bluuebunny/crossref_metadata_2025 huggingface dataset:
Probing the Origins of Voids in the Distribution of Galaxies
Authors: Ord Louise M. , Kunz Martin , Mathis Hugues , Silk Joseph
Published: April 2005

If the voids that we see today in the distribution of galaxies existed at recombination, they will leave an imprint on the cosmic microwave background (CMB). On the other hand, if these voids formed much later, their effect on the CMB will be negligible and will not be observed with the current generation of experiments. In this paper, presented at the 2004 Annual Scientific Meeting of the Astronomical Society of Australia, we discuss our ongoing investigations into voids of primordial origin. We show that if voids in the cold dark matter distribution existed at the epoch of decoupling, they could contribute significantly to the apparent rise in CMB power on small scales detected by the Cosmic Background Imager (CBI) Deep Field. Here we present our improved method for predicting the effects of primordial voids on the CMB in which we treat a void as an external source in the cold dark matter (CDM) distribution employing a Boltzmann solver. Our improved predictions include the effects of a cosmological constant (Λ) and acoustic oscillations generated by voids at early times. We find that models with relatively large voids on the last scattering surface predict too much CMB power in an Einstein–de Sitter background cosmology but could be consistent with the current CMB observations in a ΛCDM universe.
Macro‐video documentation patch tests
Authors: Schuster Christian , Kränke Birger , Szolar‐Platzer Christiane , Aberer Werner
Published: April 2005

An unequivocal distinction between allergic and irritant patch test reactions is often difficult with patch tests. This study was designed to evaluate the worth of video‐macro camera documentation for differentiation between allergic and irritant test reactions and to investigate whether there are characteristic clinical differences in patch test responses between metal salts and fragrances. Patch testing was performed with nickel sulfate, fragrance mix and an irritant, sodium lauryl sulfate 1% aq., on the upper back of 82 patients, with evaluation and computer‐aided video documentation after 48 and 72 hr. No reliable clinicomorphological criterion was found for assessing a weak patch test reaction as being definitely allergic. Even characteristic papules and vesicles were not regularly found in allergic reactions. However, unlike fragrance mix, patch test reactions to nickel sulfate were characteristic in that they showed a heterogeneous spread and an association with hair follicle openings, independent of reaction intensity. Evaluation based on additional computer‐aided video‐macro camera documentation did not add further advantage for the differentiation of allergic and irritant reactions. But well‐defined clinicomorphological features and reaction patterns to single test substances or even whole substance categories could be helpful additional criteria for evaluating patch test responses in clinical practice.
Contact allergy to gold in patients with gold‐plated intracoronary stents
Authors: Svedman C. , Tillman C. , Gustavsson C. G. , Möller H. , Frennby B. , Bruze M.
Published: April 2005

An increasingly common and effective method for the treatment of atherosclerotic disease in the coronary arteries is percutaneous transluminal coronary angioplasty (PTCA) and stenting. The stents are made of different metals. An increased rate of restenosis when using gold‐plated stents has been shown. Contact allergy to gold is common in many countries. Recently, a study has shown an increased rate of contact allergy to nickel among patients with restenosis and a nickel‐containing stent. The aims of our study were to investigate whether there was an increased rate of contact allergy to gold among patients with gold‐plated stents and if this increased the risk of restenosis. 22 patients who had received a gold‐plated stent were patch tested. An age‐ and sex‐matched population of 88 patients, previously patch tested because of a suspected contact dermatitis, served as controls. In the stent group, 10/22 (45.5%) had a contact allergy to gold, in the control group 18/88 (20.5%); the difference is statistically significant (P = 0.04). There was no significant difference regarding frequency of restenosis. Our study indicates that there is a risk of sensitizing the patient when implanting a gold‐plated stent. Further studies are needed to confirm these results and to evaluate whether there is an increased risk of restenosis.
Patch testing with a new fragrance mix detects additional patients sensitive to perfumes and missed by the current fragrance mix
Authors: Frosch Peter J. , Pirker Claudia , Rastogi Suresh C. , Andersen Klaus E. , Bruze Magnus , Svedman Cecilia , Goossens An , White Ian R. , Uter Wolfgang , Arnau Elena Giménez , Lepoittevin Jean‐Pierre , Menné Torkil , Johansen Jeanne Duus
Published: April 2005

The currently used 8% fragrance mix (FM I) does not identify all patients with a positive history of adverse reactions to fragrances. A new FM II with 6 frequently used chemicals was evaluated in 1701 consecutive patients patch tested in 6 dermatological centres in Europe. FM II was tested in 3 concentrations – 28% FM II contained 5% hydroxyisohexyl 3‐cyclohexene carboxaldehyde (Lyral®), 2% citral, 5% farnesol, 5% coumarin, 1% citronellol and 10%α‐hexyl‐cinnamic aldehyde; in 14% FM II, the single constituents' concentration was lowered to 50% and in 2.8% FM II to 10%. Each patient was classified regarding a history of adverse reactions to fragrances: certain, probable, questionable, none. Positive reactions to FM I occurred in 6.5% of the patients. Positive reactions to FM II were dose‐dependent and increased from 1.3% (2.8% FM II), through 2.9% (14% FM II) to 4.1% (28% FM II). Reactions classified as doubtful or irritant varied considerably between the 6 centres, with a mean value of 7.2% for FM I and means ranging from 1.8% to 10.6% for FM II. 8.7% of the tested patients had a certain fragrance history. Of these, 25.2% were positive to FM I; reactivity to FM II was again dose‐dependent and ranged from 8.1% to 17.6% in this subgroup. Comparing 2 groups of history – certain and none – values for sensitivity and specificity were calculated: sensitivity: FM I, 25.2%; 2.8% FM II, 8.1%; 14% FM II, 13.5%; 28% FM II, 17.6%; specificity: FM I, 96.5%; 2.8% FM II, 99.5%; 14% FM II, 98.8%; 28% FM II, 98.1%. 31/70 patients (44.3%) positive to 28% FM II were negative to FM I, with 14% FM II this proportion being 16/50 (32%). In the group of patients with a certain history, a total of 7 patients were found reacting to FM II only. Conversely, in the group of patients without any fragrance history, there were significantly more positive reactions to FM I than to any concentration of FM II. In conclusion, the new FM II detects additional patients sensitive to fragrances missed by FM I; the number of false‐positive reactions is lower with FM II than with FM I. Considering sensitivity, specificity and the frequency of doubtful reactions, the medium concentration, 14% FM II, seems to be the most appropriate diagnostic screening tool.
Use of red cells preserved in extended storage media for exchange transfusion in anti‐k haemolytic disease of the newborn
Authors: Win N. , Amess P. , Needs M. , Hewitt P. E.
Published: April 2005

