bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detecting microdamage in bone
Authors: Lee T. C. , Mohsin S. , Taylor D. , Parkesh R. , Gunnlaugsson T. , O'Brien F. J. , Giehl M. , Gowin W. 
Published: July 2003

AbstractFatigue‐induced microdamage in bone contributes to stress and fragility fractures and acts as a stimulus for bone remodelling. Detecting such microdamage is difficult as pre‐existing microdamage sustained in vivo must be differentiated from artefactual damage incurred during specimen preparation. This was addressed by bulk staining specimens in alcohol‐soluble basic fuchsin dye, but cutting and grinding them in an aqueous medium. Nonetheless, some artefactual cracks are partially stained and careful observation under transmitted light, or epifluorescence microscopy, is required. Fuchsin lodges in cracks, but is not site‐specific. Cracks are discontinuities in the calcium‐rich bone matrix and chelating agents, which bind calcium, can selectively label them. Oxytetracycline, alizarin complexone, calcein, calcein blue and xylenol orange all selectively bind microcracks and, as they fluoresce at different wavelengths and colours, can be used in sequence to label microcrack growth. New agents that only fluoresce when involved in a chelate are currently being developed – fluorescent photoinduced electron transfer (PET) sensors. Such agents enable microdamage to be quantified and crack growth to be measured and are useful histological tools in providing data for modelling the material behaviour of bone. However, a non‐invasive method is needed to measure microdamage in patients. Micro‐CT is being studied and initial work with iodine dyes linked to a chelating group has shown some promise. In the long term, it is hoped that repeated measurements can be made at critical sites and microdamage accumulation monitored. Quantification of microdamage, together with bone mass measurements, will help in predicting and preventing bone fracture failure in patients with osteoporosis.
Intrapopulation variability in mineralization density at the human femoral mid‐shaft
Authors: Goldman H. M. , Bromage T. G. , Boyde A. , Thomas C. D. L. , Clement J. G. 
Published: July 2003

AbstractOne of several microstructural variables known to affect the mechanical properties of bone is the degree of mineralization of bone matrix. The aim of this study was to examine mineralization density, and its variability with age and sex, from a biomechanical perspective. Histological sections, prepared from mid‐shaft femora obtained at autopsy from 40 individuals, were imaged using quantitative backscattered electron microscopy. Each cross‐section montage was divided into 48 segments according to anatomical position. Mean grey‐level values were quantified for each segment. One‐way anova with Tukey HSD post hoc tests were used to test for differences in mineralization between segments, age groups and sexes. Results showed a decrease in overall degree of mineralization density with adult age, but an increase in its coefficient of variation. Degree of mineralization was significantly lower in the periosteal third of the cortex, particularly in the antero‐lateral aspect. This pattern was most prevalent amongst the youngest individuals in the sample. Whereas males between ages 45–64 years had a higher average degree of mineralization than females, the opposite was true of the older age group. Mineralization significantly decreased between middle and older age groups in males, but not in females. Despite limited consistencies in the location of high and low average mineralization bone through the cortex, the degree of interindividual variation, even within a single age and sex group, overwhelmed population level trends. The patterns of variability identified in this study are consistent with results of an analysis of collagen fibre orientation using the same sample material.
The real response of bone to exercise
Authors: Boyde Alan 
Published: July 2003

AbstractThis review presents findings made in studies of large mammalian bones, especially from racehorse training experiments (2–8 years old, third metacarpal, tarsal) and human autopsy orthopaedic femoral implant retrievals and other human biopsy and autopsy cases. Samples were cleaned to analyse mineralized matrix in three dimensions, or poly methyl‐methacrylate embedded and micromilled to delete topography and study the superficial c. 0.5‐µm two‐dimensional section using quantitative backscattered electron imaging. With experimental implant studies in rabbits, observations were also made in vivo using confocal microscopy. Cracks in both calcified cartilage and bone may be removed by infilling with calcified matrix. This may be a general repair mechanism for calcified connective tissue crack repair. The fraction of the organ volume occupied by any form of bone tissue in equine distal third metacarpal extremities was increased in the more exercised groups by bone deposited within former marrow adipocytic space. Where deposited upon prior lamellar bone surfaces, this occurred without the intervention of prior resorption and without the formation of a hypermineralized cement line. Exercise inhibited osteoclastic resorption at external anatomical growth modelling sites where it normally occurs. Addition is not coupled to time‐wasting resorption: both internally and externally, it occurs both by layering on existing cancellous surfaces and by creation of new immature scaffold, with de novo incorporation of a rich, capillary blood vessel supply. The real response within bone organs subjected to mechanical overload exercise within normal physiological limits is to make more, and to lose less, bone.
WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair
Authors: Chen Lishan , Huang Shurong , Lee Lin , Davalos Albert , Schiestl Robert H. , Campisi Judith , Oshima Junko 
Published: July 2003

