bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of multi‐factorial intervention on plasma von Willebrand factor, soluble E‐selectin and tissue factor in diabetes mellitus: implications for atherosclerotic vascular disease
Authors: Lim H. S. , Chong A. Y. , Freestone B. , Blann A. D. , Lip G. Y. H.
Published: February 2005

Background  Endothelial abnormalities and a hypercoagulable state may contribute to increased cardiovascular risk in diabetes mellitus, particularly in patients with overt cardiovascular disease (CVD). We sought to determine the effect of intensified multi‐factorial cardiovascular risk intervention on indices of endothelial abnormality and hypercoagulability in diabetes, and if patients with overt CVD would derive similar benefit as those without.

Patients and methods  We measured plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction), soluble E‐selectin (sE‐sel, marking endothelial activation) and tissue factor (TF, an initiator of coagulation) by ELISA in 94 patients with diabetes mellitus (38 with CVD and 56 without overt CVD) and 34 comparable controls. Thirty‐three patients with CVD and 31 without overt CVD then participated in multi‐factorial cardiovascular risk intervention over 1 year.

Results  Plasma levels of vWf (P = 0.009), sE‐sel (P < 0.001) and TF (P < 0.001) were significantly higher in diabetic patients compared with controls, with TF highest in patients with overt CVD. Intensive multi‐factorial intervention resulted in reductions in glycated haemoglobin (HbA1c), total and LDL‐cholesterol (all P < 0.05), but no significant weight change. This was associated with reductions in vWf in patients with (by 26%P = 0.003), and without (by 47%, P < 0.001), overt CVD. TF was reduced only in patients without overt CVD (by 45%, P < 0.001). There were no significant changes in sE‐sel levels in either group.

Conclusion  Endothelial abnormalities in diabetes are only partially influenced by contemporary intensified multi‐factorial cardiovascular risk intervention. These data suggest the need for earlier and more aggressive risk factor intervention.
Renal damage in patients with Type 2 diabetes: a strong predictor of mortality
Authors: Bo S. , Ciccone G. , Rosato R. , Gancia R. , Grassi G. , Merletti F. , Pagano G. F.
Published: February 2005

Aims  (i) To compare mortality rates in a cohort of Type 2 diabetic patients with those of the general population; (ii) to assess the prognostic role of pre‐existing chronic conditions; (iii) to evaluate the impact of different severity of renal damage on mortality.

Methods  All 3892 patients with Type 2 diabetes attending our Diabetic Clinic during 1995 and alive on 1 January 1996 were identified and followed for 4.5 years. Information on vital status (100% complete) and causes of death (98.5% complete) for 599 deceased subjects was derived from death certificates.

Results  In comparison with the general population, standardized mortality ratios (× 100) were: 125 (95% confidence interval 104–148) in patients aged < 75 and 85 (75–95) in patients ≥ 75 years. Cardiovascular diseases and diabetes were responsible for most of the excess deaths. In a Cox‐proportional hazard model, renal damage was a powerful predictor of death (hazard ratio = 2.39; 95% confidence intervals = 2.00–2.85). The severity of renal damage was associated with increasing hazard ratios for death from all‐cause mortality and from specific causes (especially coronary artery disease, other cardiovascular causes and diabetes) after multiple adjustments. Other significant predictors of death were: greater age, glycated haemoglobin, smoking, lower body mass index, pre‐existing coronary and peripheral artery disease and known co‐morbidity (cirrhosis and cancer).

Conclusions  Renal damage of any severity is significantly associated with subsequent mortality from all causes and from cardiovascular diseases. These associations are not confounded by pre‐existing co‐morbidity or coronary diseases.
Greater beneficial effects of visceral fat reduction compared with subcutaneous fat reduction on parameters of the metabolic syndrome: a study of weight reduction programmes in subjects with visceral and subcutaneous obesity
Authors: Park H. S. , Lee K.
Published: February 2005

Aims  To evaluate the effect of weight reduction on parameters of the metabolic syndrome in obese patients according to their pattern of abdominal fat distribution.

Methods  A longitudinal intervention study, consisting of a 12‐week weight reduction programme, including lifestyle modification and adjuvant appetite suppressant, in 38 subjects with visceral obesity and 47 subjects with subcutaneous obesity. Visceral, subcutaneous and total adipose tissue areas were determined by CT scan at the level of L4–L5. Parameters for components of the metabolic syndrome were measured before and after weight reduction.

Results  Reductions in body weight, BMI and subcutaneous adipose tissue area were greater in the subcutaneous than in the visceral obesity group. In contrast, changes in fasting plasma glucose, insulin, and HOMA score were higher in the visceral than in the subcutaneous obesity group. Changes in visceral adipose tissue area were significantly related to changes in fasting plasma glucose, triglycerides and HOMA score.

Conclusions  Visceral fat reduction induced greater beneficial effects on parameters of the metabolic syndrome than subcutaneous fat reduction. Evaluation of changes in abdominal fat distribution is necessary when obese subjects enter a weight reduction programme.
Reduced plasma total homocysteine concentrations in Type 1 diabetes mellitus is determined by increased renal clearance
Authors: Veldman B. A. J. , Vervoort G. , Blom H. , Smits P.
Published: February 2005

Introduction  Elevated plasma levels of total homocysteine are related to the development of vascular complications. Patients with diabetes mellitus are particularly at risk for the development of these complications. Several factors determine plasma total homocysteine including renal function.

