The structural description of disordered systems has been a longstanding challenge in physical science. We propose an atomic cluster alignment method to reveal the development of three-dimensional topological ordering in a metallic liquid as it undercools to form a glass. By analyzing molecular dynamic (MD) simulation trajectories of a Cu64.5Zr35.5 alloy, we show that medium-range order (MRO) develops in the liquid as it approaches the glass transition. Specifically, around Cu sites, we observe “Bergman triacontahedron” packing (icosahedron, dodecahedron and icosahedron) that extends out to the fourth shell, forming an interpenetrating backbone network in the glass. The discovery of Bergman-type MRO from our order-mining technique provides unique insights into the topological ordering near the glass transition and the relationship between metallic glasses and quasicrystals.
We estimated the heritability of individual differences in beta cell function after a mixed meal test designed to assess a wide range of classical and model-derived beta cell function parameters.
A total of 183 healthy participants (77 men), recruited from the Netherlands Twin Register, took part in a 4 h protocol, which included a mixed meal test. Participants were Dutch twin pairs and their siblings, aged 20 to 49 years. All members within a family were of the same sex. Insulin sensitivity, insulinogenic index, insulin response and postprandial glycaemia were assessed, as well as model-derived parameters of beta cell function, in particular beta cell glucose sensitivity and insulin secretion rates. Genetic modelling provided the heritability of all traits. Multivariate genetic analyses were performed to test for overlap in the genetic factors influencing beta cell function, waist circumference and insulin sensitivity.
Significant heritabilities were found for insulinogenic index (63%), beta cell glucose sensitivity (50%), insulin secretion during the first 2 h postprandial (42–47%) and postprandial glycaemia (43–52%). Genetic factors influencing beta cell glucose sensitivity and insulin secretion during the first 30 postprandial min showed only negligible overlap with the genetic factors that influence waist circumference and insulin sensitivity.
The highest heritability for postprandial beta cell function was found for the insulinogenic index, but the most specific indices of heritability of beta cell function appeared to be beta cell glucose sensitivity and the insulin secretion rate during the first 30 min after a mixed meal.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2060-5) contains supplementary material, which is available to authorised users.
Gastro-entero pancreatic function; Genetics of type 2 diabetes; Human; Insulin secretion; Insulin sensitivity; Metabolic physiology
We assessed the cost-effectiveness of a community-based, modified Diabetes Prevention Program (DPP) designed to reduce risk factors for type 2 diabetes and cardiovascular disease.
We developed a Markov decision model to compare costs and effectiveness of a modified DPP intervention with usual care during a 3-year period. Input parameters included costs and outcomes from 2 projects that implemented a community-based modified DPP for participants with metabolic syndrome, and from other sources. The model discounted future costs and benefits by 3% annually.
At 12 months, usual care reduced relative risk of metabolic syndrome by 12.1%. A modified DPP intervention reduced relative risk by 16.2% and yielded life expectancy gains of 0.01 quality-adjusted life-years (3.67 days) at an incremental cost of $34.50 ($3,420 per quality-adjusted life-year gained). In 1-way sensitivity analyses, results were sensitive to probabilities that risk factors would be reduced with or without a modified DPP and that patients would enroll in an intervention, undergo testing, and acquire diabetes with or without an intervention if they were risk-factor–positive. Results were also sensitive to utilities for risk-factor–positive patients. In probabilistic sensitivity analysis, the intervention cost less than $20,000 per quality-adjusted life-year gained in approximately 78% of model iterations.
We consider the modified DPP delivered in community and primary care settings a sound investment.
The aim of this study was to investigate whether the final displacement of conservatively treated distal radius fractures can be predicted after primary reduction. We analysed the radiographic documents of 311 patients with a conservatively treated distal radius fracture at the time of injury, after reduction and after bony consolidation. We measured the dorsal angulation (DA), the radial angle (RA) and the radial shortening (RS) at each time point. The parameters were analysed separately for metaphyseally “stable” (A2, C1) and “unstable” (A3, C2, C3) fractures, according to the AO classification system. Spearman’s rank correlations and regression functions were determined for the analysis. The highest correlations were found for the DA between the time points ‘reduction’ and ‘complete healing’ (r = 0.75) and for the RA between the time points ‘reduction’ and ‘complete healing’ (r = 0.80). The DA and the RA after complete healing can be predicted from the regression functions.
