bluuebunny/crossref_metadata_2025 huggingface dataset:
Human-macaque comparisons illuminate variation in neutral substitution rates
Authors: Tyekucheva Svitlana , Makova Kateryna D , Karro John E , Hardison Ross C , Miller Webb , Chiaromonte Francesca
Published: April 2008

Background

The evolutionary distance between human and macaque is particularly attractive for investigating local variation in neutral substitution rates, because substitutions can be inferred more reliably than in comparisons with rodents and are less influenced by the effects of current and ancient diversity than in comparisons with closer primates. Here we investigate the human-macaque neutral substitution rate as a function of a number of genomic parameters.

Results

Using regression analyses we find that male mutation bias, male (but not female) recombination rate, distance to telomeres and substitution rates computed from orthologous regions in mouse-rat and dog-cow comparisons are prominent predictors of the neutral rate. Additionally, we demonstrate that the previously observed biphasic relationship between neutral rate and GC content can be accounted for by properly combining rates at CpG and non-CpG sites. Finally, we find the neutral rate to be negatively correlated with the densities of several classes of computationally predicted functional elements, and less so with the densities of certain classes of experimentally verified functional elements.

Conclusion

Our results suggest that while female recombination may be mainly responsible for driving evolution in GC content, male recombination may be mutagenic, and that other mutagenic mechanisms acting near telomeres, and mechanisms whose effects are shared across mammalian genomes, play significant roles. We also have evidence that the nonlinear increase in rates at high GC levels may be largely due to hyper-mutability of CpG dinucleotides. Finally, our results suggest that the performance of conservation-based prediction methods can be improved by accounting for neutral rates.
Review of smoking cessation treatments for people with mental illness
Authors: Campion Jonathan , Checinski Ken , Nurse Jo
Published: April 2008

This article reviews the current literature regarding treatments for smoking cessation in both the general population and in those with mental health problems. The gold-standard treatment for the general population is pharmacotherapy (nicotine replacement therapy, bupropion or varenicline) coupled with individual or group psychological support. This is also effective in helping people with mental illness to reduce or quit smoking, but care must be taken to avoid adverse medication interactions and to monitor antipsychotic medication in particular as cigarette consumption reduces.
Continuing the dialogue
Authors: Copeland Mary Ellen , Mead Shery
Published: April 2008

We consider the value of dialogue between healthcare professionals and
mental health service users with severe mental illnesses. Discussion with
the service user before, during and after a psychiatric crisis should help
services to offer choice even to individuals under compulsory detention.
Predictive validity of acute stress disorder in children and
adolescents
Authors: Dalgleish Tim , Meiser-Stedman Richard , Kassam-Adams Nancy , Ehlers Anke , Winston Flaura , Smith Patrick , Bryant Bridget , Mayou Richard A. , Yule William
Published: April 2008

Adult research suggests that the dissociation criterion of acute stress
disorder has limited validity in predicting posttraumatic stress disorder
(PTSD). We addressed this issue in child and adolescent survivors
(n=367) of road accidents. Dissociation accounted for no
significant unique variance in later PTSD, over and above other acute stress
disorder criteria. Furthermore, thresholds of either three or more
re-experiencing symptoms, or six or more re-experiencing/hyperarousal
symptoms, were as effective at predicting PTSD as the full acute stress
disorder diagnosis.
Efficacy of Quichua healers as psychiatric diagnosticians
Authors: Incayawar Mario
Published: April 2008

Traditional healers' practices are widespread around the world, yet their diagnostic skills have rarely been investigated. This exploratory study examines whetheryachactaitas(Quichua healers) in the Andes identify cases of psychiatric illness in their communities. For over 18 months, tenyachactaitasparticipated in the identification of 50 individuals with the condition known asllaqui.Medical and psychiatric evaluation indicated that most of those so diagnosed had a DSM–III–R mental disorder. None of the participants withllaquiwas considered healthy in biomedical or psychiatric terms. It is suggested thatyachactaitasmight indeed identify general psychiatric cases in their communities, and that this might be useful for screening purposes.
Proposals for massive expansion of psychological therapies would
be counterproductive across society
Authors: Summerfield Derek , Veale David
Published: April 2008

In 2007 the UK Government announced a substantial expansion of funding for
psychological therapies in England to provide better support for people with
conditions such as anxiety and depression. Will these services result in the
medicalisation of normal distress? Or are they simply an evidenced-based
solution for a previously unmet need? In this debate Derek Summerfield and
David Veale discuss the issues raised by these controversial proposals.
Five-year follow-up of an evidence-based prescribing intervention
Authors: Meagher David , Pullela Ananth , Meisinger Marek , Geaney Niamh , O'Brien Sinead
Published: April 2008

Aims and Method

We studied the impact of an evidence-based multidisciplinary intervention to reduce six sub-optimal aspects of psychotropic prescribing, combined as a Prescribing Practice Quality (PPQ) score over a 5-year follow-up period in a community mental health service.

Results

Sub-optimal prescribing practices were significantly reduced after 1 year and these improvements were sustained at 5-year follow-up. The PPQ scores were significantly reduced (P<0.001) in both the overall population attending at each follow-up point as well as in the ever-present population (n=163). Use of high-dose antipsychotics and thioridazine ceased entirely; use of sedative hypnotic agents was less amenable to reduction.