Aims  As early Type 1 diabetes is characterized by a relative glomerular hyperfiltration, increased renal clearance could contribute to decreased levels of homocysteine as observed in Type 1 diabetes mellitus. Therefore we investigated the relationship between plasma total homocysteine and the glomerular filtration rate (GFR).

Methods  In 92 Type 1 diabetes patients and 44 control subjects, we measured GFR and effective renal plasma flow (ERPF) by means of continuous infusion of inulin and p‐aminohippurate. Fasting plasma total homocysteine was measured using high performance liquid chromatography.

Results  GFR (121 ± 21 resp. 104 ± 14 ml/min; P < 0.001) and ERPF (563 ± 127 resp. 516 ± 121 ml/min; P = 0.05) were significantly higher in Type 1 diabetes patients as compared with control subjects. Plasma total homocysteine was reduced in Type 1 diabetes patients as compared with control subjects (11.0 ± 4.5 resp. 13.4 ± 7 µmol/l; P = 0.01). Plasma total homocysteine was strongly correlated with GFR (Type 1 diabetes patients: r = −0.43, P < 0.001; control subjects: r = −0.39, P = 0.01).

Conclusion  GFR is a major determinant of plasma total homocysteine levels in Type 1 diabetes patients as well as control subjects. The reduced plasma total homocysteine levels in diabetes patients can be explained by an increased GFR.
Foot temperature in diabetic polyneuropathy: innocent bystander or unrecognized accomplice?
Authors: Rutkove S. B. , Chapman K. M. , Acosta J. A. , Larrabee J. E.
Published: February 2005

Aim  To explore mechanisms by which temperature could influence the pathogenesis and symptoms of diabetic polyneuropathy.

Methods  We conducted a literature review attempting to identify mechanisms by which diabetic polyneuropathy could be affected by temperature.

Results  Cooling can theoretically hasten the progression of diabetic polyneuropathy through several different mechanisms. Specifically, cooling can enhance neuronal ischaemia, increase formation of reactive oxygen species, slow axonal transport, increase protein kinase C activity, and interfere with immune function. Short‐term temperature fluctuations (both warming and cooling) can initiate and exacerbate neuropathic pain by causing neuronal hyperexcitability and functional deafferentation. Although normal fluctuations of distal extremity temperature may be sufficient for these effects, impaired thermoregulation may make the distal extremities more susceptible to temperature extremes. Eventually, a ‘vicious cycle’ may ensue, resulting in neuronal deterioration with further disruption of temperature regulation. Limited epidemiological data suggest a higher prevalence of diabetic polyneuropathy in populations living in colder locations, supporting our hypothesis.

Conclusions  Variations in foot temperature may play an important but as yet unrecognized role in the development and symptoms of diabetic polyneuropathy. Further basic and clinical research exploring this concept could help elucidate the natural history of diabetic polyneuropathy and lead to novel therapeutic strategies.
Health properties of resistant starch
Authors: Nugent A. P.
Published: February 2005

Summary  Resistant starch (RS) refers to the portion of starch and starch products that resist digestion as they pass through the gastrointestinal tract. RS is an extremely broad and diverse range of materials and a number of different types exist (RS1–4). At present, these are mostly defined according to physical and chemical characteristics. RS may be categorised as a type of dietary fibre, as defined by the American Association of Cereal Chemists and the Food Nutrition Board of the Institute of Medicine of the National Academies. RS is measured in part by the methodology recommended by the Association of Official Analytical Chemists for measuring dietary fibre. Dietary intakes of RS in westernised countries are likely to be low. However, accurate comparative assessments of dietary intakes between countries, and subsequent epidemiological analysis, are absent due to the lack of consensus over of an agreed, repeatable and simple in vitro method for analysing the RS content of foods. At present, the recognised method is that of McCleary & Monaghan (2002). RS appears to confer considerable benefits to human colonic health, but has a smaller impact on lipid and glucose metabolism. Comparisons between studies are hampered by differences in study design, poor experimental design and differences in the source, type and dose of RS in the ingredients or diets used. It is likely that RS mediates some or all of its effects through the action of short chain fatty acids but interest is increasing regarding its prebiotic potential. There is also increasing interest in using RS to lower the energy value and available carbohydrate content of foods. RS can also be used to enhance the fibre content of foods and is under investigation regarding its potential to accelerate the onset of satiation and to lower the glycaemic response. Due to the difficulties in agreeing on a universal definition and method of analysis for dietary fibre, RS may be included within the term ‘fibre’ on the nutrition labels in some countries but not in others. Pressure to agree a legal definition and universal method of analysis is likely to increase due to the potential of RS to enhance colonic health, and to act as a vehicle to increase the total dietary fibre content of foodstuffs, particularly those which are low in energy and/or in total carbohydrate content.
Teacher‐child interaction in the teaching of reading: a review of research perspectives over twenty‐five years
Authors: Fisher Ros
Published: February 2005

