic status among privileged adolescents. In contrast, the explanations offered by deprived and poor adolescents for both health and illness rested on behaviour or exposure to environmental hazards. Moreover, drugs, sexually transmitted diseases and faith in God were prominent features of the accounts from deprived adolescents. The findings suggest a need for health professionals to be sensitive to people's perspectives of health and illness and their link to socio‐economic conditions. To emphasize individuals’ behaviour in the provision of health‐related information among deprived adolescents might be counter productive and reinforce victim blaming.
The relationship between religiosity and adjustment among African‐American, female, urban adolescents
Authors: Ball Joanna , Armistead Lisa , Austin Barbara‐jeanne
Published: July 2003

African‐American female adolescents living in urban environments are at risk for adverse adjustment outcomes, and thus it is imperative to identify protective factors. Religion has been found to be a significant protective resource against many types of maladaptive adjustment outcomes among adolescent samples. The present study accomplishes the following: (1) Provides a description of religiosity in a sample of African‐American female teens; (2) examines religion as a resource for these adolescents by focusing on the association between religiosity and sexual activity, self‐esteem, and general psychological functioning. Four‐hundred ninety‐two African‐American females, ages 12–19, completed measures on religiosity, sexual activity, self‐esteem, and psychological functioning. Most of the adolescents identified as Christian, reported a belief in God, and attended religious services. Greater overall religiosity was associated with greater self‐esteem and better psychological functioning. Adolescents at different levels of self‐religiosity, as well as family religiosity, evidenced significantly different self‐esteem but not psychological distress or sexual activity. Adolescents with varying levels of church attendance demonstrated differences on all three outcomes. By identifying the ways in which religion may exert a positive impact on African‐American female teens, mental health professionals can design interventions that have the potential to help improve the quality of life for these adolescents.
Kinematics of the knee at high flexion angles: An in vitro investigation
Authors: Li Guoan , Zayontz Shay , DeFrate Louis E. , Most Ephrat , Suggs Jeremy F. , Rubash Harry E.
Published: July 2003

Restoration of knee function after total knee, meniscus, or cruciate ligament surgery requires an understanding of knee behavior throughout the entire range of knee motion. However, little data are available regarding knee kinematics and kinetics at flexion angles greater than 120° (high flexion). In this study, 13° cadaveric human knee specimens were tested using an in vitro robotic experimental setup. Tibial anteroposterior translation and internal–external rotation were measured along the passive path and under simulated muscle loading from full extension to 150° of flexion. Anterior tibial translation was observed in the unloaded passive path throughout, with a peak of 31.2 ± 13.2 mm at 150°. Internal tibial rotation increased with flexion to 150° on the passive path to a maximum of 11.1 ± 6.7°. The simulated muscle loads affected tibial translation and rotation between full extension and 120° of knee flexion. Interestingly, at high flexion, the application of muscle loads had little effect on tibial translation and rotation when compared to values at 120°. The kinematic behavior of the knee at 150° was markedly different from that measured at other flexion angles. Muscle loads appear to play a minimal role in influencing tibial translation and rotation at maximal flexion. The results imply that the knee is highly constrained at high flexion, which could be due in part to compression of the posterior soft tissues (posterior capsule, menisci, muscle, fat, and skin) between the tibia and the femur. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Behaviour of the southern sea lion (Otaria flavescens) and consumption of the catch during purse-seining for jack mackerel (Trachurus symmetricus) off central Chile
Authors: Hückstädt L.A , Antezana T
Published: July 2003

The fishery for jack mackerel (Trachurus symmetricus) off central Chile competes for the resource with southern sea lions (Otaria flavescens), and during purse-seining makes the fish more accessible to the pinnipeds. Interactions with sea lions were recorded during 31 purse-seine sets off central Chile during October 1999. The sea lion behaviour associated with the fishing operations was distinctive. Feeding, movement, predator avoidance, and resting displays were identified. The sea lions approached the purse-seiner as soon as net-setting began. The number of sea lions per set (0–50) was seemingly unaffected by school size of jack mackerel, number of purse-seiners on the fishing ground, whether fishing was by night or by day, the presence of killer whales, or the species being targeted. However, the number of sea lions at a purse-seine differed significantly between fishing grounds. Other effects of fishing operations on O. flavescens included incidental mortality and capture. The amount of fish consumed by the sea lions at a set was as much as 0.4% of the catch. The results of the interaction are documented and discussed in the light of likely interaction with the whole sea lion population, as well as the impact of the interaction on the fishery.
The influence of ontogeny, physiology, and behaviour on the target strength of walleye pollock (Theragra chalcogramma)
Authors: Horne John K
Published: July 2003