Clinical Implications

Multifaceted interventions can achieve sustained improvements in prescribing practices in real-world settings.
Audit of metabolic syndrome in adults prescribed clozapine in community and long-stay in-patient populations
Authors: Morgan David , Sargeant Matthew , Chukwuma Jude , Hughes Gwenllian
Published: April 2008

Aims and Methods

To calculate the prevalence of metabolic syndrome in patients receiving clozapine in community and long-stay in-patient settings. Patients were assessed using measures specified by the Expert Panel of the US National Cholesterol Education Program.

Results

The prevalence of the metabolic syndrome was calculated as 53% in the community groups and 11% in the in-patient group, although both sample sizes (particularly the in-patient group) were small. Women were more frequently affected than men in the community population.

Clinical Implications

The higher percentage of metabolic syndrome in the community patients receiving clozapine has implications with respect to physical health. The reasons for the lower percentage in the in-patient group are unclear. Our findings point to a possible difference in the physical health of long-stay psychiatric in-patients and patients in the community.
Comparison of older people with psychosis living in the community and in care homes
Authors: Clancy Emily , Baldwin Robert C.
Published: April 2008

Aims and Method

To compare two groups of older people with chronic schizophrenia or delusional disorder living in the community and in care homes, along the domains of morbidity suggested by prior research. From the case-load of one old age psychiatrist, 22 individuals with chronic psychosis residing in care homes were compared to 23 living in their own homes. The measures used were: the Positive and Negative Symptom Score (PANSS; Kay et al, 1987); the Mini Mental State Examination (MMSE; Folstein et al, 1975); the Burvill Physical Illness Scale (Burvill et al, 1990); and an Activities of Daily Living Scale (IADL; Lawton et al, 1969).

Results

Those in care homes had significantly higher PANSS scores (38.9 v. 21.0, P<0.01), largely accounted for by significantly more deficit symptoms (14.2 v. 5.6, P<0.01). They also had poorer cognition and significantly greater impairment in daily-life activities but their medical condition was not significantly worse. Most were seen only by a psychiatrist.

Clinical Implications

The greater morbidity and disablement of older people with chronic schizophrenia or delusional disorder living in care homes is likely to be intrinsic to the disorder but does not appear to be taken into account in current service planning or delivery.
Exploration of in-patient attitudes towards smoking within a large mental health trust
Authors: Smith Jennifer , O'Callaghan Charlotte
Published: April 2008

Aims and Method

To explore the smoking habits of in-patients on psychiatric wards, their beliefs about the effects of smoking on health, and their attitudes towards hospital and government smoking policies. Face-to-face interviews with 135 in-patients were conducted.

Results

A total of 54.1% of participants smoked. Smoking was less prevalent in those aged 65 years and older (P<0.001). Non-smokers were more likely to believe smoking to be harmful to health (P=0.002). Overall, 71.1% of the participants favoured the existing smoking policy, with only 3.0% wanting a complete ban on smoking and 54.1% agreeing with banning smoking in public places.

Clinical Implications

Further studies are warranted into the views of in-patients elsewhere and to see whether attitudes change as trusts tighten their smoking policies. Outdoor smoking areas may need to be considered, although in practice this may not be possible in all trusts.
Psychiatric supervision of student university counsellors: a specialist registrar's perspective
Authors: Ganeshalingam Yogesh
Published: April 2008

The University of Greenwich located in south-east London has a diverse student population from more than a hundred countries that comprises a community of approximately 4000. To support its students the university has a confidential individual counselling service and I was given the opportunity to provide psychiatric supervision to three permanent counsellors over the 2006/2007 academic year.
To trust or not to trust? Faith issues in psychopharmacological prescribing
Authors: Khokhar Waqqas Ahmad , Hameed Imran , Ali Mohammed Mubashir , Sadiq Javaria , Bowie Peter
Published: April 2008

Aims and Method

To ascertain attitudes, awareness, knowledge and variations in prescribing habits of psychiatrists when addressing issues of faith, culture and dietary requirements (in keeping with the General Medical Council's and the Royal College of Psychiatrists' guidelines), and how these may affect the trust in doctor–patient relations. We undertook a cross-sectional postal survey aimed at clinicians in South West Yorkshire Mental Health Trust.

Results

We obtained 38 responses (40% of the total number of questionnaires sent out) from two mailshots. Although the majority of respondents indicated that they were aware of the presence of potentially forbidden animal-derived ingredients in medication, only half expressed the view that a discussion regarding the above should take place prior to prescribing such medication.

Clinical Implications

Diversity training combined with taking a genuine interest in patients' wishes will not only minimise ‘mistrust’ but also facilitate prescribing in a therapeutic relationship.
The community psychiatrist in 2008: anachronism, Cinderella or pioneer?
Authors: Holloway Frank
Published: April 2008

Contemporary psychiatry in the UK is practised in an era where the deinstitutionalisation programme is virtually complete. The vast majority of the large mental hospitals (once called asylums) that dominated mental healthcare have closed to be replaced by a complex network of community services (including a ‘virtual asylum’ of residential and nursing home provision). Psychiatrists of past generations recall the excitement (and concern) associated with the concepts of ‘community psychiatry’ and ‘community care’: some, including me, were appointed to post as a consultant community psychiatrist. In the era of ubiquitous community care is the community psychiatrist an anachronism? Or does the recent call for in-patient psychiatry to be recognised as a specialism (Dratcu, 2006) imply its obvious corollary, the specialist community psychiatrist?
Suppression of Renal α‐Dicarbonyl Compounds Generated following Ureteral Obstruction by Kidney‐Specific α‐Dicarbonyl/l‐Xylulose Reductase
Authors: Odani Hiroko , Asami Jun , Ishii Aiko , Oide Kayoko , Sudo Takako , Nakamura Atsushi , Miyata Noriyuki , Otsuka Noboru , Maeda Kenji , Nakagawa Junichi
Published: April 2008