Taking as a starting point a paper published in 1981, this paper considers the importance of interaction between teacher and pupil in learning to read. Twenty‐five years ago, the study of classroom language was relatively new. Research perspectives have moved from describing the process of interaction between teacher and child to considering the outcomes. At the same time a greater awareness of the sociocultural nature of language and classrooms has developed. An enduring theme in research from a variety of perspectives has been the call for more extended opportunities for exchanges about texts and more reciprocity in teacher‐child dialogue. Studies of classroom practice, however, evidence persistence in the use of triadic dialogue in which the teacher controls the interaction and effectively closes down discussion. Despite initiatives calling for high‐quality interaction, it is argued here that there is still no agreement about what high‐quality interaction should look like.
Phonemic analysis and reading development: some current issues
Authors: Stuart Morag
Published: February 2005

The first paper published in the Journal of Research in Reading on the topic of phonological awareness (Schreuder & van Bon, 1989) appeared some fifteen years after the seminal paper by Liberman, Shankweiler, Fischer and Carter (1974), which had demonstrated that there was a relationship between spoken word segmentation ability and reading acquisition. That the field had moved on in those fifteen years is evident in the sophistication of the questions addressed by Schreuder and van Bon. I present here a brief summary of Schreuder and van Bon's paper, and explore how some of the issues they discuss have been developed over the subsequent fifteen years.
Preterm premature rupture of membranes: diagnosis, evaluation and management strategies
Authors: Simhan Hyagriv N. , Canavan Timothy P.
Published: February 2005

Preterm premature rupture of the membranes (PPROM) is responsible for one‐third of all preterm births and affects 120,000 pregnancies in the United States each year. Effective treatment relies on accurate diagnosis and is gestational age dependent. The diagnosis of PPROM is made by a combination of clinical suspicion, patient history and some simple tests. PPROM is associated with significant maternal and neonatal morbidity and mortality from infection, umbilical cord compression, placental abruption and preterm birth. Subclinical intrauterine infection has been implicated as a major aetiological factor in the pathogenesis and subsequent maternal and neonatal morbidity associated with PPROM. The frequency of positive cultures obtained by transabdominal amniocentesis at the time of presentation with PPROM in the absence of labour is 25–40%. The majority of amniotic fluid infection in the setting of PPROM does not produce the signs and symptoms traditionally used as diagnostic criteria for clinical chorioamnionitis. Any evidence of infection by amniocentesis should be considered carefully as an indication for delivery. Documentation of amniotic fluid infection in women who present with PPROM enables us to triage our therapeutic decision making rationally. In PPROM, the optimal interval for delivery occurs when the risks of immaturity are outweighed by the risks of pregnancy prolongation (infection, abruption and cord accident). Lung maturity assessment may be a useful guide when planning delivery in the 32‐ to 34‐week interval. A gestational age approach to therapy is important and should be adjusted for each hospital's neonatal intensive care unit. Antenatal antibiotics and corticosteroid therapies have clear benefits and should be offered to all women without contraindications. During conservative management, women should be monitored closely for placental abruption, infection, labour and a non‐reassuring fetal status. Women with PPROM after 32 weeks of gestation should be considered for delivery, and after 34 weeks the benefits of delivery clearly outweigh the risks.
Controversies in diagnosis of preterm labour
Authors: Leitich Harald
Published: February 2005

Despite scientific advances, efforts to prevent preterm birth can be disappointing. Obstetric care must focus on strategies to improve the outcome of preterm infants. The major goal is to delay preterm birth long enough to allow the transfer of women about to deliver preterm to a facility with a neonatal intensive care unit and to administer corticosteroids to enhance fetal lung maturation. A prerequisite for the success of this strategy is the reliable identification of women who will give birth preterm. Although symptoms of preterm labour strongly suggest preterm birth, contractions—even if combined with cervical effacement and dilation—do not reliably predict preterm birth. The diagnosis of true preterm labour that will eventually lead to preterm birth has been facilitated by the use of transvaginal cervical ultrasonography and by the detection of fetal fibronectin (FFN) in cervicovaginal secretions. The main clinical value of these tests is that preterm birth is very unlikely if the results of both tests are negative. This may help to avoid unnecessary transfer, hospitalisation and treatment of women with false preterm labour. The detection of phosphorylated insulin‐like growth factor binding protein‐1 in cervicovaginal secretions, or elevated levels of inflammatory markers, like interleukin‐6, interleukin‐8 and tumour necrosis factor‐α (TNF‐α), also predict preterm birth in symptomatic women. These markers, however, are not routinely used to predict preterm birth in women with symptoms of preterm labour.
Management of the neonate at the limits of viability
Authors: Haumont Dominique
Published: February 2005

The active treatment of fetuses or neonates at the limits of viability is an ongoing debate for perinatal physicians. Although initiating intensive care at 26 weeks is generally accepted, the gray zone of gestational ages at which aggressive perinatal care should be offered is less clear and ranges from 22 to 25 weeks. The gray zone has remained rather unchanged over the last decade. Attitudes vary among different countries, centres and individuals. The benefit–burden ratio of neonatal intensive care is balanced differently according to competing moral values. Several factors underlie the difficulty in approaches to management decisions. Neonates lack the capacity to make decisions and most parents ignore the complexity of care during and after hospitalisation. Parents have to be informed about the survival rates and the risks of long term disabilities, but accuracy for each individual baby is very weak. Outcome data are published many years after the intensive care period, and results about the prevalence of severe disabilities over time are conflicting and vary widely (ranging from 10% to 60%). Information about more subtle disabilities which only become apparent around school age is scarce. Data on the impact of the longer term outcomes of new strategies like developmental care approaches (Neonatal Individual Developmental Care Assessment Programme: NIDCAP) are still insufficient but could prove to be an important recent step in improving outcome in extremely immature babies.
Adverse effects of tocolytic therapy
Authors: Caritis Steve
Published: February 2005