Variability in echo intensities from aquatic organisms is caused by physical factors associated with the transmission of sound through water, and by biological factors associated with the ontogeny, physiology, and behaviour of targets. Acoustic-based density estimates depend on accurately characterizing reflected or backscattered sound from any species of interest. Digitized lateral and dorsal radiographs of walleye pollock (Theragra chalcogramma) were used to characterize intra-specific variability among young-of-the-year, juvenile, and adult life-history stages. Kirchhoff-ray mode (KRM) models were used to quantify variability in backscatter intensities at 38 and 120 kHz. At these geometric scattering frequencies, swimbladder surface areas influence echo intensities. Dorsal swimbladder surface areas were proportionate to fish lengths and decreased after fish were fed. Corresponding changes in backscatter were not proportionate to the reduction in dorsal surface area. The ratio of dorsal to lateral swimbladder surface areas was consistent among gravid and non-gravid fish. Walleye pollock tilt angles were centred at 90° and did not differ among densities or between light and dark cycles. Target strength–length regressions and KRM-predicted backscatter models closely matched in situ target-strength measurements for walleye pollock in the Bering Sea. Backscatter variability can be minimized through judicious deployment of equipment and equipment-parameter settings, but the relative influence of biological factors on backscatter amplitude has not been determined.
Ultrastructural and immunohistochemical analysis of proteoglycans in mouse pubic symphysis
Authors: Pinheiro Mônica C. , Joazeiro Paulo P. , Mora Oswaldo A. , Toledo Olga M.S.
Published: July 2003

Proteoglycans were accurately localized in mouse pubic symphyseal tissues using the cuprolinic blue method. Specific glycosaminoglycans degradative enzymes, together with chondroitin sulfate and decorin antibodies, allowed the identification of glycosaminoglycans.

Chondroitin sulfate proteoglycans were the main proteoglycans observed in hyaline cartilage, fibrocartilage, and dense connective tissue. Ultrastructurally, they were seen as electron‐dense granules and filaments. The granules, rich in chondroitin sulfate chains, were exclusively found in hyaline cartilage, whereas filaments were present in cartilage, fibrocartilage, and dense connective tissue. The latter were classified by size and susceptibility to enzyme digestion into F1, F2 and F3 filaments: F1 filaments were small, thin, and collagen fibril‐associated; F2 filaments were thick, heavily stained, and localized around individual collagen fibrils and between bundles of collagen fibrils; and F3 filaments were scattered throughout elastic fiber surfaces. Considering their localization, susceptibility to chondroitinase AC and immunohistochemical detection, the symphysial F1 filaments were found to be preferentially decorin substituted with chondroitin sulfate side chains. The F2 filaments were also susceptible to chondroitinase AC treatment, whereas F3 filaments could be digested by heparitinase.

The data thus obtained on the localization and identification of pubic symphyseal proteoglycans in virgin mice may be useful in the study of structural modifications that occur throughout pregnancy.
Structural requirements for lysosomal targeting of the prosaposin precursor protein
Authors: Ham Daniela
Published: July 2003

Although the Man‐6‐P‐independent lysosomal sorting of prosaposin, a precursor of four saposins (A, B, C, and D) is not understood, a protein/lipid interaction is considered. Immunocytochemical analysis revealed that each single saposin linked to the C‐terminus of prosaposin and to secretory albumin, drives the chimeric protein to lysosomes in COS‐7 cells. Quantitative image analysis demonstrated that saposins are targeted with different efficiency (P<0.05) and in a less smooth manner than the precursor. Despite a very close homology, the charge distribution at the surface of 3D comparative models between saposins appeared different. Western blotting monitored prosaposin in cells also as a di‐ or trimeric form, whereas the chimeric saposins as monomeric. This implies that each amphipathic saposin‐like motif may be a part of the overall structural requirements for binding of the precursor to the membrane lipids of transport vesicle. The crystal structure of saposin B demonstrating two dimeric units for lipid binding supports current findings.
Factors Associated with Non-Attendance at a Secondary Prevention Clinic for Cardiac Patients
Authors: Worcester Marian Una Christine , Stojcevski Zlatko , Murphy Barbara , Goble Alan James
Published: July 2003