summary. Anti‐k is a Kell‐related antibody. There is little correlation between the maternal antibody titre and the severity of haemolytic disease of the foetus and newborn, and anaemia is usually associated with low bilirubin levels. Severe erythroblastosis has been reported with a low titre anti‐k (IAT 8–16). We report a case of severe haemolytic disease of the newborn (HDN) due to anti‐k. HDN was associated with a normal bilirubin level and reticulocytopenia. The foetus was monitored by ultrasound, and delivery by elective caesarean section (CS) was planned. The mother was admitted 1 week before the expected date of delivery, and the infant was delivered by urgent CS. The infant required exchange transfusion. As suitable plasma‐reduced (k antigen–) red cell units were not readily available, k–SAGM red cell units (preserved in extended storage media: SAGM sodium chloride, adenine, glucose and mannitol) were provided. The post‐transfusion Hb remained stable, and the infant did not require further transfusion support. Our findings (reticulocytopenia and normal bilirubin levels) support the hypothesis that the pathogenesis of anaemia and haemolysis in anti‐k HDN may be similar to that in anti‐K (suppression of erythropoesis and immune destruction of K+erythroid progenitor cells by macrophages in the foetal liver). The ideal product for exchange transfusion is plasma‐reduced RBC, less than 5‐days old. We provided a 4‐day‐old SAGM red cell unit for exchange transfusion in a term infant, and this was uneventful. Caution should be taken, however, and renal function and electrolyte levels should be monitored closely. More information is required regarding the safety of SAGM units for exchange transfusion.
The α‐amylase inhibitor of bean seed: two‐step proteolytic maturation in the protein storage vacuoles of the developing cotyledon
Authors: Santino Angelo , Daminati M. Gloria , Vitale Alessandro , Bollini Roberto
Published: April 2005

In bean [Phaseolus vulgaris L.) seeds, the α‐amylase inhibitor (αAI) is a major lectin‐related protein. We describe here its synthesis and accumulation in the protein storage vacuole (PSV) of cotyledonary cells of the developing seed. α‐Amylase inhibitor is synthesized on the endoplasmic reticulum where it is glycosylated to yield two major glycoforms. In common with other vacuolar seed proteins. αAl is transported to the PSV along the secretory pathway. via Golgi‐derived vesicles. In the Golgi complex, some of the oligosaccliaride side chains are modified. The precursor is then transported into the PSV, where the final maturation occurs in two steps. Firstly a few amino acids are removed from the C terminus, then the polypeptide is cleaved endoproteolytically to give the mature αAl form, consisting of 5 major polypeptides in the M1 range of 15000–20000. The absence of oligosaccharide side chains or their presence in the unmodified form appear to be unrelated to either intracellular transport and maturation of αA1 in the PSV.
Control of carbohydrate metabolism in a starchless mutant of Arbidopsis thaliana
Authors: Sicher Richard C. , Kremer Diane F.
Published: April 2005

The biochemical regulation of photosynthate partitioning was investigated in a starchless mutant (TC7) of Arabidopsts thaliana (L.) Henyh, that was deficient in chloroplast phosphoglucomutase (Caspar et al. 1985. Plant Physiol. 79: 11–17). Plants were raised at 20°C with a 20 h light and 4 h dark period, so that the growth rates of the mutant and wild type were similar. Two or 3 isoforms of phosphoglucomutase were separated by ion‐exchange chromatography using mutant and wild type leaf preparations, respectively. Initial rate kinetics of all isoforms were similar. Light‐saturated photosynthetic oxygen evolution rates of the mutant and wild type were 224 and 302 nmol g‐1 chlorophyll h‐1, respectively. Starch, sucrose and hexose concentrations were unchanged in wild type leaves after a dark to light transition, whereas sucrose and hexose increased in mutant leaves. Hexose‐phosphates accumulated in both genotypes in the light, although the steady‐state leaf concentrations of glucose 6‐phosphate were 3‐fold higher in mutant than in wild type samples. Fructose 2,6‐bisphosphate and glucose 1,6‐bisphosphate were lower in the mutant than in the wild type at the end of the dark period when mutant leaves were depleted of carbohydrates. Levels of UTP were lower in the mutant than in the wild type, possibly indicating that growth conditions had induced phosphate limited photosynthesis. These results are discussed in relation to the regulation of photosynthetic carbon metabolism.
Abscisic acid increases the content of free polyamines and delays mitotic activity induced by spermine in isolated embryonic axes of chick‐pea seeds
Authors: Bueno Milagros , Matilla Angel
Published: April 2005