SummaryWerner syndrome (WS) predisposes patients to cancer and premature aging, owing to mutations in WRN. The WRN protein is a RECQ‐like helicase and is thought to participate in DNA double‐strand break (DSB) repair by non‐homologous end joining (NHEJ) or homologous recombination (HR). It has been previously shown that non‐homologous DNA ends develop extensive deletions during repair in WS cells, and that this WS phenotype was complemented by wild‐type (wt) WRN. WRN possesses both 3′ → 5′ exonuclease and 3′ → 5′ helicase activities. To determine the relative contributions of each of these distinct enzymatic activities to DSB repair, we examined NHEJ and HR in WS cells (WRN–/–) complemented with either wtWRN, exonuclease‐defective WRN (E–), helicase‐defective WRN (H–) or exonuclease/helicase‐defective WRN (E–H–). The single E– and H– mutants each partially complemented the NHEJ abnormality of WRN–/– cells. Strikingly, the E–H– double mutant complemented the WS deficiency nearly as efficiently as did wtWRN. Similarly, the double mutant complemented the moderate HR deficiency of WS cells nearly as well as did wtWRN, whereas the E– and H– single mutants increased HR to levels higher than those restored by either E–H– or wtWRN. These results suggest that balanced exonuclease and helicase activities of WRN are required for optimal HR. Moreover, WRN appears to play a structural role, independent of its enzymatic activities, in optimizing HR and efficient NHEJ repair. Another human RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting that mammalian RECQ helicases have distinct functions that can finely regulate recombination events.
Are mice calorically restricted in nature?
Authors: Austad Steven N. , Kristan Deborah M. 
Published: July 2003

SummaryAn important question about traditional caloric restriction (CR) experiments on laboratory mice is how food intake in the laboratory compares with that of wild mice in nature. Such knowledge would allow us to distinguish between two opposing views of the anti‐aging effect of CR – whether CR represents, in laboratory animals, a return to a more normal level of food intake, compared with excess food consumption typical of laboratory conditions or whether CR represents restriction below that of animals living in nature, i.e. the conditions under which house mice evolved. To address this issue, we compared energy use of three mouse genotypes: (1) laboratory‐selected mouse strains (= laboratory mice), (2) house mice that were four generations or fewer removed from the wild (= wild‐derived mice) and (3) mice living in nature (= wild mice). We found, after correcting for body mass, that ad libitum fed laboratory mice eat no more than wild mice. In fact, under demanding natural conditions, wild mice eat even more than ad libitum fed laboratory mice. Laboratory mice do, however, eat more than wild‐derived mice housed in similar captive conditions. Therefore, laboratory mice have been selected during the course of domestication for increased food intake compared with captive wild mice, but they are not particularly gluttonous compared with wild mice in nature. We conclude that CR experiments do in fact restrict energy consumption beyond that typically experienced by mice in nature. Therefore, the retarded aging observed with CR is not due to eliminating the detrimental effects of overeating.
Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis
Authors: Ding Hongliu , Schwarz Dianne S. , Keene Alex , Affar El Bachir , Fenton Laura , Xia Xugang , Shi Yang , Zamore Phillip D. , Xu Zuoshang 
Published: July 2003