Background: A randomised controlled trial was undertaken to test the effectiveness of a secondary prevention clinic. Secondary prevention programs can improve prognosis after an acute cardiac illness. It is therefore important to encourage high participation rates. Aim: The present study was a post-hoc analysis to identify factors associated with patients’ non-attendance at the clinic. Methods: We compared the baseline socio-demographic and clinical characteristics of 83 (73.5% male) non-attending patients and a random sample of 96 (85.4% male) attending patients. Self-reported data were gathered during interviews conducted on an average of 30 months after hospital admission to investigate long-term outcomes of the clinic. Results: Using logistic regression analysis, we found that non-attendance was significantly and independently associated with being female, being under 60 years of age, having no history of high cholesterol and having no angina prior to the event. In bivariate analyses, non-attendance was also associated with being born overseas and not having private health insurance. Conclusions: Likely non-attending patients should be identified early and more effective strategies should be devised to facilitate their participation in secondary prevention programs.
Smallpox: A Disease of the Past? Consideration for Midwives
Authors: Constantin Carolyn M. , Martinelli Angela M. , Foster Stanley O. , Bonney Elizabeth A. , Strickland Ora L.
Published: July 2003

Smallpox infection was often more severe in pregnant women than in non‐pregnant women or in men, regardless of vaccination status. Women with smallpox infection during pregnancy have higher rates of abortions, stillbirths, and preterm deliveries than women without the disease. Pregnant women have high incidences of hemorrhagic‐type and flat‐type smallpox, which are associated with extremely high fatality rates. Although smallpox was eradicated in the late 1970s, current international concern exists regarding the potential use of smallpox virus as an agent for bioterrorism. This manuscript reviews clinical aspects of smallpox, smallpox immunization, and outcomes in pregnant women.
Lactational Atrophic Vaginitis
Authors: Palmer Amy R. , Likis Frances E.
Published: July 2003

Atrophic vaginitis is typically associated with the hypoestrogenic state of menopause. However, lactation also decreases estrogen levels and can cause symptomatic urogenital atrophy. Discussion of this clinical phenomenon in the literature is minimal. A case report of atrophic vaginitis at 13 months postpartum is presented. Mechanisms of action, evaluation, and treatments for lactational atrophic vaginitis are reviewed with recommendations for further research on this topic.
Cultural Competence in Health Care: A Practical Guide
Authors: Van Hoover Cheri
Published: July 2003

By Anne Rundle, Maria Carvalho, and Mary Robinson (Editors). San Francisco: Jossey‐Bass, 1999. 234 pages. $40.00, paperback. Reviewed by: Susan Murphy Cohen, BSN, SNM, Graduate Student In Nurse Midwifery, University of Kansas School of Nursing, Kansas City, KS
Decarburization of Fe/C melts in a crucible: Effects of gas flow rate and composition
Authors: Zughbi Habib Daoud
Published: July 2003

Decarburization of iron–carbon melts contained in a bath has been experimentally investigated. In some experiments controlled Fe/C melts were used whereas in others commercial type metal containing some impurities was used. The effects of a wide range of gas injection flowrates, percentage composition of the decarburizing component and nature of the decarburizing gas were investigated. The presence of nitrogen or argon as inert gas has also been investigated. Results showed that decarburization rate increases with an increase in the concentration of O2 or CO2 in the decarburizing gas. It was also observed that higher decarburization rate and more vigorous reaction were observed when O2 was used as oxidizing gas instead of CO2. Finally, the presence of N2 instead of Ar as inert gas in the oxidizing gas mixture, did not make any significant difference to the decarburization rate.
Chemical potentials of oxygen within four‐phase assemblages of the system CaO–SiO2–Al2O3–FeO
Authors: Enaka T. , Uchida Y. , Hasegawa M. , Naito M. , McLean A. , Iwase M.
Published: July 2003

Within the system CaO + SiO2+ Al2O3+ FeO, there are a number of four‐phase assemblages. Chemical potentials of oxygen within such assemblages have been determined by using an electrochemical technique incorporating zirconia solid electrolyte.
Hepatitis C and pregnancy: An update
Authors: Giles Michelle , Hellard Margaret , Sasadeusz Joe
Published: July 2003