Renal unilateral ureteral obstruction (UUO) causes acute generation of α‐dicarbonyl stress substances, such as glyoxal, 3‐deoxyglucosone, and methylglyoxal, in the kidneys. These α‐dicarbonyl compounds are prone to form advanced glycation end products (AGEs) via the nonenzymatic Maillard reaction. Using transgenic (Tg) mice overexpressing a kidney‐specific short‐chain oxidoreductase, α‐dicarbonyl/L‐xylulose reductase (DCXR), we measured generation of α‐dicarbonyls following UUO by means of electrospray ionization/liquid chromatography/mass spectrometry in their kidney extracts. The accumulation of 3‐deoxyglucosone was significantly reduced in the kidneys of the mice Tg for DCXR compared to their wild‐type littermates, demonstrating 4.91 ± 2.04 vs. 6.45 ± 1.85 ng/mg protein (P = 0.044) for the obstructed kidneys, and 3.68 ± 1.95 vs. 5.20 ± 1.39 ng/mg protein (P = 0.026) for the contralateral kidneys. Despite the reduction in accumulated α‐dicarbonyls, collagen III content in kidneys of the Tg mice and their wild‐type littermates showed no difference as monitored by in situ hybridization. Collectively, DCXR may function in the removal of renal α‐dicarbonyl compounds under oxidative circumstances, but it is not sufficient to suppress acute renal fibrosis during 7 days UUO.
Maillard Reaction Products in the Escherichia coli–derived Therapeutic Protein Interferon Alfacon‐1
Authors: Mironova Roumyana , Sredovska Angelina , Ivanov Ivan , Niwa Toshimitsu
Published: April 2008

We have recently shown that recombinant human interferon‐γ is affected by early stages of the Maillard reaction during its production in Escherichia coli. Over time, advanced glycation end products accumulated in the purified protein, accompanied with degradation, cross‐linking, and a drop in the protein's biologic activity. Here, we provide further evidence for the presence of Maillard reaction products in another E. coli–derived therapeutic protein, interferon alfacon‐1. These products might interfere with both treatment efficacy and patient safety.
The Sense of Smell
Authors: Breer H.
Published: April 2008

The sensory and hedonic evaluation of most food‐related flavors is mainly dependent on olfactory perception. The sense of smell is able to recognize and discriminate myriads of airborne molecules with great accuracy and sensitivity. The primary processes of odor perception are mediated by the chemosensory olfactory neurons in the nasal epithelium, which upon interaction with appropriate odorants elicit a chemo–electrical transduction process converting the chemical signal into electrical impulses. The encoded information is conveyed onto distinct glomeruli, inducing topographic activity patterns in the olfactory bulb. The emerging chemotopic maps are decoded in the olfactory cortex, leading to the perception of distinct flavors.
Receptor for Advanced Glycation End Product Polymorphisms and Type 2 Diabetes
Authors: Gaens Katrien H.J. , Van Der Kallen Carla J.H. , Van Greevenbroek Marleen M.J. , Feskens Edith J. , Stehouwer Coen D.A. , Schalkwijk Casper G.
Published: April 2008

Genetic variation in the receptor for advanced glycation end products (RAGE) gene may alter the expression and function of RAGE and affect disease development and outcome. We investigated whether single nucleotide polymorphisms (SNPs) in RAGE were associated with diabetes and parameters of glucose homeostasis. In total, nine SNPs of RAGE were analyzed in individuals with and without type 2 diabetes in CODAM: a cohort study of diabetes and atherosclerosis, Maastricht. A significant difference in genotype frequency of SNP rs3134945 was observed between the nondiabetic control subjects, subjects with impaired glucose metabolism, and diabetic patients. The C allele of this polymorphism was significantly associated with higher fasting glucose concentrations, 2‐h postload glucose concentrations, insulin levels, and homeostasis model assessment of insulin resistance. These results indicate that SNP rs3134945 or a locus in linkage disequilibrium with this polymorphism may be involved in the development of insulin resistance and diabetes. Because the functionality of this polymorphism is not known, the mechanism whereby this polymorphism contributes to the development of insulin resistance and diabetes has to be further elucidated.
Maillard Reaction versus Other Nonenzymatic Modifications in Neurodegenerative Processes
Authors: Pamplona Reinald , Ilieva Ekaterina , Ayala Victoria , Bellmunt Maria Josep , Cacabelos Daniel , Dalfo Esther , Ferrer Isidre , Portero‐Otin Manuel
Published: April 2008

Nonenzymatic protein modifications are generated from direct oxidation of amino acid side chains and from reaction of the nucleophilic side chains of specific amino acids with reactive carbonyl species. These reactions give rise to specific markers that have been analyzed in different neurodegenerative diseases sharing protein aggregation, such as Alzheimer's disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, Creutzfeldt‐Jakob disease, and amyotrophic lateral sclerosis. Collectively, available data demonstrate that oxidative stress homeostasis, mitochondrial function, and energy metabolism are key factors in determining the disease‐specific pattern of protein molecular damage. In addition, these findings suggest the lack of a “gold marker of oxidative stress,” and, consequently, they strengthen the need for a molecular dissection of the nonenzymatic reactions underlying neurodegenerative processes.
Some Natural Compounds EnhanceNɛ‐(Carboxymethyl)lysine Formation
Authors: Fujiwara Yukio , Kiyota Naoko , Motomura Keita , Mera Katsumi , Takeya Motohiro , Ikeda Tsuyoshi , Nagai Ryoji
Published: April 2008