SummaryRNA interference (RNAi) can achieve sequence‐selective inactivation of gene expression in a wide variety of eukaryotes by introducing double‐stranded RNA corresponding to the target gene. Here we explore the potential of RNAi as a therapy for amyotrophic lateral sclerosis (ALS) caused by mutations in the Cu, Zn superoxide dismutase (SOD1) gene. Although the mutant SOD1 is toxic, the wild‐type SOD1 performs important functions. Therefore, the ideal therapeutic strategy should be to selectively inhibit the mutant, but not the wild‐type SOD1 expression. Because most SOD1 mutations are single nucleotide changes, to selectively silence the mutant requires single‐nucleotide specificity. By coupling rational design of small interfering RNAs (siRNAs) with their validation in RNAi reactions in vitro and in vivo, we have identified siRNA sequences with this specificity. A similarly designed sequence, when expressed as small hairpin RNA (shRNA) under the control of an RNA polymerase III (pol III) promoter, retains the single‐nucleotide specificity. Thus, RNAi is a promising therapy for ALS and other disorders caused by dominant, gain‐of‐function gene mutations.
Metalloporphyrins improve the survival of Sod2‐deficient neurons
Authors: Patel Manisha N. 
Published: July 2003

SummaryThe objective of this study was to determine whether metalloporphyrin catalytic antioxidants influence the survival of neuronal cultures in an in vitro model of age‐related mitochondrial oxidative stress. Neuronal cultures were prepared from cerebral cortices of manganese superoxide dismutase (MnSOD or Sod2) knockout (homozygous –/–, heterozygous –/+ or wild‐type +/+) mice. The ability of catalytic antioxidants, manganese tetrakis‐(4‐benzoic acid) porphyrin (MnTBAP) and manganese tetrakis‐(N‐ethyl‐2‐pyridyl) porphyrin (MnTE‐2‐PyP) to influence the survival of cultured cerebrocortical neurones from Sod2‐replete (+/+) and Sod2‐deficient (+/– or –/–) mice was assessed. Sod2–/– cultures showed accelerated cell death in serum‐free conditions when grown in ambient oxygen. MnTBAP and MnTE‐2‐PyP delayed the death of Sod2–/– cultures and improved the survival of Sod2+/+ and Sod2+/– cultures in serum‐free conditions. The results suggest that metalloporphyrin antioxidants can delay neuronal death resulting specifically from increased mitochondrial oxidative stress. Furthermore, Sod2‐deficient neuronal cultures provide a simple model system to screen the biological efficacy of mitochondrial antioxidants.
Genomic regions responsible for manganese superoxide dismutase regulation in Drosophila melanogaster
Authors: Paul Anirban , Duttaroy Atanu 
Published: July 2003

SummaryThe transcription of manganese superoxide dismutase (MnSOD), expression of which is essential for detoxification of superoxide radicals from mitochondria, has been shown to be regulated in vitro by many factors and conditions including oxidative stress, cytokines, lipopolysaccharide, cytoplasmic myc (c‐myc), p53 and tumour necrosis factors. Here we describe genomic regions in Drosophila melanogaster with regulatory effects on transcription of the MnSOD gene at an organism‐wide level. To understand the integrated regulation of MnSOD expression we screened chromosomes of D. melanogaster to locate deficiencies that altered the expression of MnSOD. Suppressors of MnSOD were screened by assessing the relative message abundance of MnSOD in 149 deletions covering approximately 81% of the Drosophila genome. The chromosomal deficiency Df(2R)017 significantly up‐regulated MnSOD mRNA by 1.7‐fold. Deficiency in four other genomic intervals, Df(1)ct‐J4, Df(2L)BSC4, Df(3L)66C‐G28 and Df(3R)Scr, down‐regulated MnSOD expression. Changes in MnSOD expression were positively associated with paraquat sensitivity of the deletion genotypes. Thus, at least one candidate enhancer and four candidate suppressors exist in the Drosophila genome to regulate the transcriptional activity of the MnSOD gene in vivo.
Necrotic Facial Papules in an Adolescent: C2 Deficiency with Eventual Development of Lupus Erythematosus
Authors: Lyon Valerie B. , Nocton James J. , Drolet Beth Ann , Esterly Nancy B. 
Published: July 2003