Hepatitis C is a slowly progressive disease with significant long‐term sequelae including cirrhosis, liver failure and hepatocellular carcinoma. Many women of childbearing years are infected with this virus and are at risk of transmitting it to their offspring. Despite this, there are many unanswered questions about hepatitis C and pregnancy including who to screen, the risk factors associated with infection, how these women should be managed during pregnancy and the options available to them after delivery.
Revised key messages for hormone replacement therapy from the New Zealand Guidelines Group
Authors: Roberts Helen , Lethaby Anne
Published: July 2003

The publication of the Women's Health Initiative Study in 2002 has led to changes in the advice for women considering hormone replacement therapy (HRT) use. Along with other organisations worldwide, the New Zealand Guidelines Group (NZGG) revised their key messages for the appropriate prescribing of HRT. Long‐term HRT use was not recommended, nor was the use of HRT for the prevention of coronary heart disease and stroke. While acknowledging the effectiveness of HRT for relief of menopausal symptoms, the group felt that women needed to be informed of the potential risks. Methodological criticisms of Women's Health Initiative (WHI) are discussed along with suggestions of how the study findings may be used for individual decision‐making. In addition to presenting the new advice from the NZGG, the present paper compares these findings with other international bodies and seeks to present some consensus that may help decision‐making for women who are symptomatic at menopause.
Clinical aspects of gestational trophoblastic disease: A review based partly on 25‐year experience of a statewide registry
Authors: Khoo Soo‐Keat
Published: July 2003

Background:  Gestational trophoblastic disease is a fascinating group of pregnancy disorders characterised by abnormal proliferation of trophoblast, ranging from benign to malignant. Because the disease is uncommon, there is a need to formulate management with the assistance of collective information.

Methodology:  A review of available information from English written literature was undertaken, especially data reported by registries around the world (Charing Cross Hospital in England, the North‐western University and the New England area in the USA as well as our own experience in Queensland, Australia). Where possible, collated data from relevant studies were analysed to answer some of the questions posed in clinical practice, with reference to metastatic disease to liver and brain, twinning of molar gestation and coexisting fetus, and placental‐site tumour.

Results:  We found that molar gestation can be classified according to its clinical presentation which influences the time taken to reach human chorionic gonadotropin (HCG) ‘negativity’ and the risk of persisting disease. Categorisation of risk is the basis for choice of chemotherapy to achieve good outcomes. Metastases to liver and brain remain problems in management; the development of ‘new’ metastases during chemotherapy is a very poor prognostic factor. In the variant of twinning with molar gestation and coexisting fetus, it is important to elucidate the fetal karyotype in planning management: a 69XXX fetus is not salvageable but a normal 46XX or 46XY fetus faces the prospect of early preterm delivery. The placental‐site tumour is very rare; localised disease is curable by surgery; chemotherapy is less effective in disseminated disease. From collated worldwide data, the recurrence rate after one mole is 1.3% and after two or more is 20%. Reproductive outcome in subsequent pregnancies, even after multidrug chemotherapy, is not different from the general population. Because of the increased risk long‐term of second tumours after multidrug chemotherapy a closer surveillance of these patients is necessary.

Conclusion:  In general, the disease in its persisting or malignant form is ‘a cancer model par excellence’ because of an identifiable precursor condition, a reliable HCG marker, and sensitivity of the disease to cytotoxic drugs. With current management, retention of fertility is possible and normal reproductive outcome assured.
Utilization of long‐chain fatty acids in human skeletal muscle during exercise
Authors: Kiens B. , Roepstorff C.
Published: July 2003

Long‐chain fatty acids (LCFA) are important sources of energy in contracting skeletal muscle: during the course of endurance exercise the contribution of LCFA in energy metabolism increases whereas when the intensity of exercise increases, the energy need is covered more and more by carbohydrates. Although this has been known for nearly 100 years, the mechanisms controlling fatty acid uptake and oxidation during various exercise modes are still not completely elucidated. Besides passive diffusion, data suggest that both membrane‐associated and cytosolic fatty acid binding proteins are involved in the uptake of LCFA into skeletal muscle. However, data from human studies suggest that the regulation of fatty acid utilization in skeletal muscle during exercise lies mainly within the entrance into the mitochondria or metabolism within the mitochondria. Although possible compartmentalization within the cell makes definitive conclusions difficult, available evidence suggests that changes in malonyl CoA concentration in muscle do not play a major regulatory role in controlling LCFA oxidation during exercise in man. In contrast, it is suggested that the availability of free carnitine may play a major regulatory role in oxidation of LCFA during exercise.
Plasmalemmal fatty acid transport is regulated in heart and skeletal muscle by contraction, insulin and leptin, and in obesity and diabetes
Authors: Bonen A. , Benton C. R. , Campbell S. E. , Chabowski A. , Clarke D. C. , Han X.‐X. , Glatz J. F. C. , Luiken J. J. F. P.
Published: July 2003