Since pyridoxamine, which traps intermediates in the Maillard reaction and lipid peroxidation reaction, significantly inhibits the development of retinopathy and neuropathy in the streptozotocin‐induced diabetic rat, treatment with advanced glycation end product inhibitors and antioxidants may be a potential strategy for the prevention of clinical diabetic complications. However, the paradoxical effect of green tea has been reported; although plasma hydroperoxide levels were ameliorated, the level of Nɛ‐(carboxyethyl)lysine (CML) in tendon and plasma was increased by the oral administration of green tea to diabetic rats. In the present study, we measured the effect of natural compounds on CML formation by enzyme‐linked immunosorbent assay. A significant amount of CML was observed when bovine serum albumin was incubated with ribose for 7 days. Under the same conditions, natural compounds, such as desgalactotigonin, showed inhibitory effects, whereas quercetin and acteoside enhanced CML formation, indicating that natural compounds contain both inhibitors and enhancers for CML formation.
Methylglyoxal and Methylglyoxal‐arginine Adducts Do Not Directly Inhibit Endothelial Nitric Oxide Synthase
Authors: Brouwers Olaf , Teerlink Tom , Van Bezu Jan , Barto Rob , Stehouwer Coen D.A. , Schalkwijk Casper G.
Published: April 2008

Increased formation of the reactive dicarbonyl compound methylglyoxal (MGO) and MGO‐derived advanced glycation end products (AGEs) seems to be implicated in endothelial dysfunction and the development of diabetic vascular complications. MGO reacts with arginine residues in proteins to generate the major glycated adducts 5‐hydro‐5‐methylimidazolone (MG‐H1) and argpyrimidine (AP). We investigated whether the free forms of these adducts contribute to vascular cell dysfunction by inhibition of endothelial nitric oxide synthase (eNOS). MG‐H1 and AP were synthesized and purified by reversed‐phase chromatography, and the conversion of labeled L‐arginine to L‐citrulline was used to monitor eNOS activity. In contrast to the endogenous eNOS inhibitor asymmetric dimethylarginine (half maximal inhibitory concentration, approximately 5 μmol/L), pathophysiological concentrations of MGO and MG‐H1 and AP did not inhibit eNOS activity. Although MGO‐derived AGEs are implicated in the development of diabetic vascular complications, this study indicates that this is not mediated via direct inhibition of eNOS activity.
Oxidative Stress and Advanced Glycation in Diabetic Nephropathy
Authors: Coughlan Melinda T. , Mibus Amy L. , Forbes Josephine M.
Published: April 2008

Nephropathy remains a significant cause of morbidity and mortality in the diabetic population and is the leading cause of end‐stage renal failure in the Western World. As a result of the diabetic milieu, increased generation of reactive oxygen species (ROS) is thought to play a key role in the progression of diabetic nephropathy. Recent experimental studies have suggested that the receptor for advanced glycation end products (RAGE), which is central to the advanced glycation pathway, may mediate renal structural and functional damage via oxidative stress. This review focuses on how RAGE and subsequent ROS generation play a deleterious role in the diabetic kidney, promoting cross‐talk among signaling pathways, ultimately leading to renal dysfunction.
Inhibition of Advanced Glycation End Products
Authors: Miyata Toshio , Izuhara Yuko
Published: April 2008

Several factors have been incriminated in the genesis of diabetic nephropathy. To elucidate their interplay, we have used a hypertensive, obese, diabetic rat model with nephropathy (SHR/NDmcr‐cp) that mimics human type 2 diabetes. This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal advanced glycation end product (AGE) accumulation. In order to achieve renoprotection, which was evaluated by histology and albuminuria, various therapeutic approaches were used: caloric restriction, antihypertensive agents (angiotensin II receptor blocker [ARB] and calcium channel blocker), lipid‐ (bezafibrate) or glucose‐lowering (insulin and pioglitazone) agents, and cobalt chloride (a hypoxia‐inducible factor activator). Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with decreased AGE formation, with the exception of insulin, which induces hyperinsulinemia, eventually leading to an overproduction of transforming growth factor‐β. AGE formation is reduced directly by in vitro active compounds (e.g., ARBs) or indirectly by in vitro inactive compounds (e.g., pioglitazone and cobalt). In the latter cases, AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers. It remains to be seen whether the renoprotection offered by these various approaches may be additive.
Food Anoxia and the Formation of Either Flavor or Toxic Compounds by Amino Acid Degradation Initiated by Oxidized Lipids
Authors: Hidalgo Francisco J. , Zamora Rosario
Published: April 2008

Amino acid degradation plays an important role in the formation of both flavors and toxic compounds during food processing. These reactions are produced, to a significant extent, as a consequence of the Maillard reaction among amino acids and carbohydrates. However, recent studies have shown that lipids also take part in these reactions. This article reviews the current knowledge of the contribution of lipids to both flavor and toxic‐compound formation by amino acid degradation, describing the formation of Strecker aldehydes and the conversion of amino acids into their vinylogous derivatives as a consequence of lipid–amino acid reactions. Current data suggest that amino acids can be converted into either Strecker aldehydes or vinylogous derivatives by many lipid derivatives, which exhibit diverse reactivities for both reactions. Reaction conditions, including the presence of oxygen, also play a major role in the Strecker aldehyde/vinylogous derivative ratio obtained. Nevertheless, the high number of lipid derivatives involved, the different alternative pathways, and the existence of both positive and negative synergisms between lipids and carbohydrates make it hard to predict the effect of reaction conditions in the Strecker aldehyde/vinylogous derivative ratio obtained in complex food systems.
Approaches to Wine Aroma
Authors: Almy John , De Revel Gilles
Published: April 2008