The rationale for using tocolytics in preterm labour is to enable transfer of the mother to a tertiary centre and to prolong pregnancy sufficiently so that glucocorticoids can be administered to the mother. There is little question that these short term objectives can be achieved with contemporary tocolytics. Whether tocolytics can maintain pregnancy for sufficient periods to enable in utero maturation to occur remains an unresolved question. When a decision is made to use tocolytics, the clinician is faced with a multitude of choices with side effects, efficacy and ease of administration generally being the most important considerations. Placebo‐controlled studies suggest that the β‐agonists, prostaglandin inhibitors and atosiban are effective in prolonging pregnancy for 24–48 hours. Of these three agents, atosiban has the best safety profile. There are no placebo‐controlled studies with calcium channel blockers or nitric oxide donors. However, because of their ease of use and efficacy compared with the β‐agonists, calcium channel blockers are widely used. Calcium channel blockers appear to have a better safety profile than the β‐agonists, but there are still significant cardiovascular side effects associated with their use. Indomethacin, although proven to be efficacious, has a safety profile that limits its utility for other than short courses. Magnesium sulphate is the most commonly used tocolytic in the United States, despite a lack of evidence for its efficacy. Although magnesium sulphate appears to have a good safety profile, serious side effects have been reported with its use. The choice of tocolytics is commonly based on personal preference. Whichever tocolytic is chosen, the fundamental parturitional process is not reversed by contemporary treatment, rather a reduction in uterine response to a stimulant; thus, the expectations of tocolytic treatment need to be reconsidered.
A review of the role for magnesium sulphate in preterm labour
Authors: Mittendorf Robert , Pryde Peter G.
Published: February 2005

During the last decade, the body of medical knowledge concerning the use of pharmacological doses of magnesium sulphate (MgSO4) for preterm labour has increased substantially. Several randomised controlled trials (RCTs) have provided compelling evidence that MgSO4 is the drug of choice for maternal seizure prophylaxis in pre‐eclampsia, whether preterm or term. In contrast, a recent Cochrane systematic review of the relevant contemporary literature has found no evidence basis to support the use of MgSO4 for tocolysis in preterm labour. Furthermore, associated with high‐dosage tocolytic MgSO4, recent data indicate a possible increased risk for neonatal intraventricular haemorrhage (IVH), as well as increased total paediatric mortality. It is possible, on the other hand, that the prophylactic administration of much lower dosages of MgSO4, in selected cases of preterm labour, may have a neuroprotective effect for a small number of infants.
The bioethics of preterm labour
Authors: Steer Philip
Published: February 2005

Until recently, bioethics (ethics related to biology or, more specifically, in the context of preterm labour, medical ethics) was considered mainly to relate to the active treatment or investigation of patients. Collection of data, excised specimens or even whole organs was considered to be relatively uncontentious as it did not impinge directly upon the health of the individual concerned. However, in the UK in particular, the practice of collecting data, tissues or even whole organs has recently come under the spotlight of public scrutiny, particularly following the Alder Hey Enquiry. Coincidentally with a decline in public confidence in the probity of authority, medical scientists increasingly have to justify the accumulation of data about individuals.
Impact of medically assisted fertility on preterm birth
Authors: Filicori M. , Cognigni G.E. , Gamberini E. , Troilo E. , Parmegiani L. , Bernardi S.
Published: February 2005

Preterm birth is a frequent problem in women who undergo treatment for infertility. Many factors appear to contribute to the occurrence of this complication. Infertile women seem to have a predisposition to giving birth preterm and to having low birthweight babies. These complications also occur in women with a history of infertility who achieve pregnancy without treatment and who have singleton pregnancies. Assisted reproduction patients treated with in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) have a disproportionately high occurrence of preterm births even with singleton pregnancies. Spontaneous preterm labour may be related to underlying medical conditions of the female partner, as its occurrence is not increased in subjects treated with ICSI (i.e. when the infertility problem is associated with male reproductive dysfunction in normal female partners). Multiple pregnancy is the factor most likely to be related to preterm birth in infertile women. The administration of drugs to induce ovulation either alone or combined with intrauterine insemination causes a significant increase in multiple pregnancies. The occurrence of higher order multiple pregnancy is also increased. Multiple pregnancy in women undergoing IVF or ICSI is related to the number of embryos transferred at the end of treatment. The transfer of more than two embryos in women under 35 is not associated with an increased chance of conception, while the occurrence of multiple pregnancy is significantly increased. Women over 40 may benefit from the transfer of more than two embryos, with fewer risks of multiple pregnancy. Single embryo transfer is increasingly considered a workable clinical option, particularly in young women. Hopefully, a more cautious approach to infertility management will reduce the occurrence of multiple pregnancy, spontaneous preterm labour and the high number of low birthweight infants born after treating these women.
Maintenance tocolysis
Authors: Thornton James G.
Published: February 2005

Background  Women who are undelivered after 48 hours of tocolysis remain at increased risk of preterm labour, but it is not clear whether prolonged treatment is effective.