The Compress® implant (Biomet, Warsaw, IN) is an innovative device developed to enable massive endoprosthetic fixation through the application of compressive forces at the bone-implant interface. This design provides immediate, stable anchorage and helps to avoid the long-term complication of aseptic loosening secondary to stress shielding and particle-induced osteolysis seen in conventional, stemmed megaprostheses. The purpose of our study was to evaluate the in vivo biological effects of the high compressive forces attained. Twelve consecutive Compress® patients undergoing revision surgery for infection, periprosthetic fracture, or local tumour recurrence were reviewed in order to exclude the possibility of osteonecrosis at the prosthetic interface. Compressive forces ranged from 400–800 lb. Duration of implantation averaged 3.3 years (range 0.4–12.2 years). Two patients with infection demonstrated loosening at the bone-prosthetic interface; otherwise, there was no radiographic evidence of prosthetic failure in any of the patients. No patient demonstrated histological evidence of osteonecrosis. In fact, new woven bone and other findings consistent with viable bone were noted in all of the retrieved specimens.
Methods: People originating from Surinam (n = 798) and the Netherlands Antilles (n = 227) were recruited in order to study the heterosexual spread of HIV within ethnic groups. Log binomial regression was used to study determinants for homeland travel over the past 5 years; logistic regression was used to study determinants of unprotected sex on these visits.
Results: Of the migrants, 38% of men and 42% of women visited their homeland. Visits were most likely among men who had lived ⩾7 years in the Netherlands, were employed, had a high educational level and were/had been married. For women, visiting was associated with older age and living in the Netherlands for ⩾8 years. Of migrants visiting their homeland, 47% of men and 11% of women acquired a local sexual partner. For male travellers, Surinamese origin (adjusted OR 10.66; 95% CI 1.72 to 104.48) and a history of ⩾1 sexually transmitted infection (STI) (adjusted OR 12.51; 95% CI 3.75 to 46.95) were associated with having unprotected sex with local partners. For women, having >1 partner in the past 5 years (OR 13.57; 95% CI 2.57 to 250.28) was associated with unprotected sex with local partners.
Conclusion: Migrants are at substantial risk for HIV and STIs while visiting their homeland. It is important to reach migrants, who are likely to engage in unprotected sex during visits, for pretravel health education. Additional research on risk behaviour in the homeland and the Netherlands is needed to identify migrants with high risk behaviour.
To evaluate barriers to and strategies for medication adherence and predictors of adherence and the primary outcome in the Diabetes Prevention Program (DPP).
RESEARCH DESIGN AND METHODS
Within a randomized, controlled primary prevention study for type 2 diabetes, we collected data on study medication adherence, its predictors, and health outcomes in 27 clinical centers across mainland U.S. and Hawaii. Medication arm participants included 2,155 adults with impaired glucose tolerance randomly assigned to either metformin or matched placebo treatment arms. Structured interviews were used to promote medication adherence and to collect data regarding adherence. Adherence was measured by pill count. The primary DPP outcome of type 2 diabetes was assessed by fasting plasma glucose and oral glucose tolerance test.
Older age-groups were more adherent than the youngest group (P = 0.01) in the metformin group. The most frequently reported barrier to adherence was “forgetting” (22%). Women reported more adverse effects of metformin (15 vs. 10%, P = 0.002) in the metformin group. Odds of nonadherence increased as participants reported more than one barrier (odds ratio 19.1, P < 0.001). Odds of adherence increased as participants reported multiple strategies to take medication (2.69, P < 0.0001). There was a 38.2% risk reduction for developing diabetes for those adherent to metformin compared with those adherent to placebo (P < 0.0003).
DPP medication adherence results are unique in primary prevention for a chronic disease in a large multiethnic sample. Our finding that adherence was associated with risk reduction for diabetes supports the development of brief interventions in clinical settings where medication adherence is a challenge.