The effects of abscisic acid (ABA) on the free polyamine: spermine (Spm), spermidine (Spd), putrescine (Put) and cadaverine (Cad) content, mitotic index (MI) and DNA synthesis have been studied in embryonic axes isolated from chick‐pea (Cicer ariennum L.) seeds. Spermine and spermidine decreased in controls during the first 24 h of germination, the former by 70% and the latter by 20%. This decrease was slowed down by ABA (5 μM or 25 μM) in response to its concentration; at 24 h the values for Spm and Spd were 3‐fold and 1.5‐fold those of the controls, respectively. Exogenous ABA induced the synthesis of Put from 0 to 24 h, by which time the content of this polyamine had doubled. The controls at 24 h registered the same Put content as those with 25 μM ABA, suggesting that ABA had ceased to induce Put synthesis. The pattern for cadaverine ABA‐induced synthesis was similar to that of Put. From 18 to 24 h, however, the level of Cad in the controls was 3 times higher than in the treatments. The mitotic index in meristem cells reached a maximum at 30–36 h, when cell elongation stopped in the sub‐apical region. This maximum was lowered by exogenous ABA in response to the concentration and occurred 12 h earlier in the presence of Spm (0.1–1.0 mM), which induced high MI levels during the period studied. With 10 mM Spm, two complete waves of mitosis were observed, but when Spm and ABA were added together, the tetramine had no observable effect. Spermine stimulated 3H‐thymidine uptake as well as DNA synthesis, with a maximum at 12 h, but did not counteract the inhibitory effect of ABA. Our results suggest that ABA causes changes in mitotic activity that Spm cannot overcome.
Fast‐track barium enema: meeting the two‐week wait rule for patients with suspected colorectal cancer
Authors: Glancy D. G. , Card M. , Sylvester P. A. , Thomas M. G. , Durdey P. , Callaway M. , Virjee J.
Published: April 2005

Objectives  To meet the introduction of the two‐week wait (TWW) rule for patients with suspected colorectal cancer, a fast‐track barium enema (FTBE) service was set up. This study was conducted to evaluate the success of this approach in preparation for meeting the forthcoming targets on waiting times to treatment from referral and diagnosis.

Methods  All patients were offered a double‐contrast barium enema within two‐weeks, except those with a palpable rectal mass. FTBE were double‐reported by specialist gastrointestinal radiologists. Patients with a suspected malignancy were booked for an urgent staging CT and outpatient appointment, whilst the remaining patients were referred back to their general practitioner with a report. Prospective data were collected and two 16‐month periods analysed.

Results  Three hundred and nine patients had a FTBE over the first 16‐month period and 277 (89.6%) were seen within two‐weeks. Mean times from initial referral to staging CT and first outpatient appointment were 30.7 and 36.0 days, respectively. Cancer was confirmed histologically in 32 (10.4%) patients. Of 267 patients without a malignancy, 46 (17.2%) were referred back to the colorectal outpatient or endoscopy service within 6‐months. The number of referrals increased with time from a mean of 19.3 per month in the first period to 27.8 in the second, but the percentage with a suspected malignancy remained similar at 13.6% and 10.1%, respectively.

Conclusion  FTBE diagnosed malignancy accurately and facilitated rapid staging. The TWW target was met in almost 90% of patients, whilst the impact on the colorectal outpatient and endoscopy service was minimized.
Skipped spawning in female iteroparous fishes
Authors: Rideout Rick M , Rose George A , Burton Margaret P M
Published: April 2005

It is often assumed that iteroparous fishes spawn annually once reaching sexual maturity, but this is not always the case. This paper reviews available information on skipped spawning in female teleost fishes. All instances of non‐annual spawning are described as one of three types (retaining, reabsorbing, resting), depending on where in the normal spawning cycle development has been interrupted. Retaining ripe eggs is caused by conditions experienced during the spawning season (fish density, mate availability, pollution), whereas failure to start vitellogenesis (resting) or the breakdown of all oocytes that enter into vitellogenesis (reabsorbing) is caused by factors experienced prior to the spawning season (primarily temperature and poor nutrition). It is speculated that the relative shortage of data on non‐annual spawning may be because of difficulties in identifying non‐reproductive individuals. In an attempt to rectify this situation, the criteria needed to identify females undergoing the three forms of spawning omission are presented in terms of external appearance of gonads, gonad indices, and histological analysis. The energy saved by not spawning in a poor year may lead to increased survival and the probability of spawning in subsequent years. As the cumulative number of progeny gained by surviving to spawn in multiple subsequent years outweighs the number of progeny lost by not spawning in a given single year, occasional omission of spawning may constitute an adaptive trait in long‐lived iteroparous fishes.
Principles and approaches to abate seabird by‐catch in longline fisheries
Authors: Gilman Eric , Brothers Nigel , Kobayashi Donald R.
Published: April 2005