The model reaction of cysteine and diacetyl under winemaking conditions resulted in the identification of over 40 products. Of these, 12 were also identified in wine samples. Several products of the model system contained unexpected structures that do not fit the four‐carbon skeletal pattern of diacetyl. Possible synthetic routes to one of these products, trimethylpyrazine, are presented.
Methylglyoxal: Its Presence in Beverages and Potential Scavengers
Authors: Tan Di , Wang Yu , Lo Chih‐Yu , Sang Shengmin , Ho Chi‐Tang
Published: April 2008

Nonenzymic glycation, also known as the Maillard reaction, is a complex series of reactions between reducing sugars and amino compounds. Previous studies have demonstrated that reactive dicarbonyl compounds (e.g., methylglyoxal [MG] and glyoxal [GO]), formed as intermediate products of the Maillard reaction, irreversibly and progressively modify proteins over time and yield advanced glycation end products (AGEs), which are thought to contribute to the development of diabetes mellitus and its complications. Several studies have shown that higher levels of MG are present in diabetic patients' plasma than in healthy people's plasma. Thus, decreasing the levels of MG and GO will be an effective approach to reduce the formation of AGEs and the development of diabetic complications. Here, we briefly describe our effort in searching for non‐ or less‐toxic trapping agents of reactive dicarbonyl species from dietary sources. In addition, we have discovered that commercial beverages contain extremely high levels of MG. The potential hazardous effects of dietary MG on humans remain to be explored.
Antioxidant Activity and Chemical Properties of Crude and Fractionated Maillard Reaction Products Derived from Four Sugar–Amino Acid Maillard Reaction Model Systems
Authors: Chen Xiu‐Min , Kitts David D.
Published: April 2008

Antioxidant activity of Maillard reaction products (MRPs) derived from four sugar–amino acid Maillard reaction model systems (glucose [Glc] or ribose [Rib] reacted with glycine [Gly] and L‐lysine [Lys]) were examined in terms of chemical properties and molecular weight fractionation of reaction products. Rib–amino acid model systems produced MRPs with higher antioxidant activity than Glc–amino acid model MRPs (P < 0.05, Rib–Lys > Rib–Gly > Glc–Lys > Glc–Gly). In the same sugar or same amino acid model systems, antioxidant activity of MRPs was negatively related to the final pH, fluorescent intensity, and the content of dicarbonyl compounds. Antioxidant activity positively related to the production of late‐stage browning MRPs. Fraction I from the Glc–Lys model system separated by gel filtration chromatography had the highest oxygen radical absorbance capacity (ORAC) value (1736 μmol Trolox/g MRP). Fraction IV from the Rib–Lys model system had a higher ORAC value compared to Fraction III. This result indicated that high molecular weight MRPs do not necessarily have higher antioxidant activity compared to low molecular weight MRPs.
Reversal of Hyperglycemia‐Induced Angiogenesis Deficit of Human Endothelial Cells by Overexpression of Glyoxalase 1In Vitro
Authors: Ahmed Usman , Dobler Darin , Larkin Sarah J. , Rabbani Naila , Thornalley Paul J.
Published: April 2008

Dicarbonyl glycation of RGD and GFOGER sites in type IV collagen has been associated with decreased angiogenesis. In this study, we investigated whether overexpression of glyoxalase 1 to decrease dicarbonyl glycation would prevent the angiogenesis deficit induced by hyperglycemia in vitro. Transfection of human microvascular endothelial cells resulted in a four‐fold increase in glyoxalase 1 activity compared with controls. Incubation of human microvascular endothelial cells in model hyperglycemia produced a 32% decrease in formation of tube structures that was prevented by glyoxalase 1 overexpression. We conclude that increased protection against dicarbonyl glycation of endothelial cell protein protects hyperglycemia‐induced angiogenesis deficit.
Strategy for the Study of the Health Impact of Dietary Maillard Products in Clinical Studies
Authors: Pouillart Philippe , Mauprivez Hélène , Ait‐Ameur Lamia , Cayzeele Amélie , Lecerf Jean‐Michel , Tessier Frédéric J. , Birlouez‐Aragon I.
Published: April 2008

The study of the health impact of dietary Maillard products (MPs) in realistic clinical studies requires the design of nutritionally equivalent diets with high and low levels of MPs. This difficult challenge may be achieved by setting the high‐MP diet at the regular daily level, where the common use of grilling, frying, and roasting processes allows significant amounts of carboxymethyllysine, hydroxymethylfurfural and acrylamide to be formed. In such conditions, we show that major lipid degradation does not occur, nor does degradation of vitamin E or thiamine. Based on this finding, the low‐MP diet; must be constructed accordingly, by replacing all high‐temperature techniques with steam cooking or the absence of cooking. The cooking fat must be replaced with similar raw fat as seasoning in the low‐MP diet, the high caloric density resulting from water loss in the high‐MP diet must be compensated by higher food quantities offered in the low‐MP diet, and the vitamin loss in fruit and vegetables resulting from high temperatures in the high‐MP diet can be circumvented by increasing the corresponding portion size. In the ICARE study, equilibrated diets were proposed, fulfilling all nutritional needs, but with a 3‐ to 45‐fold difference in MP concentrations. Individual quantification of nutritional and MP intakes will ensure the nutritional equivalence of the two diets and allow for quantification of the specific impact of ingested MPs.
The Dicarbonyl Proteome
Authors: Rabbani Naila , Thornalley Paul J.
Published: April 2008