It has been assumed that the uptake of long chain fatty acids (LCFAs) into skeletal muscle and the heart muscle, as well as other tissues, occurred via passive diffusion. In recent years our work has shown that the LCFA uptake into skeletal muscle is a highly regulated process. The use of giant sarcolemmal vesicles obtained from skeletal muscle and heart has been used to demonstrate that LCFA uptake into these tissues occurs via a protein‐mediated mechanism involving the 40 kDa plasma membrane associated fatty acid binding protein (FABPpm) and the 88 kDa fatty acid translocase, the homologue of human CD36 (FAT/CD36). Both are ubiquitously expressed proteins and correlate with LCFA uptake into heart and muscle, consistent with the known differences in LCFA metabolism in these tissues. It has recently been found that FAT/CD36 is present in an intracellular (endosomal) compartment from which it can be translocated to the plasma membrane within minutes by muscle contraction and by insulin, to stimulate LCFA uptake. In rodent models of obesity and type 1 diabetes LCFA uptake into heart and muscle is also increased, either by permanently relocating FAT/CD36 to the plasma membrane without altering its expression (obesity) or by increasing the expression of both FAT/CD36 and FABPpm (type 1 diabetes). Chronic leptin treatment decreases LCFA transporters and transport in muscle. Clearly, recent evidence has established that LCFA uptake into heart and muscle is regulated acutely and chronically.
The role of uncoupling proteins in the regulation of metabolism
Authors: Erlanson‐Albertsson C.
Published: July 2003

Investigations of variations in metabolic efficiency and thermogenesis have a short and turbulent history. In small animals, non‐shivering thermogenesis and diet‐induced thermogenesis have a great impact on overall body weight, and the question is whether mechanisms to waste energy have evolved also in human energy metabolism. The candidate molecules for this adaptive thermogenesis are the uncoupling proteins. This is a newly discovered family of proteins, consisting of at least five proteins, namely UCP1, UCP2, UCP3, UCP4 and UCP5. Although a role for UCP1 in thermogenesis is unequivocal, the physiological function of the newer uncoupling proteins is as yet unclear. UCP1 is present in brown adipose tissue and has a well‐documented role in cold‐induced thermogenesis. The targeted disruption of the UCP1‐gene rendered animals that were cold sensitive, but not obese. UCP2 mRNA has a ubiquitous distribution in tissue, namely, in skeletal muscle, white and brown adipose tissue, the gastro‐intestinal tract, the lung and the spleen. By targeting the UCP2‐gene there was no effect on whole body energy metabolism, but instead, a reduced ability to protect against free‐radical oxygen species. UCP2 has also been shown to act as a negative regulator for insulin secretion. UCP3 is present in skeletal muscle. Targeted disruption of the UCP3‐gene gave no effect on whole body energy metabolism, but showed the mitochondria in muscle to be more coupled. In conclusion, the uncoupling proteins may be important in various specific ways, as protectors of free radical oxygen species and as regulators of ATP‐dependent processes.
GLUT4 activation: thoughts on possible mechanisms
Authors: Michelle Furtado L. , Poon V. , Klip A.
Published: July 2003