DPP, Diabetes Prevention Program
Aseptic loosening is well known following endoprosthetic replacement (EPR) using cemented intramedullary stems (CISs). The Compress® (CPS) implant uses a novel spring system, achieving immediate, high compression fixation that induces bone hypertrophy and avoids stress shielding. We compared 26 oncologic distal femoral CPS patients treated at the University of California, San Francisco (UCSF, USA) with 26 matched CIS patients from the Royal Orthopaedic Hospital, Birmingham (ROH, UK). The predominant diagnosis was osteosarcoma. Each centre had only one device-related prosthetic failure. In the short term these results show CPS to be safe and effective. We await longer follow-up to assess the ongoing potential for prosthetic failure.
Background/aim: Alterations of the immune system may have a role in thrombogenesis. Artery sites occluded with thrombi apparently release pro-inflammatory cytokines. Non-arteritic anterior ischaemic optic neuropathy (NAION) results from occlusion of the blood supply to the optic nerve. The aim of this study was to analyse levels of pro-inflammatory cytokines in patients with acute event of NAION.
Methods: Study participants included 10 patients (12 eyes) with NAION and 20 age matched controls with the same risk factors for atherosclerosis disease. Peripheral blood samples were obtained immediately at the acute onset of NAION. Plasma interleukin 8 (IL-8), IL-6, and tumour necrosis factor alpha (TNF-α) levels were measured immediately following diagnosis and during the follow up intervals.
Results: The plasma levels of IL-8 were significantly higher in NAION patients at the time of diagnosis in comparison to the control group (p = 0.002), and decreased during the follow up period (6–12 months) (p = 0.05). There were no differences in plasma levels of IL-6 and TNF-α between NAION patients and controls, either in the acute phase or during the follow up period.
Conclusion: Plasma levels of IL-8 are elevated during the acute phase of NAION, but not IL-6 and TNF-α. These elevated levels are in accordance with other acute vascular thrombosis. The clinical significance of these findings should be further evaluated.
interleukins; tumour necrosis factor; anterior ischaemic optic neuropathy
Simultaneous measurement of intramuscular pressure (IMP), tissue oxygen partial pressure (pO2) and EMG fatigue parameters in the multifidus muscle during a fatigue-inducing sustained muscular contraction. The study investigated the following hypotheses: (1) Increases in IMP result in tissue hypoxia; (2) Tissue hypoxia is responsible for loss of function in the musculature. The nutrient supply to muscle during muscle contraction is still not fully understood. It is assumed that muscle contraction causes increased tissue pressure resulting in compromised perfusion and tissue hypoxia. This tissue hypoxia, in turn, leads to muscle fatigue and therefore to loss of function. To the authors’ knowledge, no study has addressed IMP, pO2 and EMG fatigue parameters in the same muscle to gain a deeper sight into muscle perfusion during contraction. As back muscles need to have a constant muscular tension to maintain trunk stability during stance and locomotion, muscle fatigue due to prolonged contraction-induced hypoxia could be an explanation for low back pain. Sixteen healthy subjects performed an isometric muscular contraction exercise at 60% of maximum force until the point of localized muscular fatigue. During this exercise, the individual changes of IMP, pO2 and the median frequency (MF) of the surface EMG signal of the multifidus muscle were recorded simultaneously. In 12 subjects with a documented increase in intramuscular pressure, only five showed a decrease in tissue oxygen partial pressure, while this parameter remained unchanged in six other subjects and even increased in one. A fall in tissue pO2 was associated with a drop in MF in only five subjects, while there was no correlation between these parameters in the other 11 subjects. To summarize, an increase in IMP correlated with a decrease in pO2 and a drop in MF in only five out of 16 subjects. High intramuscular pressure values are not always associated with a hypoxia in muscle tissue. Tissue hypoxia is not automatically associated with a median frequency shift in the EMG signal’s power spectrum.
Tissue oxygenation; Muscular fatigue; Intramuscular pressure; Multifidus muscle; Isometric back extension
High dose rate (HDR) endobronchial brachytherapy is a
palliative treatment for symptomatic airway obstruction by malignant tumours. We report a novel use of HDR brachytherapy for treating non-malignant bronchial obstruction. The patient had a metal stent placed in a reconstructed airway after a bronchial tear to ensure patency. Granulation tissue formation in and around the stent caused
symptomatic occlusion of the airway, necessitating multiple laser
applications. A single treatment of HDR brachytherapy (1000 cGy) was
delivered following laser therapy. The patient remains well 15 months
after treatment with no evidence of recurrent granulation tissue
formation on bronchoscopy. HDR brachytherapy is an effective treatment
for non-malignant airway obstruction.