Reactive, physiological, dicarbonyl, glycating agents, glyoxal and methylglyoxal, are arginine‐directed glycating agents forming mainly hydroimidazolone residues. Arginine residues have high‐frequency occurrence in sites of protein–protein, enzyme substrate and protein–nucleotide binding sites. There is emerging evidence that functionally important arginine residues in proteins are often activated toward dicarbonyl glycation—leading to functional impairment. When uncontrolled, this is associated with aging, degenerative diseases, and metabolic disorders where dicarbonyl glycation may be viewed as damage to the proteome. The glyoxalase system, particularly glyoxalase 1, is the vanguard against dicarbonyl glycation in physiological systems. Functional regulation of glyoxalase 1 suggests a role for dicarbonyl glycation in cell signaling. Although extents of modification are usually low, the dicarbonyl proteome is a critical feature of the impact of glycation on physiological function—particularly in mitochondrial dysfunction, vascular disease, and potentially in disorders of lipoprotein metabolism.
The Other Side of the Maillard Reaction
Authors: Nagaraj Ram H. , Biswas Ashis , Miller Antonia , Oya‐Ito Tomoko , Bhat Manjunatha
Published: April 2008

The Maillard reaction plays an important role in eye lens aging and cataract formation. Methylglyoxal (MGO) is a metabolic dicarbonyl compound present in the lens. It reacts with arginine residues in lens proteins to form advanced glycation end products (AGEs), such as hydroimidazolones and argpyrimidine. α‐Crystallin, comprising αA‐ and αB‐crystallin, is a major protein of the lens and it functions as a chaperone protein. We have found that upon reaction with MGO, human αA‐crystallin becomes a more effective chaperone. Modification of specific arginine residues to AGEs appears to be the reason. Mutation of these arginine residues to alanine mirrors the effect of MGO, suggesting neutralization of the positive charge on arginine residues as a cause for improved chaperone function. Reaction with MGO also blocks the loss of the chaperone function of αA‐crystallin caused by nonenzymatic glycation by ascorbate and ribose. These findings suggest that low levels of MGO might help the lens remain transparent during aging.
Plasma Concentration and Urinary Excretion of Nɛ‐(Carboxymethyl)lysine in Breast Milk– and Formula‐fed Infants
Authors: Šebeková Katarína , Saavedra Giselle , Zumpe Cornelia , Somoza Veronika , Klenovicsová Kristína , Birlouez‐Aragon Ines
Published: April 2008

Industrial processing of infant formulas (IFs) induces the formation of Maillard products, namely Nɛ‐(carboxymethyl)lysine (CML). CML content is expected to be several times higher in IFs than in fresh human breast milk. To elucidate whether CML is absorbed from IFs into the bloodstream, CML concentration in the plasma and urine were analyzed in 6‐month‐old infants (34 breast fed and 25 fed exclusively with IFs) and in 56 samples of human breast milk and 16 commercial IFs. We found that IFs contain higher amounts of CML compared to mother's milk (median: 70‐fold; range: 28‐ to 389‐fold), and CML content was higher in hydrolyzed IFs than in nonhydrolyzed IFs (P < 0.03). Plasma CML levels were 46% higher (P < 0.01) and urinary excretion of CML was 60‐fold higher (P < 0.001) in the formula‐fed infants than in the breast‐fed group. Infants fed with hydrolyzed IFs displayed significantly higher plasma CML levels than those on nonhydrolyzed formulations. We conclude that CML from IFs is absorbed into the circulatory system and is rapidly excreted in the urine.
Origin and Yields of Acetic Acid in Pentose‐based Maillard Reaction Systems
Authors: Davidek Tomas , Gouézec Elisabeth , Devaud Stéphanie , Blank Imre
Published: April 2008

The formation of acetic acid from pentoses was studied in aqueous buffered systems (90–120°C, pH 6.0–8.0) containing equimolar concentrations of 13C‐labeled xylose and glycine. Acetic acid was quantified by gas chromatography–mass spectroscopy using an isotope dilution assay. Acetic acid was mainly formed from the C‐1/C‐2 carbon atoms of xylose (77–87%), while small amounts were also formed from the C‐4/C‐5 atoms of the pentose sugar (9–15%). Temperature and pH had only a small effect on the relative contribution of the sugar carbon atoms to acetic acid. These results support β‐dicarbonyl cleavage of 1‐deoxypento‐2,4‐diulose as a major pathway leading to acetic acid in pentose‐based Maillard reaction systems under food processing conditions. Acetic acid was confirmed as a major degradation product of pentoses at the early stage of the Maillard reaction, yielding 16 mol% and 28 mol% at pH 6.0 and pH 8.0, respectively.
Central Nervous System Regulation of Energy Metabolism
Authors: Nogueiras Ruben , Tschöp Matthias H. , Zigman Jeffrey M.
Published: April 2008

In this brief review, we introduce some major themes in the regulation of energy, lipid, and glucose metabolism by the central nervous system (CNS). Rather than comprehensively discussing the field, we instead will discuss some of the key findings made regarding the interaction of the hormones ghrelin and leptin with the CNS.
The RAGE Pathway
Authors: Lukic Ivan K. , Humpert Per M. , Nawroth Peter P. , Bierhaus Angelika
Published: April 2008