A family of facilitative glucose transporters or GLUTs mediates glucose uptake by cells and tissues. The glucose transporter isoform GLUT4, which is the predominant isoform expressed in mature muscle and fat tissues, is primarily responsible for the increase in glucose uptake in response to insulin stimulation. Recent work in our laboratory suggests that there are two divergent responses initiated by insulin stimulation. The first response involves the recruitment of GLUT4 transporters from intracellular reserves and their subsequent insertion into the plasma membrane. The second pathway results in an increase in the intrinsic activity of the transporters. This review will discuss evidence supporting the divergence of the two pathways regulating glucose uptake and, in particular, evidence for the increased intrinsic activity of GLUT4 in response to insulin stimulation. Inhibitors of p38 mitogen‐activated protein kinase (MAPK) affected only the arm leading to the insulin‐stimulated activation of GLUT4. This implicates p38 MAPK involvement in the regulation of this pathway. There is further evidence that p38 MAPK is itself recruited to the plasma membrane. The role of the phosphorylation state of the glucose transporter in response to insulin stimulation has been studied and indicates that, contrary to what might be predicted, there is actually a decrease in its phosphorylation at the plasma membrane in response to insulin. The relationship of this change to glucose uptake remains to be established. Other possible mechanisms regulating GLUT4 activity include binding of (+) or (−) modulators of its function.
Peroxisome proliferator‐activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle
Authors: Gilde A. J. , Van Bilsen M.
Published: July 2003

The peroxisome proliferator‐activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. The three isoforms (PPARα, β/δ and γ) have been implicated in the regulation of the expression of genes involved in lipid metabolism. Although their prominent role in lipid homeostasis is well established, the way in which the activity of each of the PPAR isoforms is regulated under physiological and pathological conditions is still subject of intensive research. In skeletal as well as cardiac muscle cells it has been demonstrated that the expression of a large panel of proteins involved in the transport and metabolic conversion of fatty acids is under control of PPARs. The pivotal role of the PPARα isoform in cardiac fatty acid metabolism has been confirmed in PPARα‐null mice. The exact role of PPARβ/δ in the regulation of muscle metabolism is still a matter of debate. Whereas several studies provided evidence to support the notion that PPARα and PPARβ/δ have redundant roles, other studies suggest that PPARα activity is counteracted by PPARβ/δ. Marked effects of bona fide PPARγ ligands (the anti‐diabetic thiazolidinediones) on skeletal and cardiac muscle function and phenotype, have also been reported. However, next to activating PPARγ, the thiazolidinediones do affect other cellular processes as well. To date it is being realized that the control of the trans‐activating capacity of each of the PPAR isoforms is multi‐factorial and, in addition to ligand availability, depends on such factors as isoform‐specific phosphorylation and selective interaction with various proteins acting either as co‐activator or co‐repressor.
The role of intramuscular lipid in insulin resistance
Authors: Hegarty B. D. , Furler S. M. , Ye J. , Cooney G. J. , Kraegen E. W.
Published: July 2003

There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose–fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long‐chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC θ and ɛ). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid‐induced muscle insulin resistance. Dietary lipid‐induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both γ and α) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP‐activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3–5‐h acute free fatty acid elevation, 1–4 days intravenous glucose infusion or several weeks of high‐fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism.
Push/pull mechanisms of GLUT4 traffic in muscle cells
Authors: Rudich A. , Klip A.
Published: July 2003

Aims:  Understanding the mechanisms by which insulin regulates glucose transporter 4 (GLUT4) traffic in skeletal muscle has been a major challenge since the discoveries of glucose transporter's translocation and the cloning of GLUT4. Here we summarize our work of the past 5 years on the regulation of GLUT4 traffic in skeletal muscle cells.

Methods:  L6 cells overexpressing GLUT4 harbouring an exofacial myc epitope gave us the opportunity to perform dynamic assessments of GLUT4 exocytosis, endocytosis, as well as a means to follow GLUT4 molecules along their journey through intracellular compartments.

Results:  We found that insulin stimulation, which results in the expected gain in surface GLUT4, is mostly attributed to enhanced GLUT4 exocytosis, and does not significantly affect the initial rate of internalization. Two mechanisms by which insulin enhances GLUT4 exocytosis are described: ‘Pull’ relates to actin remodelling‐based segregation of the insulin signalling molecules and the directed recruitment of GLUT4/VAMP2 containing vesicles. ‘Push’ is the accelerated inter‐endosomal transit of endocytosed GLUT4 molecules through the recycling endosome. The interface between the two types of regulatory input by insulin is suggested to be the budding of GLUT4 from the transferrin receptor (TfR)‐containing, recycling endosome.