Mortality in longline fisheries is a critical global threat to most albatross and large petrel species. Here we identify key principles and approaches to identify and achieve broad use of effective seabird by‐catch avoidance methods. Despite the availability of highly effective and cost‐saving seabird avoidance methods, few longline fleets employ them. Given the political context and capacity of management authorities of the majority of longline fisheries, it is critical to identify seabird avoidance strategies that are not only highly effective, but are also economically viable and commercially practical. Adoption of an international performance standard for longline baited hook–sink rate, and prescribing minimum gear weighting designs that meet this standard that are achievable by all longline fisheries, would be an important step forward towards resolving low use of seabird avoidance methods by vessels, including those in illegal, unregulated and unreported fisheries. Due to differences between fleets, no single seabird avoidance measure is likely to be effective and practical in all longline fisheries. Therefore, testing of seabird avoidance methods in individual fleets is needed to determine efficacy and economic viability. Longline fishers should directly participate in these trials as they have a large repository of knowledge and skills to effectively develop and improve seabird by‐catch avoidance techniques, and this provides industry with a sense of ownership for uptake of effective by‐catch reduction methods. Establishing protected areas containing seabird colonies and adjacent waters within a nation's EEZ can be an expedient method to address seabird by‐catch. However, establishing high seas marine protected areas to restrict longline fishing in seabird foraging areas, which would require extensive and dynamic boundaries and large buffer zones, may not be a viable short‐term solution because of the extensive time anticipated to resolve legal complications with international treaties, to achieve international consensus and political will, and to acquire requisite extensive resources for surveillance and enforcement. Analysis of results of research on seabird avoidance methods reveals that the most reliable comparisons of the efficacy of alternative strategies are from comparing the effectiveness of methods tested in a single experiment. Benefits from standardizing the reporting of seabird by‐catch rates to account for seabird abundance are described. To provide the most precise inputs for seabird population models, estimates of seabird mortality in longline fisheries should account for seabird falloff from hooks before hauling, delayed mortality of seabirds caught but freed from gear, and mortality caused by hooks discarded in offal.
Production of biologically active human interleukin‐4 in transgenic tobacco and potato
Authors: Ma Shengwu , Huang Yan , Davis Antonelle , Yin Ziqin , Mi Qingsheng , Menassa Rima , Brandle James E. , Jevnikar Anthony M.
Published: April 2005

Interleukin‐4 (IL‐4) is a pleiotropic cytokine that plays a key regulatory role in the immune system. Recombinant human IL‐4 (rhIL‐4) offers great potential for the treatment of cancer, viral and autoimmune diseases. Unfortunately, the high production cost of IL‐4 associated with conventional expression systems has, until now, limited broader clinical testing, particularly with regard to the more convenient and safer oral delivery of IL‐4 as opposed to parenteral injection in patients. In this study, we investigated the feasibility of transgenic plants for the cost‐effective production of rhIL‐4. IL‐4 expression vectors with different modifications under the control of a constitutive cauliflower mosaic virus 35S (CaMV 35S) promoter were introduced into tobacco by Agrobacterium‐mediated transformation. Transgenic tobaccos expressing various levels of rhIL‐4 protein were generated. Higher expression was achieved through IL‐4 retention in the endoplasmic reticulum (ER), with the maximal accumulation being approximately 0.1% of total soluble protein (TSP) in the leaves. No improvement in expression was further achieved by replacing the native signal peptide of IL‐4 with the plant signal peptide. The best rhIL‐4‐expressing vector shown in tobacco was selected and further transferred into potato plants. The analysis of transgenic tubers also revealed various levels of rhIL‐4, with the highest being 0.08% of TSP. Sensitive in vitro T‐cell proliferation assays showed that plant‐derived rhIL‐4 retained full biological activity. These results suggest that plants can be used to produce biologically active rhIL‐4 and probably many other mammalian proteins of medical significance. Moreover, the production of plants expressing rhIL‐4 will enable the testing of plant rhIL‐4 by oral delivery for the treatment of clinical diseases.
The gene for fragrance in rice
Authors: Bradbury Louis M. T. , Fitzgerald Timothy L. , Henry Robert J. , Jin Qingsheng , Waters Daniel L. E.
Published: April 2005

The flavour or fragrance of basmati and jasmine rice is associated with the presence of 2‐acetyl‐1‐pyrroline. A recessive gene (fgr) on chromosome 8 of rice has been linked to this important trait. Here, we show that a gene with homology to the gene that encodes betaine aldehyde dehydrogenase (BAD) has significant polymorphisms in the coding region of fragrant genotypes relative to non‐fragrant genotypes. The accumulation of 2‐acetyl‐1‐pyrroline in fragrant rice genotypes may be explained by the presence of mutations resulting in a loss of function of the fgr gene product. The allele in fragrant genotypes has a mutation introducing a stop codon upstream of key amino acid sequences conserved in other BADs. The fgr gene corresponds to the gene encoding BAD2 in rice, while BAD1 is encoded by a gene on chromosome 4. BAD has been linked to stress tolerance in plants. However, the apparent loss of function of BAD2 does not seem to limit the growth of fragrant rice genotypes. Fragrance in domesticated rice has apparently originated from a common ancestor and may have evolved in a genetically isolated population, or may be the outcome of a separate domestication event. This is an example of effective human selection for a recessive trait during domestication.
Hobnail haemangioma associated with the menstrual cycle
Authors: Ortiz‐Rey JA , González‐Ruiz A , Miguel P San , Álvarez C , Iglesias B , Antón I
Published: April 2005

We report the third case in the literature of a hobnail haemangioma with cyclic changes throughout the menstrual cycle in a 36‐year‐old woman, suggesting a hormonal basis for the variations in the tumour. This patient was under oral contraceptive treatment due to ovarian endometriosis, making the clinical diagnosis difficult.
Rosacea and its management: an overview
Authors: Gupta AK , Chaudhry MM
Published: April 2005

Background  Rosacea is a chronic inflammatory disorder that affects 10% of the population. The prevalence of rosacea is highest among fair‐skinned individuals, particularly those of Celtic and northern European descent. Since a cure for rosacea does not yet exist, management and treatment regimens are designed to suppress the inflammatory lesions, erythema, and to a lesser extent, the telangiectasia involved with rosacea.