The molecular mechanisms underlying loss of pain perception in diabetic neuropathy are poorly understood. Experimental diabetic neuropathy models recently provided evidence that engagement of the receptor for advanced glycation end products (RAGE) and RAGE‐dependent sustained activation of the proinflammatory transcription factor nuclear factor kappa B might significantly contribute to reduced nociception. Most importantly, diabetes‐induced loss of pain perception is largely prevented in RAGE‐deficient mice compared to RAGE‐bearing wild‐type mice. Identifying RAGE‐dependent inflammation as one pathomechanism underlying neuronal dysfunction might provide the basis for new therapeutic approaches.
Receptor for Advanced Glycation End Product Expression in Experimental Diabetic Retinopathy
Authors: Wang Yumei , Vom Hagen Franziska , Pfister Frederick , Bierhaus Angelika , Feng Yuxi , Gans Reinhold , Hammes Hans‐Peter
Published: April 2008

The advanced glycation end product (AGE)–receptor for AGE (RAGE) pathway is involved in the pathogenesis of diabetic microvascular damage. The special distribution of RAGE and its engagement has an impact on the development of diabetic retinopathy. In the present study, we used immunofluorescence and confocal laser microscopy to study RAGE expression with special emphasis on Müller glia in Sprague Dawley rats. RAGE expression was low in nondiabetic retinae and was found in ganglion cells and Müller cell end feet. In diabetic retinae, upregulated RAGE was predominantly expressed in retinal glia. Since Müller cells are important in the regulation of important features of early retinal vascular damage, such as vascular permeability, homeostasis, and response to stress, RAGE appears to be a central modulator in diabetic retinopathy.
Vitamin C–mediated Maillard Reaction in the Lens Probed in a Transgenic‐mouse Model
Authors: Fan Xingjun , Monnier Vincent M.
Published: April 2008

Aging human lens crystallins are progressively modified by yellow glycation, oxidation, and cross‐linked carbonyl compounds that have deleterious properties on protein structure and stability. In order to test the hypothesis that some of these compounds originate from oxidized vitamin C, we have overexpressed the human vitamin C transporter 2 (hSCVT2) in the mouse lens. We find that levels of ascorbic and dehydroascorbic acid are highly elevated compared to the wild type and that the lenses have accumulated yellow color and advanced Maillard reaction products identical with those of the human lens. Treatment of the mice with nucleophilic inhibitors can slow down the process, opening new avenues for the pharmacological prevention of senile cataractogenesis.
PAI1 stimulates assembly of the fibronectin matrix in osteosarcoma cells through crosstalk between the αvβ5 and α5β1 integrins
Authors: Vial Daniel , McKeown-Longo Paula J.
Published: April 2008

The plasminogen activation system regulates matrix remodeling through both proteolytic and non-proteolytic mechanisms. Studies were undertaken to determine the effects of the plasminogen activator inhibitor 1 (PAI1) on the assembly of the fibronectin matrix. The addition of PAI1 to MG-63 cells caused a 1.5- to threefold increase in the rate of fibronectin matrix assembly which was associated with an increase in β integrin activation. PAI1 treatment led to a marked decrease in focal contacts and stress fibers, whereas tensin-containing matrix contacts remained unaffected. The effects of PAI1 on matrix assembly were independent of both urokinase-type plasminogen activator (uPA) and urokinase-type plasminogen activator receptor (uPAR), indicating that the stimulation of matrix assembly by PAI1 does not depend on its anti-proteolytic activity or on the association of uPAR with integrin receptors. Antagonists of the αvβ5 integrin mimicked the effect of PAI1 on cell morphology and fibronectin matrix deposition, indicating that stimulation of matrix assembly by PAI1 required disruption of the interaction between the αvβ5 integrin and vitronectin. Consistent with this conclusion, the Q123K PAI1 mutant which does not bind vitronectin had no effect on matrix assembly. Our data identify PAI1 as a novel regulator of fibronectin matrix assembly, and indicate that this regulation occurs through a previously undescribed crosstalk between the αvβ5 and α5β1 integrins.
BNIP2 extra long inhibits RhoA and cellular transformation by Lbc RhoGEF via its BCH domain
Authors: Soh Unice J. K. , Low Boon Chuan
Published: April 2008

Increased expression of BCH-motif-containing molecule at the C-terminal region 1 (BMCC1) correlates with a favourable prognosis in neuroblastoma, but the underlying mechanism remains unknown. We here isolated BNIPXL (BNIP2 Extra Long) as a single contig of the extended, in-vitro-assembled BMCC1. Here, we show that in addition to homophilic interactions, the BNIP2 and Cdc42GAP homology (BCH) domain of BNIPXL interacts with specific conformers of RhoA and also mediates association with the catalytic DH-PH domains of Lbc, a RhoA-specific guanine nucleotide exchange factor (RhoGEF). BNIPXL does not recognize the constitutive active G14V and Q63L mutants of RhoA but targets the fast-cycling F30L and the dominant-negative T19N mutants. A second region at the N-terminus of BNIPXL also targets the proline-rich region of Lbc. Whereas overexpression of BNIPXL reduces active RhoA levels, knockdown of BNIPXL expression has the reverse effect. Consequently, BNIPXL inhibits Lbc-induced oncogenic transformation. Interestingly, BNIPXL can also interact with RhoC, but not with RhoB. Given the importance of RhoA and RhoGEF signaling in tumorigenesis, BNIPXL could suppress cellular transformation by preventing sustained Rho activation in concert with restricting RhoA and Lbc binding via its BCH domain. This could provide a general mechanism for regulating RhoGEFs and their target GTPases.
Isoform B of myosin II heavy chain mediates actomyosin contractility during TNFα-induced apoptosis
Authors: Solinet Sara , Vitale María Leiza
Published: April 2008