Objective  To review the current evidence for the effectiveness of maintenance tocolysis.

Methods  The results of published systematic reviews were summarised.

Results  Four systematic reviews and two trials published too recently for inclusion were identified. Maintenance tocolysis with β‐agonists and magnesium sulphate was ineffective in prolonging gestation or reducing any adverse fetal outcomes. One trial of maintenance tocolysis with nifedipine was underpowered to rule out an effect on prolonging gestation. One trial using the oxytocin receptor blocker, atosiban, showed that this drug used as maintenance tocolysis does prolong gestation, but the trial was too small to demonstrate any reduction in substantive fetal outcomes.

Conclusions  There is insufficient evidence to justify the routine use of maintenance tocolysis in preterm labour. It remains plausible that prolongation of gestation might be beneficial in selected cases of very preterm labour where fetal compromise and infection have been ruled out. The only tocolytic that has been shown to prolong gestation when used as maintenance therapy is atosiban.
Control of death receptor and mitochondrial‐dependent apoptosis by c‐Jun N‐terminal kinase in hippocampal CA1 neurones following global transient ischaemia
Authors: Carboni Sonia , Antonsson Bruno , Gaillard Pascale , Gotteland Jean‐Pierre , Gillon Jean‐Yves , Vitte Pierre‐Alain
Published: February 2005

c‐Jun N‐terminal kinase (JNK), a member of the mitogen‐activated protein kinase family, is activated in response to a number of extracellular stimuli, including inflammatory cytokines, UV irradiation and ischaemia. A large body of evidence supports a role for JNK signalling in stress‐induced apoptosis. It has been hypothesized that JNK may contribute to the apoptotic response by regulating the intrinsic cell death pathway involving the mitochondria. Here, we examined the role of the JNK signalling pathway in hippocampal CA1 apoptotic neurones following transient ischaemia in gerbils. We showed early activation of death receptor‐dependent apoptosis (caspase‐8 activation 2 days after ischaemia) and a biphasic activation of caspase‐3 and caspase‐9 after ischaemia. Activation of the mitochondrial pathway, as measured by cytochrome c release, appeared as a late event (5–7 days after ischaemia). AS601245, a novel JNK inhibitor, antagonized activation of both pathways and significantly protected CA1 neurones from cell death. Our results suggest a key role of JNK in the control of death receptor and mitochondrial‐dependent apoptosis after transient ischaemia.
Aph‐1 interacts at the cell surface with proteins in the active γ‐secretase complex and membrane‐tethered Notch
Authors: Hansson Emil M. , Strömberg Kia , Bergstedt Susanne , Yu Gang , Näslund Jan , Lundkvist Johan , Lendahl Urban
Published: February 2005

The activity of the γ‐secretase complex is critical for the processing of a number of transmembrane proteins, including Notch. Functional γ‐secretase activity can be reconstituted from four proteins – presenilin, nicastrin, Pen‐2 and Aph‐1 – but the role of the individual proteins remains unclear. In this report we describe the cellular localization and protein interactions of Aph‐1, with particular regard to Notch receptor processing. We found that Aph‐1 is present at the cell surface, where it interacts with Pen‐2, the mature forms of presenilin and nicastrin, and full‐length Notch. Aph‐1 also interacts with a truncated form of Notch, which is a direct substrate for γ‐secretase, but not with the Notch intracellular domain. Immunoprecipitation data for Notch and Aph‐1 showed that the Notch‐containing γ‐secretase complexes most likely form a small subset of the total number of γ‐secretase complexes. In conclusion, these data demonstrate that Aph‐1 is present at the cell surface, presumably in active γ‐secretase complexes, and interacts with the Notch receptor, both before and after ligand activation.
Monoamine transporter inhibitors and norepinephrine reduce dopamine‐dependent iron toxicity in cells derived from the substantia nigra
Authors: Paris Irmgard , Martinez‐Alvarado Pedro , Perez‐Pastene Carolina , Vieira Marcelo N. N. , Olea‐Azar Claudio , Raisman‐Vozari Rita , Cardenas Sergio , Graumann Rebeca , Caviedes Pablo , Segura‐Aguilar Juan
Published: February 2005

The role of dopamine in iron uptake into catecholaminergic neurons, and dopamine oxidation to aminochrome and its one‐electron reduction in iron‐mediated neurotoxicity, was studied in RCSN‐3 cells, which express both tyrosine hydroxylase and monoamine transporters. The mean ± SD uptake of 100 µm59FeCl3 in RCSN‐3 cells was 25 ± 4 pmol per min per mg, which increased to 28 ± 8 pmol per min per mg when complexed with dopamine (Fe(III)–dopamine). This uptake was inhibited by 2 µm nomifensine (43%p < 0.05), 100 µm imipramine (62%p < 0.01), 30 µm reboxetine (71%p < 0.01) and 2 mm dopamine (84%p < 0.01). The uptake of 59Fe–dopamine complex was Na+, Cl– and temperature dependent. No toxic effects in RCSN‐3 cells were observed when the cells were incubated with 100 µm FeCl3 alone or complexed with dopamine. However, 100 µm Fe(III)–dopamine in the presence of 100 µm dicoumarol, an inhibitor of DT‐diaphorase, induced toxicity (44% cell death; p < 0.001), which was inhibited by 2 µm nomifensine, 30 µm reboxetine and 2 mm norepinephrine. The neuroprotective action of norepinephrine can be explained by (1) its ability to form complexes with Fe3+, (2) the uptake of Fe–norepinephrine complex via the norepinephrine transporter and (3) lack of toxicity of the Fe–norepinephrine complex even when DT‐diaphorase is inhibited. These results support the proposed neuroprotective role of DT‐diaphorase and norepinephrine.
Process elongation of oligodendrocytes is promoted by the Kelch‐related actin‐binding protein Mayven
Authors: Jiang Shuxian , Avraham Hava Karsenty , Park Shin‐Young , Kim Tae‐Aug , Bu Xia , Seng Seyha , Avraham Shalom
Published: February 2005