Objectives  This review outlines the treatment options that are available to patients with rosacea.

Methods  Published literature involving the treatment or management of rosacea was examined and summarized.

Results  Patients who find that they blush and flush frequently, or have a family history of rosacea are advised to avoid the physiological and environmental stimuli that can cause increased facial redness. Topical agents such as metronidazole, azelaic acid cream or sulfur preparations are effective in managing rosacea. Patients who have progressed to erythematotelangiectatic and papulopustular rosacea may benefit from the use of an oral antibiotic, such as tetracycline, and in severe or recalcitrant cases, isotretinoin to bring the rosacea flare‐up under control. Treatment with a topical agent, such as metronidazole, may help maintain remission. Patients with ocular involvement may benefit from a long‐term course of an antibiotic and the use of metronidazole gel. A surgical alternative, laser therapy, is recommended for the treatment of telangiectasias and rhinophyma. Patients with distraught feelings due to their rosacea may consider cosmetic camouflage to cover the signs of rosacea.

Conclusions  With the wide variety of oral and topical agents available for the effective management of rosacea, patients no longer need to feel self‐conscious because of their disorder.
Apolipoprotein J (clusterin) activates rodent microglia in vivo and in vitro
Authors: Xie Z. , Harris‐White M. E. , Wals P. A. , Frautschy S. A. , Finch C. E. , Morgan T. E.
Published: April 2005

Apolipoprotein J (apoJ; also known as clusterin and sulfated glycoprotein (SGP)‐2) is associated with senile plaques in degenerating regions of Alzheimer's disease brains, where activated microglia are also prominent. We show a functional link between apoJ and activated microglia by demonstrating that exogenous apoJ activates rodent microglia in vivo and in vitro. Intracerebroventricular infusion of purified human plasma apoJ (∼4 µg over 28 days) activated parenchymal microglia to a phenotype characterized by enlarged cell bodies and processes (phosphotyrosine immunostaining). In vitro, primary rat microglia were also activated by apoJ, with changes in morphology and induction of major histocompatibility complex class II (MHCII) antigen. ApoJ increased the secretion of reactive nitrogen intermediates in a dose‐dependent manner (EC50 112 nm), which was completely blocked by aminoguanidine (AG), a nitric oxide synthase inhibitor. However, AG did not block the increased secretion of tumor necrosis factor‐α by apoJ (EC50 55 nm). Microglial activation by apoJ was also blocked by an anti‐apoJ monoclonal antibody (G7), and by chemical cleavage of apoJ with 2‐nitro‐5‐thiocyanobenzoate. The mitogen‐activated protein kinase kinase and protein kinase C inhibitors PD98059 and H7 inhibited apoJ‐mediated induction of reactive nitrogen intermediate secretion from cultured microglia. As a functional measure, apoJ‐activated microglia secreted neurotoxic agents in a microglia–neuron co‐culture model. We hypothesize that ApoJ contributes to chronic inflammation and neurotoxicity through direct effects on microglia.
Stromal cell‐derived factor‐1α directly modulates voltage‐dependent currents of the action potential in mammalian neuronal cells
Authors: Guyon A. , Rovère C. , Cervantes A. , Allaeys I. , Nahon J. L.
Published: April 2005

Stromal cell‐derived factor‐1α (SDF‐1α) is a chemokine whose receptor, CXCR4, is distributed in specific brain areas including hypothalamus. SDF‐1α has recently been found to play important roles in neurons, although direct modulation of voltage‐gated ionic channels has never been shown. In order to clarify this issue, we performed patch‐clamp experiments in fetal mouse hypothalamic neurons in culture. SDF‐1α (10 nm) decreased the peak and rising slope of the action potentials and spike discharge frequency in 22% of hypothalamic neurons tested. This effect was blocked by the CXCR4 antagonist AMD 3100 (1 µm) but not by the metabotropic glutamate receptor antagonist MCPG (500 µm), indicating a direct action of SDF‐1α on its cognate receptor. This effect involved a depression of both inward and outward voltage‐dependent currents of the action potential. We confirmed these effects in the human neuroblastoma cell line SH‐SY5Y, which endogenously expresses CXCR4. Voltage‐clamp experiments revealed that SDF‐1α induced a 20% decrease in the peak of the tetrodotoxin‐sensitive sodium current and tetraethylammonium‐sensitive delayed rectifier potassium current, respectively. Both effects were concentration dependent, and blocked by AMD 3100 (200 nm). This dual effect was reduced or blocked by 0.4 mm GTPγS G‐protein pre‐activation or by pre‐treatment with the G‐protein inhibitor pertussis toxin (200 ng/mL), suggesting that it is mediated via activation of a Gi/o protein. This study extends the functions of SDF‐1α to a direct modulation of voltage‐dependent membrane currents of neuronal cells.
Prion protein glycosylation
Authors: Lawson Victoria A. , Collins Steven J. , Masters Colin L. , Hill Andrew F.
Published: April 2005