Abstract: A 14‐year‐old girl was admitted to the hospital because of persistent throat pain, fever, fatigue, 25 pound weight loss, and leukopenia. On physical examination she was thin, ill‐appearing, and had necrotic papules on the face and palpable cervical lymph nodes. Presumptive differential diagnosis included occult malignancy and infection. Numerous investigative procedures failed to elucidate a source. Vasculitis was eventually appreciated after repeat skin biopsy. Numerous serologic studies were performed and were notable for a very low level of the second component of complement without direct evidence of lupus erythematosus (LE) or other autoimmune conditions. A diagnosis of C2 deficiency‐associated vasculitis was made. She was treated with high‐dose prednisone and cyclophosphamide with resolution of her symptoms. Two years later she returned with marked malar erythema. Antinuclear and Smith antibodies were then detected and a diagnosis of LE was made. She was treated with hydroxychloroquine and sun‐avoidance measures with clearance of the malar rash.
The North American experience with the Ablate and Pace Trial (APT) for medically refractory atrial fibrillation
Authors: Wood M. A. , Kay G. N. , Ellenbogen K. A. 
Published: July 2003

Abstract
The Ablate and Pace Trial (APT) was a prospective registry study of clinical outcomes and survival following ablation and pacing therapy for medically refractory atrial fibril-lation. One hundred and fifty-six patients were enrolled at 16 centres in North America. The mean patient age was 66±11 years, with mean left ventricular ejection fraction of 48%±18%. Seventy-eight percent of the patients had structural heart disease.
During one year of follow up, multiple measures of quality-of-life showed significant and sustained improvement following ablation and pacing therapy. Also, left ventricular ejection increased significantly for patients with baseline left ventricular ejection fraction <45%. Metabolic exercise testing showed trends toward improved exercise tolerance; however, these did not achieve statistical significance. The one year overall survival was 85%, with 3% of patients experiencing sudden death.
In summary, this large, non-randomized, trial showed significant improvement in quality of life and left ventricular function following ablation and pacing therapy. Ablation and pacing therapy is a viable strategy for palliative management of patients with medically refractory, highly symptomatic atrial fibrillation.
Ablation of the atrioventricular junction
Authors: Marshall H. J. , Griffith M. J. 
Published: July 2003

Abstract
Atrioventricular junctional ablation is an attempt to interrupt conduction from the atrium to the ventricle using radiofrequency energy. The objective is to ablate the compact atrioventricular node as high as possible, leaving a stable ventricular escape rhythm. The compact node is identified in part by its relation to His recordings and partly through the known anatomy. In our series of 115 consecutive patients, atrioventricular block was achieved from the right side in 96% of patients and the remainder had the atrioventricular node ablated from the left side. Long-term success, i.e. complete heart block, was achieved in all patients. Complications in this and other series are rare, but there remains concern about sudden death in these patients.
Prospective, randomized study of atrioventricular ablation and mode-switching, dual chamber pacemaker implantation versus medical therapy in drug-resistant paroxysmal atrial fibrillation
Authors: Brignole M. , Gianfranchi L. , Menozzi C. , Alboni P. , Musso G. , Bongiorni M. G. , Gasparini M. , Raviele A. , Lolli G. , Paparella N. , Acquarone S. 
Published: July 2003

Abstract
We performed a prospective randomized 6-month evaluation of the clinical effects of atrioventricular junctional ablation together with placement of a DDDR mode-switching pacemaker vs pharmacological treatment in 43 patients with intolerable paroxysmal atrial fibrillation not controlled with antiarrhythmic drugs. Ablation and pacemaker treatment were highly effective and superior to drug therapy in controlling symptoms and improving quality of life. However, discontinuation of drug therapy exposed patients to further recurrences of paroxysmal atrial fibrillation and the risk of developing permanent atrial fibrillation.
Determinants of development of permanent atrial fibrillation and its treatment
Authors: Gianfranchi L. , Brignole M. , Menozzi C. , Lolli G. , Bottoni N. 
Published: July 2003