Rearrangement of the cytoskeleton leading to the extension of cellular processes is essential for the myelination of axons by oligodendrocytes. We observed that the actin‐binding protein, Mayven, is expressed during all stages of the oligodendrocyte lineage, and that its expression is up‐regulated during oligodendrocyte differentiation. Mayven is localized in the cytoplasm and along the cell processes. Mayven also binds actin, and is involved in the cytoskeletal reorganization in oligodendrocyte precursor cells (O‐2A cells) that leads to process elongation. Mayven overexpression resulted in an increase in the process outgrowth of O‐2A cells and in the lengths of the processes, while microinjection of Mayven‐specific antibodies inhibited process extension in these cells. Furthermore, O‐2A cells transduced with recombinant retroviral sense Mayven (pMIG‐W‐Mayven) showed an increase in the number of oligodendrocyte processes with outgrowth, while recombinant retroviral antisense Mayven (pMIG‐W‐Mayven‐AS) blocked O‐2A process extension. Interestingly, co‐localization and association of Mayven with Fyn kinase were found in O‐2A cells, and these interactions were increased during the outgrowth of oligodendrocyte processes. This association was mediated via the SH3 domain ligand (a.a. 1–45) of Mayven and the SH3 domain of Fyn, suggesting that Mayven may act as a linker to bind Fyn, via its N‐terminus. Thus, Mayven plays a role in the dynamics of cytoskeletal rearrangement leading to the process extension of oligodendrocytes.
Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytes
Authors: Bruzzone Roberto , Barbe Michael T. , Jakob Nurith J. , Monyer Hannah
Published: February 2005

Several new findings have emphasized the role of neuron‐specific gap junction proteins (connexins) and electrical synapses in processing sensory information and in synchronizing the activity of neuronal networks. We have recently shown that pannexins constitute an additional family of proteins that can form gap junction channels in a heterologous expression system and are also widely expressed in distinct neuronal populations in the brain, where they may represent a novel class of electrical synapses. In this study, we have exploited the hemichannel‐forming properties of pannexins to investigate their sensitivity to well‐known connexin blockers. By combining biochemical and electrophysiological approaches, we report here further evidence for the interaction of pannexin1 (Px1) with Px2 and demonstrate that the pharmacological sensitivity of heteromeric Px1/Px2 is similar to that of homomeric Px1 channels. In contrast to most connexins, both Px1 and Px1/Px2 hemichannels were not gated by external Ca2+. In addition, they exhibited a remarkable sensitivity to blockade by carbenoxolone (with an IC50 of ∼5 μm), whereas flufenamic acid exerted only a modest inhibitory effect. The opposite was true in the case of connexin46 (Cx46), thus indicating that gap junction blockers are able to selectively modulate pannexin and connexin channels.
Inherited and acquired interactions between ACHE and PON1 polymorphisms modulate plasma acetylcholinesterase and paraoxonase activities
Authors: Bryk Boris , BenMoyal‐Segal Liat , Podoly Erez , Livnah Oded , Eisenkraft Arik , Luria Shai , Cohen Amir , Yehezkelli Yoav , Hourvitz Ariel , Soreq Hermona
Published: February 2005

The 5.5 Mb chromosome 7q21–22 ACHE/PON1 locus harbours the ACHE gene encoding the acetylcholine hydrolyzing, organophosphate (OP)‐inhibitable acetylcholinesterase protein and the paraoxonase gene PON1, yielding the OP‐hydrolyzing PON1 enzyme which also displays arylesterase activity. In search of inherited and acquired ACHE–PON1 interactions we genotyped seven polymorphic sites and determined the hydrolytic activities of the corresponding plasma enzymes and of the AChE‐homologous butyrylcholinesetrase (BChE) in 157 healthy Israelis. AChE, arylesterase, BChE and paraoxonase activities in plasma displayed 5.4‐, 6.5‐, 7.2‐ and 15.5‐fold variability, respectively, with genotype‐specific differences between carriers of distinct compound polymorphisms. AChE, BChE and arylesterase but not paraoxonase activity increased with age, depending on leucine at PON1 position 55. In contrast, carriers of PON1 M55 displayed decreased arylesterase activity independent of the − 108 promoter polymorphism. Predicted structural consequences of the PON1 L55M substitution demonstrated spatial shifts in adjacent residues. Molecular modelling showed substrate interactions with the enzyme variants, explaining the changes in substrate specificity induced by the Q192R substitution. Intriguingly, PON1, but not BChE or arylesterase, activities displayed inverse association with AChE activity. Our findings demonstrate that polymorphism(s) in the adjacent PON1 and ACHE genes affect each other's expression, predicting for carriers of biochemically debilitating ACHE/PON1 polymorphisms adverse genome–environment interactions.
Mutagenesis studies of conserved proline residues of human P2X1 receptors for ATP indicate that proline 272 contributes to channel function
Authors: Roberts Jonathan A. , Evans Richard J.
Published: February 2005