The transmissible spongiform encephalopathies (TSE), or prion diseases are a group of transmissible neurodegenerative disorders of humans and animals. Although the infectious agent (the ‘prion’) has not yet been formally defined at the molecular level, much evidence exists to suggest that the major or sole component is an abnormal isoform of the host encoded prion protein (PrP). Different strains or isolates of the infectious agent exist, which exhibit characteristic disease phenotypes when transmitted to susceptible animals. In the absence of a nucleic acid genome it has been hard to accommodate the existence of TSE strains within the protein‐only model of prion replication. Recent work examining the conformation and glycosylation patterns of disease‐associated PrP has shown that these post‐translational modifications show strain‐specific properties and contribute to the molecular basis of TSE strain variation. This article will review the role of glycosylation in the susceptibility of cellular PrP to conversion to the disease‐associated conformation and the role of glycosylation as a marker of TSE strain type.
“ENVIRONMENT”, “NEEDS” AND REAL INCOME COMPARISONS(1)
Authors: Beckerman W.
Published: April 2005

Conventional measures of national product make no pretence of including everything that affects welfare. As increasing attention is being paid to environmental pollution, the problem of incorporating certain non‐economic variables into the analysis of well‐being becomes more relevant. The object of this note is to show how a difference in “needs” for, and hence expenditures on, anti‐pollutants, which will show up in conventional national accounts comparisons as differences in “tastes”, should be converted into differences in real income.
Seizure‐associated Abnormalities in Epilepsy: Evidence from MR Imaging
Authors: Briellmann Regula S. , Wellard R. Mark , Jackson Graeme D.
Published: April 2005

Summary: Acute seizure‐associated changes have been described in the animal and human literature. Controversy exists over whether seizures cause permanent damage to the brain, and whether a (prolonged) seizure can induce changes that lead to an epileptic lesion, resulting in habitual seizures and epilepsy. Current magnetic resonance imaging (MRI) offers a variety of imaging tools and is capable of detecting acute seizure‐associated changes. In contrast to the histologic examination, serial MRI studies are possible and allow longitudinal observation of the fate of these changes. This report reviews the literature on acute seizure‐associated effects emphasizing the MRI evidence.
SIV‐specific T lymphocyte responses in PBMC and lymphoid tissues of SIV‐infected pigtailed macaques during suppressive combination antiretroviral therapy
Authors: Carruth Lucy M. , Christine Zink M. , Tarwater Patrick M. , Miller Michael D. , Li Ming , Queen Laurie A. , Mankowski Joseph L. , Shen Anding , Siliciano Robert F. , Clements Janice E.
Published: April 2005

Abstract:  There is currently no SIV macaque model in which the effects of combination antiretroviral therapy on tissue immune responses and latent reservoirs have been measured. This study was performed to define the impact of combination therapy on the specificity and distribution of the T lymphocyte response in multiple tissue compartments. Pigtailed macaques (Macaca nemestrina) were infected with SIV/17E‐Fr and treated with combination antiretroviral therapy consisting of 9‐R‐(2‐phosphonomethoxypropyl)adenine (PMPA) and beta‐2′,3′‐dideoxy‐3′‐thia‐5‐fluorocytidine (FTC). The SIV‐specific T lymphocyte response was measured in peripheral blood, spleen and several lymph nodes at necropsy by IFN‐γ Elispot analysis. Two animals (one treated, one untreated) had high acute peak viremia, which was associated with lower SIV‐specific T lymphocyte responses in the peripheral blood and lymphoid tissues. In the treated animal, viremia was controlled to low or undetectable for the study duration, and virus‐specific responses remained low. The untreated animal remained viremic throughout the study and developed clinical symptoms of AIDS. In contrast, the two animals that had lower acute peak viremia (one treated, one untreated) had more robust T lymphocyte responses, and controlled viral replication. Virus‐specific responses were detected in the treated animal despite 6 months of suppressive therapy. These data suggest that in this model, in the context of acute peak viremia and weak T cell responses, combination therapy may be essential to control virus replication and disease progression. Conversely, in the setting of low initial viremia and robust T lymphocyte responses, treatment does not have a detrimental effect on the immune response.
Assessment of nutritional status in rhesus monkeys: comparison of dual‐energy X‐ray absorptiometry and stable isotope dilution
Authors: Blanc Stéphane , Colman Ricki , Kemnitz Joseph , Weindruch Richard , Baum Scott , Ramsey Jon , Schoeller Dale
Published: April 2005

Abstract:  Body composition estimates from dual‐energy X‐ray absorptiometry and stable isotope dilution (2H and 18O) were compared in 61 rhesus monkeys (Macaca mulatta) from the ongoing long‐term energy restriction study at the University of Wisconsin. Their average age was 18.9 ± 2.5 y/o. Of the animals, 51% were in the energy restricted group and 38% were females. Although the correlation between methods was highly significant for fat mass (R2 = 0.97, SEE = 0.25 kg or 7.5%, P < 0.0001) and fat‐free mass (R2 = 0.98, SEE = 0.29 kg or 3.6%, P < 0.0001), we observed that dual‐energy X‐ray absorptiometry underestimated fat mass by 0.67 ± 0.26 kg (7.5%, P < 0.0001) and overestimated fat‐free mass by 0.57 ± 0.29 kg (20%, P < 0.0001) when compared with isotope dilution. Taken together with data from the literature, the present results emphasize the usefulness of dual‐energy X‐ray absorptiometry to derive body composition and thus nutritional status in monkeys, but demonstrate the importance of validation experiments for a given DXA model and software.
The Immune Response to Human Metapneumovirus Is Associated with Aberrant Immunity and Impaired Virus Clearance in BALB/c Mice
Authors: Alvarez Rene , Tripp Ralph A.
Published: April 2005