Conclusions:  We propose a model on the identity of the GLUT4 pools responsible for GLUT4 recruitment to the plasma membrane in the basal state, or following insulin or hyperosmolarity stimuli.
Regulation of glycogen synthase in skeletal muscle during exercise
Authors: Nielsen J. N. , Richter E. A.
Published: July 2003

Glycogen synthase (GS) catalyses the incorporation of uridine diphosphate‐glucose into glycogen in skeletal muscle. In concert with the glucose transport step, GS activity is thought to be rate‐limiting in the disposal of glucose as muscle glycogen. Glycogen synthase is regulated by both allosteric factors (primarily glucose 6‐phosphate) and covalent modification by reversible phosphorylation and dephosphorylation leading to inactivation and activation of GS, respectively. Exercise activates both stimulatory and inhibitory regulators of GS and it is thought that the resultant activity of GS during exercise depends on the relative strength of opposing signals. However, the mechanisms by which exercise regulates GS activity are not fully understood. Glycogen breakdown, the GM–protein phosphatase 1 complex and possibly cellular relocalization of GS may be considered important factors involved in the stimulation of GS activity during exercise, while adenosine monophosphate‐activated protein kinase and plasma adrenaline (via protein kinase A) can be considered as essential for the exercise‐induced inhibitory signals to GS.
Cytoplasmic fatty acid‐binding protein facilitates fatty acid utilization by skeletal muscle
Authors: Glatz J. F. C. , Schaap F. G. , Binas B. , Bonen A. , Van Der Vusse G. J. , Luiken J. J. F. P.
Published: July 2003

The intracellular transport of long‐chain fatty acids in muscle cells is facilitated to a great extent by heart‐type cytoplasmic fatty acid‐binding protein (H‐FABP). By virtue of the marked affinity of this 14.5‐kDa protein for fatty acids, H‐FABP dramatically increases their concentration in the aqueous cytoplasm by non‐covalent binding, thereby facilitating both the transition of fatty acids from membranes to the aqueous space and their diffusional transport from membranes (e.g. sarcolemma) to other cellular compartments (e.g. mitochondria). Striking features are the relative abundance of H‐FABP in muscle, especially in oxidative muscle fibres, and the modulation of the muscular H‐FABP content in concert with the modulation of other proteins and enzymes involved in fatty acid handling and utilization. Newer studies with mice carrying a homozygous or heterozygous deletion of the H‐FABP gene show that, in comparison with wild‐type mice, hindlimb muscles from heterozygous animals have a markedly lowered (−66%) H‐FABP content but unaltered palmitate uptake rate, while in hindlimb muscles from homozygous animals (no H‐FABP present) palmitate uptake was reduced by 45%. These findings indicate that H‐FABP is present in relative excess and plays a substantial, but merely permissive role in fatty acid uptake by skeletal muscles.
Fate of fatty acids at rest and during exercise: regulatory mechanisms
Authors: Jensen M. D.
Published: July 2003

Fatty acids are a major fuel source for humans both at rest and during exercise. Plasma free fatty acids (FFA), although present only in micromolar concentrations, are the major circulating lipid fuel. FFA availability can increase two‐ to four‐fold with moderate intensity exercise. Other potential sources of fatty acids include circulating very low‐density lipoprotein (VLDL) triglycerides (TGs) (∼1/5 the fuel availability of FFA) and intramyocellular TGs (∼2 mmol kg−1 muscle). At rest ∼40% of systemic FFA uptake occurs in the splanchnic bed and uptake in legs is ∼15–20%. During leg exercise the uptake of FFA in leg tissue increases to 30–60% of systemic uptake and splanchnic uptake decreases to 15%. The fate of VLDL TG fatty acids has not been adequately studied. Intramyocellular TG hydrolysis increases during exercise, but the factors that regulate this response are not clear. The fact that contraction of isolated muscles can stimulate the hydrolysis and oxidation of intramyocellular TGs (in the absence of hormonal or neural input) suggests an intracellular regulation of this process. Additional regulation from changes in catecholamines and insulin may also occur. During moderate intensity exercise circulating FFA and intramyocellular TG provide roughly equal portions of fatty acids for oxidation. In addition to endurance training, dietary factors have been shown to modulate the fatty acid oxidation response to exercise. Much remains to be learned about fatty acid trafficking during exercise. What role do VLDL TG play? How is the oxidation of intramyocellular TGs regulated? Techniques to address these questions in humans are only now becoming available.
Frequent association between MEN 2A and cutaneous lichen amyloidosis
Authors: Verga Uberta , Fugazzola Laura , Cambiaghi Stefano , Pritelli Chiara , Alessi Elvio , Cortelazzi Donatella , Gangi Emanuela , Beck‐Peccoz Paolo
Published: July 2003