Abstract
We evaluated the rate of progression of permanent atrial fibrillation (AF) and identified clinical factors that predict this event in 63 consecutive patients who had undergone AV junctional ablation and DDDR pacemaker implantation for drug-refractory paroxysmal atrial fibrillation/flutter. Immediately after ablation, anti-arrhythmic drugs were discontinued in all cases. Permanent AF was con-sidered to have developed if AF was present on two consecutive 6-monthly examinations with no interim documented sinus rhythm. During a mean follow-up of 23±16 months, 22 (35%) of the 63 patients developed permanent AF. The actuarial estimate of progression of permanent AF was 22%, 40% and 56%, respectively, 1, 2 and 3 years after ablation. Age and underlying heart disease were independent predictors of progression of permanent AF. Only one (6%) of 16 patients with idiopathic AF had permanent AF (low risk group). Among the 47 patients with structural heart disease, permanent AF developed in 18 (62%) of the 29 who were aged >75 years or had >12 arrhythmic episodes per year and a symptom duration >4 years (high risk group), but only in three (17%) of the remaining 18 patients who did not (intermediate risk group). In conclusion, during a 3-year follow-up period, about half of the patients with a history of drug-refractory paroxysmal AF did not develop permanent AF after AV junctional ablation and dual-chamber pacemaker implantation, even in the absence of anti-arrhythmic drug therapy. Moreover, subgroups of patients whose risk of permanent AF progression differed were identified on the basis of simple baseline clinical variables. The results of this study form the necessary background for the correct management of patients after AV junction ablation and for the planning of future trials in this field.
Chronic atrial fibrillation in patients with paroxysmal atrial fibrillation, atrioventricular node ablation and pacemakers
Authors: McComb J. M. , Gribbin G. M. 
Published: July 2003

Abstract
Aims
This study examined the factors associated with the development of chronic (or permanent) atrial fibrillation (AF) in patients who had undergone atrioventricular (AV) node ablation with permanent pacing because of paroxysmal AF.
Methods
A retrospective review of case notes of all 65 consecutive patients identified as having had paroxysmal atrial arrhythmias, AV node ablation and permanent pacemaker implantation was performed. Atrial rhythm was established from all pacing records and from the surface ECG. Treatment with anti-arrhythmic drugs and with warfarin was recorded. A multivariate analysis was undertaken, using atrial rhythm on final ECG and chronic AF as outcome measures.
Results
During a mean follow-up of 30 months, 42% of patients with paroxysmal AF had developed chronic AF. Multivariate analysis showed that increasing age, history of electrical cardioversion and VVI pacing all contributed to the development of chronic AF. 25/62 patients were taking warfarin, and four had had strokes (2·5%/year).
Conclusions
The majority of patients with paroxysmal atrial arrhythmias treated with AV node ablation and pacing develop chronic AF eventually. Stroke remains a risk, particularly in those who develop chronic AF.
Assessment of accessory pathway and atrial refractoriness by transoesophageal and intracardiac atrial stimulation
Authors: Nanthakumar K. , Bergfeldt L. , Darpö B. 
Published: July 2003

Abstract
Aims
Measurement of the refractory properties of asymptomatic overt accessory pathways is performed to assess the risk for significant arrhythmias. We hypothesized that a transoesophageal atrial stimulation (TAS) protocol would accurately predict simultaneously measured invasive intra cardiac stimulation (ICS) of the anterograde effective refractory period of the accessory pathway (AP-ERP)
Methods and Results
Fourteen single pathway Wolff-Parkinson-White (WPW) syndrome patients underwent TAS during ICS and 24 h prior to it. The AP-ERP was measured using incremental atrial extra stimuli from TAS, the right atrium (RA) and the coronary sinus (CS) using drive trains of 500 and 600 ms. Stimulus latency was measured from intracardiac electrocardiograms. For methodological comparison, Altman–Bland analysis was used to create the limits of agreement (within-patient mean of differences±two standard deviations). There were no or small differences in the AP-ERP, as assessed by TAS, compared to RA and CS. Methodological disagreement between the three sites were common, however, and the limits of agreement ranged from ±30 to±76 ms. The concordance between TAS and RA, with regards to the AP-ERP value of 270 ms, was 63% when measured as S1S2 and was 67% when measured as A1A2. The stimulation site delay was significantly shorter for TAS compared to RA and CS sites. The two TAS procedures performed a day apart, revealed a coefficient of variation of 9% and a coefficient of reproducibility of 63 ms.
Conclusions
Despite adequate reproducibility, TAS fails to predict the AP-ERP by ICS. Differences in stimulus latency is responsible, in part, for the disagreement. In-vasive ICS cannot be replaced by TAS for risk stratifying WPW patients.