Human metapneumovirus (HMPV), recently identified in isolates from children hospitalized with acute respiratory tract illness, is associated with clinical diagnosis of pneumonia, asthma exacerbation, and acute bronchiolitis in young children. HMPV has been shown to cocirculate with respiratory syncytial virus (RSV) and mediate clinical disease features similarly to RSV. Little is known regarding the pathophysiology or immune response associated with HMPV infection; thus, animal models are needed to better understand the mechanisms of immunity and disease pathogenesis associated with infection. In this study, we examine features of the innate and adaptive immune response to HMPV infection in a BALB/c mouse model. Primary HMPV infection elicits weak innate and aberrant adaptive immune responses characterized by induction of a Th2-type cytokine response at later stages of infection that coincides with increased interleukin-10 expression and persistent virus replication in the lung. Examination of the cytotoxic T lymphocyte and antibody response to HMPV infection revealed a delayed response, but passive transfer of HMPV-specific antibodies provided considerable protection. These features are consistent with virus persistence and indicate that the immune response to HMPV is unique compared to the immune response to RSV.
Human Serum Facilitates Hepatitis C Virus Infection, and Neutralizing Responses Inversely Correlate with Viral Replication Kinetics at the Acute Phase of Hepatitis C Virus Infection
Authors: Lavillette Dimitri , Morice Yoann , Germanidis Georgios , Donot Peggy , Soulier Alexandre , Pagkalos Emanuil , Sakellariou Georgios , Intrator Liliane , Bartosch Birke , Pawlotsky Jean-Michel , Cosset François-Loïc
Published: April 2005

The factors leading to spontaneous clearance of hepatitis C virus (HCV) or to viral persistence are elusive. Understanding virus-host interactions that enable acute HCV clearance is key to the development of more effective therapeutic and prophylactic strategies. Here, using a sensitive neutralization assay based on infectious HCV pseudoparticles (HCVpp), we have studied the kinetics of humoral responses in a cohort of acute-phase patients infected during a single nosocomial outbreak in a hemodialysis center. The 17 patients were monitored for the spontaneous outcome of HCV infection for 6 months before a treatment decision was made. Blood samples were taken frequently (15 ± 4 per patient). Phylogenetic analysis of the predominant virus(es) revealed infection by only one of two genotype 1b strains. While all patients seroconverted, their sera induced two opposing effects in HCVpp infection assays: inhibition and facilitation. Furthermore, the ability of sera to facilitate or inhibit infection correlated with the presence of either infecting HCV strain and divided the patients into two groups. In group 1, the progressive emergence of a relatively strong neutralizing response correlated with a fluctuating decrease in high initial viremia, leading to control of viral replication. Patients in group 2 failed to reduce viremia within the acute phase, and no neutralizing responses were detected despite seroconversion. Strikingly, sera of group 2, as well as naïve sera, facilitated infection by HCVpp displaying HCV glycoproteins from different genotypes and strains, including those retrieved from patients. These results provide new insights into the mechanisms of viral persistence and immune control of viremia.
The Locus Encompassing the Latency-Associated Transcript of Herpes Simplex Virus Type 1 Interferes with and Delays Interferon Expression in Productively Infected Neuroblastoma Cells and Trigeminal Ganglia of Acutely Infected Mice
Authors: Peng Weiping , Henderson Gail , Inman Melissa , BenMohamed Lbachir , Perng Guey-Chuen , Wechsler Steven L. , Jones Clinton
Published: April 2005

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is the only abundant viral transcript expressed in latently infected neurons. LAT inhibits apoptosis, suggesting that it regulates latency by promoting the survival of infected neurons. The LAT locus also contains a newly described gene (AL), which is antisense to LAT and partially overlaps LAT encoding sequences. When human (SK-N-SH) or mouse (neuro-2A) neuroblastoma cells were infected with a virus that does not express LAT or AL gene products (dLAT2903), beta interferon (IFN-β) and IFN-α RNA expression was detected earlier relative to the same cells infected with HSV-1 strains that express LAT and AL. Infection of neuro-2A cells with dLAT2903 also led to higher levels of IFN-β promoter activity than in cells infected with wild-type (wt) HSV-1. In contrast, IFN RNA expression was the same when human lung fibroblasts were infected with dLAT2903 or wt HSV-1. When BALB/c mice were infected with dLAT2903, IFN-α and IFN-β RNA expression was readily detected in trigeminal ganglia (TG) 4 days after infection. These transcripts were not detected in TG of mice infected with wt HSV-1 or dLAT2903R (marker-rescued dLAT2903) until 6 days postinfection. When TG single-cell suspensions from infected BALB/c mice were prepared and incubated in vitro with wt HSV-1 as a source of antigen, TG cultures prepared from mice infected with dLAT2903 produced and secreted higher levels of IFN protein than wt HSV-1 or dLAT2903R. Collectively, these studies suggest that the LAT locus interferes with and delays IFN expression.
Immunization with the Gene Expressing Woodchuck Hepatitis Virus Nucleocapsid Protein Fused to Cytotoxic-T-Lymphocyte-Associated Antigen 4 Leads to Enhanced Specific Immune Responses in Mice and Woodchucks
Authors: Lu Mengji , Isogawa Masanori , Xu Yang , Hilken Gero
Published: April 2005