objective Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are genetic diseases due to activating mutations of the RET proto‐oncogene. Affected patients develop medullary thyroid carcinoma (100%), in an isolated form (FMTC) or in association with phaeochromocytoma (30–50%), and primary hyperparathyroidism (10–20%) (MEN 2A). The presence of cutaneous lichen amyloidosis (CLA) has been anecdotally described in few families harbouring RET proto‐oncogene mutation in codon 634. The aim of the study was to evaluate the incidence of CLA in MEN 2A/FMTC families.

patients and design Ten MEN 2A/FMTC families were studied and RET gene mutations identified in all. Complete dermatological assessment was carried out in each family member. Skin biopsy for histological studies was performed in patients with CLA.

results Among 10 MEN 2A/FMTC families, the presence of CLA was found only in patients belonging to the three families with MEN 2A and RET mutation in codon 634. Nine of 25 patients (36%) with codon 634 mutation presented CLA, though two of them did not show CLA skin lesions but the typical neurological pruritus in the upper back. In all patients, neurological pruritus was present since infancy as a precocious marker of the disorder. The dermatological study of patients with CLA skin lesions added further evidence that pruritus has a pivotal role in the development of CLA, the amyloid deposition being the consequence of repeated scratching. Light microscopy revealed orthokeratotic hyperkeratosis, with elongation of the rete ridges, rare intramalpighian apoptic keratinocytes and deposits of amorphous material in the superficial dermis. Examination under ultraviolet light showed thioflavin T‐positive staining, confirming the presence of amyloid in the papillary dermis. The use of Capsaicin at the dilution of 0·025% had a mild efficacy on the cutaneous symptoms.

conclusions Among the members of the three families with MEN 2A and RET 634 mutation, the incidence of CLA was 36%, a figure similar to that reported in the literature for phaeochromocytoma (30–50%) and even higher than that for hyperparathyroidism (10–20%). The present data confirm that CLA is linked to codon 634 RET mutations and is a precocious marker of the disorder.
Thyroglobulin epitope recognition in a post iodine‐supplemented Sri Lankan population
Authors: Okosieme O. E. , Premawardhana L. D. K. E. , Jayasinghe A. , De Silva D. G. H. , Smyth P. P. A. , Parkes A. B. , Lejeune P. J. , Ruf J. , Lazarus J. H.
Published: July 2003

objective We previously reported a high prevalence of raised thyroglobulin autoantibodies (TgAb) in apparently healthy Sri Lankan schoolgirls following salt iodination. To characterize these antibodies further we determined the epitopes on thyroglobulin (Tg) with which they react and compared these with serum obtained from both healthy subjects and established autoimmune thyroid disease (AITD) patients from the UK. To extend our study to a wider population within Sri Lanka, we in addition determined the epitopes recognized by a group of AITD patients selected from a thyroid clinic in Sri Lanka, as well as apparently healthy female Sri Lankan tea workers of distinct ethnicity from the schoolgirls and AITD patients.

design Sri Lankan schoolgirls (n = 282) and adult female tea estate workers (n = 208) were examined for thyroid autoimmune markers. Sera with high TgAb (> 98 kIU/l) were selected from these two groups (n = 36 and 45, respectively) to study epitope‐binding patterns. We also examined the sera from 16 AITD patients attending a thyroid clinic in Colombo, 16 patients with AITD from the thyroid clinic at the University Hospital of Wales and 16 sera from healthy control UK women with no evidence of thyroid disease. To determine the epitopes on Tg recognized by the subjects’ TgAb, we employed a panel of Tg mouse monoclonal antibodies labelled with alkaline phosphatase in a competitive enzyme‐linked immunosorbent assay reaction with the subjects’ serum.

results and conclusions A majority of the Sri Lankan schoolgirls did not react with the immunodominant epitopes and did not differ significantly from healthy subjects from the UK in their Tg epitope recognition pattern. On the other hand, tea estate workers and Sri Lankan AITD patients recognized typical autoimmune thyroid disease epitopes and, in addition, recognized a separate cluster not previously associated with either the autoimmune state or the healthy state. The significance of this cluster requires further clarification.