Cells that are treated long-term with TNFα or short-term with TGFα together with cycloheximide (CHX) undergo apoptosis. Cell shrinkage and detachment during apoptosis is dependent on actomyosin contractility. Myosin II heavy chain (MHCII) isoforms have shared and distinct functions. Here, we investigated whether the involvement of MHCII isoforms A and B (MHCIIA and MHCIIB, respectively) in cell shrinkage and detachment differs during apoptosis. We show that TNFα induces caspase-dependent MHCIIA degradation, whereas MHCIIB levels and association with the cytoskeleton remained virtually unchanged in TtT/GF cells and NIH 3T3 fibroblasts. MHCIIA proteolysis also occurred in fibroblasts that lack MHCIIB when treated with TNFα and CHX together. The absence of MHCIIB did not affect cell death rate. However, MHCIIB–/– cells showed more resistance to TNFα–induced actin disassembly, cell shrinkage and detachment than wild-type fibroblasts, indicating the participation of MHCIIB in these events. Moreover, inhibition of atypical PKCζ, which targets MHCIIB but not MHCIIA, blocked TNFα-induced shrinkage and detachment in TtT/GF cells and wild-type fibroblasts, but the inhibitory effect was significantly reduced in MHCIIB–/– fibroblasts. TNFα treatment increased cytoskeleton-associated myosin light chain (MLC) phosphorylation but did not induce actin cleavage. In conclusion, our results demonstrate that MHCIIB, together with MLC phosphorylation and actin, constitute the actomyosin cytoskeleton that mediates contractility during apoptosis.
Outcome measures for orthopaedic interventions on the hip
Authors: Ashby E. , Grocott M. P. W. , Haddad F. S.
Published: April 2008

Orthopaedic outcome measures are used to evaluate the effect of operative interventions. They are used for audit and research. Knowledge of these measures is becoming increasingly important with league tables comparing surgeons and hospitals being made accessible to the profession and the general public.

Several types of tool are available to describe outcome after hip surgery such as generic quality-of-life questionnaires, disease-specific quality-of-life questionnaires, hip-specific outcome measures and general short-term clinical measures. We provide an overview of the outcome measures commonly used to evaluate hip interventions.
The survival of support rings in complex acetabular revision surgery
Authors: Carroll F. A. , Hoad-Reddick D. A. , Kerry R. M. , Stockley I.
Published: April 2008

Between 1980 and 2000, 63 support rings were used in the management of acetabular deficiency in a series of 60 patients, with a mean follow-up of 8.75 years (2 months to 23.8 years). There was a minimum five-year follow-up for successful reconstructions. The indication for revision surgery was aseptic loosening in 30 cases and infection in 33. All cases were Paprosky III defects; IIIA in 33 patients (52.4%) and IIIB in 30 (47.6%), including four with pelvic dissociation. A total of 26 patients (43.3%) have died since surgery, and 34 (56.7%) remain under clinical review. With acetabular revision for infection or aseptic loosening as the definition of failure, we report success in 53 (84%) of the reconstructions. A total of 12 failures (19%) required further surgery, four (6.3%) for aseptic loosening of the acetabular construct, six (9.5%) for recurrent infection and two (3.2%) for recurrent dislocation requiring captive components. Complications, seen in 11 patients (18.3%), included six femoral or sciatic neuropraxias which all resolved, one grade III heterotopic ossification, one on-table acetabular revision for instability, and three early post-operative dislocations managed by manipulation under anaesthesia, with no further instability.

We recommend support rings and morcellised bone graft for significant acetabular bone deficiency that cannot be reconstructed using mesh.
Intramedullary nailing of fractures of the tibia in diabetics
Authors: Aderinto J. , Keating J. F.
Published: April 2008

We reviewed 27 diabetic patients who sustained a tibial fracture treated with a reamed intramedullary nail and compared them with a control group who did not have diabetes. There were 23 closed fractures and four were open. Union was delayed until after six months in 12 of the 23 (52%) diabetic patients with closed fractures and ten of the 23 (43%) control patients (p = 0.768). In two patients with diabetes (9%), closed tibial fractures failed to unite and required exchange nailing, whereas all closed fractures in the control group healed without further surgery (p = 0.489). In both the diabetic and control groups with closed fractures two patients (9%) developed superficial infections. There were two (9%) deep infections in diabetic patients with closed fractures, but none in the control group (p = 0.489).

Overall, there was no significant difference in the rate of complications between the diabetic patients and the control group, but there was a tendency for more severe infections in patients with diabetes.
Reconstruction for instability of the sternoclavicular joint using the tendon of the sternocleidomastoid muscle
Authors: Armstrong A. L. , Dias J. J.
Published: April 2008

We describe a new method of stabilising a painful unstable sternoclavicular joint using the sternocleidomastoid tendon and passing it through the medial clavicle and onto the manubrium sternum. This method is simple, reproducible and avoids the potential risks of reefing the joint to the first rib. The technique was used in seven cases of sternoclavicular joint instability in six patients who were reviewed at a mean of 39.7 months (15 to 63). Instability was markedly reduced or eliminated in all cases, but in one there was occasional persistant subluxation. There were minor scar complications after two procedures and one patient had transient ulnar neuritis.

This procedure provides satisfactory results in the medium term.
The functional relevance of neurological recovery 20 years or more after lumbar discectomy
Authors: Marshall R. W.
Published: April 2008

The indications for lumbar discectomy are pain and neurological dysfunction. This paper considers the extent and timing of neurological recovery following spinal decompression.