Proline residues can play a major role in the secondary structure of proteins. In the extracellular ATP binding loop of P2X receptors there are four totally conserved proline residues (P2X1 receptor numbering; P93, P166, P228 and P272) and three less conserved residues P196 (six of seven isoforms), P174 and P225 (five of seven isoforms). We have mutated individual conserved proline residues in the human P2X1 receptor and determined their properties. Mutants were expressed in Xenopus oocytes and characterized using a two‐electrode voltage clamp. Mutants P166A, P174A, P196A, P225A and P228A had no effect on ATP potency compared with wild‐type and P93A had a fourfold decrease in ATP potency. The P272A, P272D and P272K receptor mutants were expressed at the cell surface; however, these mutants were non‐functional. In contrast, P272I, P272G and P272F produced functional channels, with either no effect or a 2.5‐ or 6.5‐fold increase in ATP potency, respectively. At P272F receptors the apparent affinity of the ATP analogue antagonist 2′,3′‐O‐(2,4,6‐trinitrophenyl)‐ATP was increased by 12.5‐fold. These results suggest that individual proline residues are not essential for normal P2X receptor function and that the receptor conformation around P272 contributes to ATP binding at the receptor.
Molecular characterization of the family of choline transporter‐like proteins and their splice variants
Authors: Traiffort E. , Ruat M. , O'Regan S. , Meunier F. M.
Published: February 2005

We show here that the choline transporter‐like (CTL) family is more extensive than initially described with five genes in humans and complex alternative splicing. In adult rat tissues, CTL2–4 mRNAs are mainly detected in peripheral tissues, while CTL1 is widely expressed throughout the nervous system. During rat post‐natal development, CTL1 is expressed in several subpopulations of neurones and in the white matter, where its spatio‐temporal distribution profile recalls that of myelin basic protein, an oligodendrocyte marker. We identified two major rat splice variants of CTL1 (CTL1a and CTL1b) differing in their carboxy‐terminal tails with both able to increase choline transport after transfection in neuroblastoma cells. In the developing brain, CTL1a is expressed in both neurones and oligodendroglial cells, whereas CTL1b is restricted to oligodendroglial cells. These findings suggest specific roles for CTL1 splice variants in both neuronal and oligodendrocyte physiology.
Microdot test of foveal function. A comparison with visual acuity at high and low contrast
Authors: Malmer L. , Martin L.
Published: February 2005

Purpose:  To define normal values across age from novel computerized tests of foveal vision and to compare the findings with visual acuity (VA) at high and low contrast.

Subjects and methods:  Sixty‐one healthy volunteers, aged 22–87, with subjectively normal vision participated in the study. The right eye from each subject was tested with Snellen letter VA at high contrast, at 10% contrast using the Tri‐VA test and with the Rarebit Microdot Fovea Test (RMFT), in addition to biomicroscopy and fundus examination.

Results:  The median letter VA was 0.77 minimum angle of resolution (MAR; range 0.63–1.54) with a significant decline in letter VA with increasing age (r = 0.7, p < 0.001). The median Tri‐VA resolution threshold at 10% contrast was 1.8 MAR (range 0.9–4.1) and a significant age effect (r = 0.7) was observed, most pronounced above 65 years. The median RMFT hit rate was 100% (range 97–100) in the age group below 65 years and 87.5% (range 34–98) in subjects older than 65 years.

Conclusion:  The study shows a decline in foveal function with age with all three methods, reflecting the loss of neural detectors with increasing age. The hit rate to microdot stimuli appears to be a sensitive measure, which can be used for fine‐graded evaluation of foveal function.
Effect of training on attitudes and expertise of optometrists towards people with intellectual disabilities
Authors: Adler Paul , Cregg Mary , Duignan Ann , Ilett Gordon , Margaret Woodhouse J.
Published: February 2005

Purpose:  To determine whether participation in an educational programme, which comprised both lectures and supervised patient contacts, did more to improve the attitudes, expertise, knowledge and confidence of optometrists and student optometrists towards people with intellectual disabilities (ID) compared with receiving didactic lectures only.

Methods:  Optometrists and student optometrists were invited to take part in vision screening. A series of lectures were provided followed by supervised practice for a minimum of 2 days. A questionnaire was administered before the commencement of the training, and afterwards, in order to assess the impact of the training. The results were compared with a group of control subjects who received similar lectures without the clinical experience.

Results:  For both groups there were statistically significant improvements in self‐reported knowledge of ophthalmic complications of ID, confidence in working with people with ID, and there was a significantly reduced perceived need for further training after the courses. There was a significantly better result for the group experiencing patient contact particularly in respect of self‐reported attitudes towards people with ID. Confidence in dealing with people with ID was related to the number of such patients seen over the last year.