OBJECTIVE: To examine the value of two kinds of patient-level dat a (cost and diagnoses) for identifying a very small subgroup of a general population with high future costs that may be mitigated with medical management. DATA SOURCES: The study used the MEDSTAT Market Scan (R) Research Database, consisting of inpatient and ambulatory health care encounter records for individuals covered by employee- sponsored benefit plans during 1997 and 1998. STUDY DESIGN: Prior cost and a diagnostic cost group (DCG) risk model were each used with 1997 data to identify 0.5-percent-sized "top groups" of people most likely to be expensive in 1998. We compared the distributions of people, cost, and diseases commonly targeted for disease management for people in the two top groups and, as a bench mark, in the full population. PRINCIPAL FINDINGS: the prior cost- and DCG-identified top groups overlapped by only 38 percent. Each top group consisted of people with high year-two costs and high rates of diabetes, heart failure, major lung disease, and depression. The DCG top group identified people who are both somewhat more expensive ($27,292 vs. $25,981) and more likely ( 49.4 percent vs. 43.8 percent ) th an the prior-cost top group to have at least one of the diseases commonly targeted for disease management. The overlap group average cost was $46,219. CONCLUSIONS: Diagnosis-based risk models are at least as powerful as prior cost for identifying people who will be expensive. Combined cost and diagnostic data are even more powerful and more operation ally useful, especially because the diagnostic information identifies the medical problems that may be managed to achieve better out comes and lower costs.
The dorsal approach is increasingly preferred in the surgical treatment of vertebral fractures. However, the access and the implant's position cause muscle loss, which can lead to instability and a reduced capacity for rehabilitation. Morphological factors (bones, intervertebral discs) are typically blamed for chronic pain syndromes in the literature, while less importance is attached to functional factors (muscles). The objective of this study was therefore to investigate the isolated influence of dorsal spinal instrumentation on the back muscles by means of electromyography (EMG). A total of 32 patients with conditions after dorsal spondylodesis following the fracture of a vertebral body and 32 subjects with healthy backs were enrolled in this study. The EMG signal was recorded in three different muscle groups during isometric extension exercise. The evaluation was performed by comparing the mean rectified amplitudes of the three muscle groups in the patients and controls. The patients had significantly lower amplitudes in the multifidus muscle (MF) and significantly higher amplitudes in the iliocostal muscle (IL). Patients with severe pain were found to have lower electric muscle potentials in all investigated muscle groups than patients with mild pain. The muscle damage which was established in the multifidus muscle is compensated by increased activity in the iliocostal muscle. On the basis of anatomical considerations, the damage pattern can be identified as having been caused by surgery. It is extremely unlikely that trauma is the cause.