A number of options are available to modify and improve DNA vaccines. An interesting approach to improve DNA vaccines is to fuse bioactive domains, like cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), to an antigen. Such fusion antigens are expressed in vivo and directed to immune cells by the specific bioactive domain and therefore possess great potential to induce and modulate antigen-specific immune responses. In the present study, we tested this new approach for immunomodulation against hepadnavirus infection in the woodchuck model. Plasmids expressing the nucleocapsid protein (WHcAg) and e antigen (WHeAg) of woodchuck hepatitis virus (WHV) alone or in fusion to the extracellular domain of woodchuck CTLA-4 and CD28 were constructed. Immunizations of mice with plasmids expressing WHcAg or WHeAg led to a specific immunoglobulin G2a (IgG2a)-dominant antibody response. In contrast, fusions of WHcAg to CTLA-4 and CD28 induced a specific antibody response with comparable levels of IgG1 and IgG2a. Furthermore, the specific IgG1 response to WHcAg/WHeAg developed immediately after a single immunization with the CTLA-4-WHcAg fusion. Woodchucks were immunized with plasmids expressing WHeAg or the CTLA-4-WHcAg fusion and subsequently challenged with WHV. CTLA-4-WHcAg showed an improved efficacy in induction of protective immune responses to WHV. In particular, the anti-WHsAg antibody response developed earlier after challenge in woodchucks that received immunizations with CTLA-4-WHcAg, consistent with the hypothesis that anti-WHs response is dependent on a Th cell response to WHcAg. In conclusion, the use of fusion genes represents a generally applicable strategy to improve DNA vaccination.
Human Immunodeficiency Virus Type 1 Stimulates the Expression and Production of Secretory Leukocyte Protease Inhibitor (SLPI) in Oral Epithelial Cells: a Role for SLPI in Innate Mucosal Immunity
Authors: Jana N. K. , Gray L. R. , Shugars D. C.
Published: April 2005

The innate immune response is a key barrier against pathogenic microorganisms such as human immunodeficiency virus type 1 (HIV-1). Because HIV-1 is rarely transmitted orally, we hypothesized that oral epithelial cells participate in the innate immune defense against this virus. We further hypothesized that secretory leukocyte protease inhibitor (SLPI), a 12-kDa mucosal antiviral protein, is a component of the host immune response to this virus. Here we demonstrated constitutive expression and production of SLPI in immortalized human oral keratinocytes. Brief exposure of cells to HIV-1 BaL and HXB2 significantly increased SLPI mRNA and protein production compared to that in mock-exposed cells (
P
< 0.01), as evaluated by real-time quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay. HIV-1-mediated stimulation of SLPI occurred at the transcriptional level, was dose and time dependent, was elicited by heat-inactivated and infectious viruses, and did not depend on cellular infection. Experiments with purified retroviral proteins showed that the stimulatory effect was induced specifically by external envelope glycoproteins from HIV-1 and simian immunodeficiency virus. SLPI responsiveness to HIV-1 was also observed in an unrelated oral epithelial cell line and in normal (nonimmortalized) human oral epithelial cells isolated from healthy uninfected gingival tissues. In this first report of SLPI regulation by HIV-1, we show that the expression and production of the antimicrobial and anti-inflammatory protein can be stimulated in oral epithelial cells by the virus through interactions with gp120 in the absence of direct infection. These findings indicate that SLPI is a component of the oral mucosal response to HIV-1.
Functional Chimeras of Human Immunodeficiency Virus Type 1 gp120 and Influenza A Virus (H3) Hemagglutinin
Authors: Copeland K. M. , Elliot A. J. , Daniels R. S.
Published: April 2005

In an attempt to produce a protein that will allow determination of the native human immunodeficiency virus type 1 (HIV-1) gp120 (Env) structure in its trimeric state, we fused the globular head of gp120 to the stalk region of influenza virus A (X31) hemagglutinin (HA). The chimeric protein (EnvHA) has been expressed by using a recombinant vaccinia virus system, and its functional characteristics were determined. EnvHA is expressed as a 120- to 150-kDa protein that can oligomerize to form dimers and trimers. It retains the low-pH (5.2 to 5.4) requirement of X31-HA to trigger membrane fusion but, unlike X31-HA, it is not absolutely dependent on exogenously added trypsin for protein processing to release the HA2 fusion peptide. In terms of receptor binding the chimeric protein retains specificity for human CD4 but, in relation to the membrane fusion event, it appears to lose the Env coreceptor specificity of the parental HIV-1 strains: NL43 for CXCR4 and JRFL for CCR5. These properties suggest that stable, functional EnvHAs are being produced and that they may be exploited in terms of structural studies. Further, the potential of introducing the
envHA
genes into influenza viruses, by use of reverse genetics, and their use as a therapeutic vaccine for HIV are discussed.
Accumulation of Amino Acid Substitutions Promotes Irreversible Structural Changes in the Hemagglutinin of Human Influenza AH3 Virus during Evolution
Authors: Nakajima Katsuhisa , Nobusawa Eri , Nagy Alexander , Nakajima Setsuko
Published: April 2005

In order to clarify the effect of an accumulation of amino acid substitutions on the hemadsorption character of the influenza AH3 virus hemagglutinin (HA) protein, we introduced single-point amino acid changes into the HA1 domain of the HA proteins of influenza viruses isolated in 1968 (A/Aichi/2/68) and 1997 (A/Sydney/5/97) by using PCR-based random mutation or site-directed mutagenesis. These substitutions were classified as positive or negative according to their effects on the hemadsorption activity. The rate of positive substitutions was about 50% for both strains. Of 44 amino acid changes that were identical in the two strains with regard to both the substituted amino acids and their positions in the HA1 domain, 22% of the changes that were positive in A/Aichi/2/68 were negative in A/Sydney/5/97 and 27% of the changes that were negative in A/Aichi/2/68 were positive in A/Sydney/5/97. A similar discordance rate was also seen for the antigenic sites. These results suggest that the accumulation of amino acid substitutions in the HA protein during evolution promoted irreversible structural changes and therefore that antigenic changes in the H3HA protein may not be limited.