Conclusions:  Training incorporating clinical experience, and using real patients, is particularly effective, although there is still benefit in providing lecture type courses. It is recommended that, whenever possible, courses are provided that offer hands‐on experience with real patients. There is a need for further research using validated attitudinal scales to investigate the attitudes of optometrists to people with ID.
Use of a high molecular weight fluorescein (fluorexon) ophthalmic strip in assessments of tear film break‐up time in contact lens wearers and non‐contact lens wearers
Authors: Doughty Michael J. , Jalota Vinati , Bennett Emma , Naase Taher , Oblak Emil
Published: February 2005

Purpose:  To assess whether fluorexon strips could be used in tear stability [tear film break‐up time (TBUT)] measures, as compared with fluorescein strips.

Methods:  The pre‐ocular tear film stability was assessed in 40 adults (19–29 years of age), half of whom were adapted soft contact lens wearers, using the dye‐assisted tear film break‐up time (TBUT) method. The measures were carried out between 10.00 and 17.00 hours, with contact lens wearers removing their lenses just before the assessments. For all subjects, fluorescein or fluorexon ophthalmic strips (pre‐wetted with preservative‐free saline) were used to add dye to the tear film, the TBUT was assessed three times and then the eye lightly irrigated with saline. The measures were repeated 45 min later with the other dye, with half the subjects receiving fluorescein first and the other half receiving fluorexon first.

Results:  Overall, the mean TBUT times were 12.2 ± 5.9 s for fluorescein and 12.6 ± 5.6 s for fluorexon (p = n.s.), but the non‐lens wearers had longer TBUT times (14.6 and 14.5 s for the two dyes) compared with contact lens wearers (9.8 and 10.7 s, p < 0.01). While the inter‐subject variability (as S.D.) was larger for non‐contact lens wearers, the intra‐subject variability [as coefficient of variation (COV)] was greater in the contact lens wearers when fluorescein was used (p < 0.001). When analysed as a function of the time of day that the measures were made, there were clear trends for both the fluorescein and fluorexon. TBUT values to increase in non‐contact lens wearers and decrease in contact lens wearers. These trends failed to reach statistical significance, but the results with the contact lens wearers showed less variation than the non‐contact lens wearers.

Conclusion:  The use of a fluorexon dye‐impregnated strip (pre‐wetted with preservative‐free saline) yielded comparable results with a fluorescein strip for assessments of tear film stability based on TBUT. The studies also indicate that further research is needed on changes in TBUT values during the day.
Intra‐ and interrater agreement and reliability of the Functional Field Score
Authors: Langelaan Maaike , Wouters Bill , Moll Annette C. , de Boer Michiel R. , van Rens Ger H. M. B.
Published: February 2005

In 2001, the American Medical Association adopted the Functional Vision Score (FVS). It is built on Functional Acuity Scores (FAS) and Functional Field Scores (FFS). The purpose of this study was to evaluate the intra‐ and interrater reproducibility of the FFS. The study sample was composed of 62 persons, mean age 41.8 years, from the population of patients who visited a rehabilitation centre for visually impaired adults. We analysed 30 FFSs of isopter III‐4e and 58 of isopter V‐4e. Two raters independently scored the plots. The smallest detectable difference (SDD) and the weighted kappa quantified agreement. The SDDs were smaller than the minimal clinically important difference (MCID) of 10 points. Thus, the MCID can be distinguished from measurement error. The intraclass correlation coefficient (ICC) quantified reliability. The intra‐ and inter ICCs were high (ICCs > 0.98). We concluded that both intra‐ and interrater reliability of the FFS were excellent.
Increasing the proportion of binocular vision makes horizontal prism adaptation complete
Authors: Brautaset R. L. , Jennings J. A. M.
Published: February 2005

In previous phoria adaptation experiments on normal subjects adaptation tends to reach only approximately 2/3 of the prism‐induced phoria while clinical experience indicates that prism adaptation is usually complete. The present data show that increasing the proportion of binocular experience through the phoria‐inducing prism allows adaptation to become complete. Longer periods of binocular vision give a better indication of vergence adaptation function. This is particularly important in experiments where normal and abnormal adaptive abilities are being compared.
Supportive Relationships as a Moderator of the Effects of Parent and Peer Drinking on Adolescent Drinking
Authors: Urberg Kathryn , Goldstein Marilyn S. , Toro Paul A.
Published: February 2005

The goal of this study was to explore whether supportiveness from a parent or a friend moderated the effects of the supportive person's drinking on the trajectory of adolescent alcohol abuse/dependence symptoms. High‐risk adolescents recruited from shelters and a matched sample of adolescents recruited from the sheltered adolescent's former neighborhood completed assessments at baseline, 6, 12, and 18 months. Measures included the Social Network Interview, assessing the drinking and supportiveness of everyone in the network. The alcohol module of the Diagnostic Interview Schedule for Children was also administered. Hierarchical Linear Modeling identified predictors of the trajectory of alcohol symptoms of the 401 adolescents over 18 months. The results showed that the baseline levels of parental drinking predicted increased symptoms over time only for those with low parental support. In contrast, the baseline level of peer alcohol use predicted increased symptoms over time only for those with high peer support. The pattern of results did not differ for shelter youth compared to neighborhood controls.