Lumbar Spine Surgery Muscle Surface EMG Vertebral fracture
Neurofibromatosis has been known to involve blood vessels
throughout the body. Pulmonary involvement with interstitial fibrosing alveolitis has been described but no case of pulmonary vascular involvement has been reported to date. A 51 year old patient with cutaneous neurofibromatosis is described who presented with severe pulmonary hypertension and radiographic, scintigraphic, and
angiographic evidence of chronic thromboembolic pulmonary
hypertension. Severe intimal fibrosis consistent with vascular
involvement with neurofibromatosis was found on endarterectomy with
no evidence of pulmonary thromboembolism. Neurofibromatosis of
pulmonary arteries should be considered as a possible cause of
High levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in breast cancer tissue extracts have been associated with rapid disease progression. In these studies, different enzyme-linked immunosorbent assay (ELISA) kits have been applied for the quantification, and consequently the ranges of uPA and PAI-1 levels reported differ considerably. Therefore, the Receptor and Biomarker Study Group (RBSG) of the European Organization for Research and Treatment of Cancer (EORTC) and a consortium of the BIOMED-1 project 'Clinical Relevance of Proteases in Tumor Invasion and Metastasis' initiated three collaborative between-laboratory assessment trials aimed at controlling uPA and PAI-1 antigen analyses. For this purpose, two control preparations were produced from different sources: pooled human breast cancer specimens (QC-240893) and human breast cancer xenografts raised in nude mice (QC-101094). The lyophilized preparations were stable for prolonged times (at least 3 and 27 months respectively) at 4 degrees C. Furthermore, a good parallelism following dilution was found for uPA and PAI-1. The data from QC trial no. 1 clearly indicated that acceptable between-laboratory coefficients of variation (CVs) for uPA (<8.2%) and PAI-1 (<16.6%) in QC-240893 could be achieved when the same type of ELISA kit (American Diagnostica) was used. From the second trial, in which ten EORTC laboratories each received five identical lyophilized QC-101094 samples, it appeared that the within-laboratory variations for uPA and PAI-1 determinations obtained by 'experienced' laboratories were lower (<12.9%) than those from non-experienced laboratories (<36.4%). In a third QC trial, five BIOMED-1 laboratories, all of which employed ELISA procedures for uPA and PAI-1, participated in six subsequent quality assessment rounds receiving five samples of QC-101094. Although for each laboratory the within-run CVs for uPA as well as for PAI-1 were low (<7.8%), the between-run CVs were found to be considerably higher (up to 56.2% for uPA and to 27.6% for PAI-1). Consequently, because of the different ELISA formats used, the absolute analyte values measured in the different laboratories varied substantially. The use of 'common external standards' in the different ELISAs resulted in a significant reduction of the between-laboratory CVs from 61.3% to 15.7% (uPA) and from 42.1% to 19.1% (PAI-1). The present data demonstrate that in multicentre studies the same ELISA kit should be used, and that external quality assurance (QA) is mandatory. Furthermore, it appears from the present study that standardization of the protein assay as a tissular parameter is imperative.
Urokinase plasminogen activator (uPA) is a serine protease involved in cancer invasion and metastasis. uPA acts in vivo by binding to a membrane receptor known as uPAR. In this study, uPA and uPAR levels were semiquantitated by immunocytochemistry in 36 primary breast carcinomas. Using monoclonal antibody HD-UK 1, uPA was detected both in stromal and in malignant cells. However, the predominant location was in the stromal cells. Using double-staining, cells containing uPA were also found to coexpress either cytokeratin (an epithelial cell marker) or more frequently KP1 (a macrophage/monocyte cell marker). With monoclonal antibody HD-uPAR 13.1, uPAR was localized principally to spindle- or macrophage-like stromal cells, especially when these cells surrounded invasive breast cancer. In contrast, uPAR was only rarely detected in cancer cells and was not detected in normal epithelia surrounding tumour or in areas of adenosis. uPA levels in both stromal and epithelial cells were significantly correlated with those for uPAR. We conclude that both uPA and its receptor are mostly present in stromal cells in invasive breast carcinomas. These results suggest that stromal cells collaborate with malignant cells to mediate metastasis.
The streptococcal plasmid pMV158 replicates by the rolling-circle mechanism. One feature of this replication mechanism is the generation of single-stranded DNA intermediates which are converted to double-stranded molecules. Lagging-strand synthesis initiates from the plasmid single-stranded origin, sso. We have used the pMV158-derivative plasmid pLS1 (containing the ssoA type of lagging-strand origin) and a set of pLS1 derivatives with mutations in two conserved regions of the ssoA (the recombination site B [RSB] and a conserved 6-nucleotide sequence [CS-6]) to identify sequences important for plasmid lagging-strand replication in Streptococcus pneumoniae. Cells containing plasmids with mutations in the RSB accumulated 30-fold more single-stranded DNA than cells containing plasmids with mutations in the CS-6 sequence. Specificity of lagging-strand synthesis was tested by the development of a new in vitro replication system with pneumococcal cell extracts. Four major initiation sites of lagging-strand DNA synthesis were observed. The specificity of initiation was maintained in plasmids with mutations in the CS-6 region. Mutations in the RSB region, on the other hand, resulted in the loss of specific initiation of lagging-strand synthesis and also severely reduced the efficiency of replication.