PPY-cell hyperplasia accompanying NENs: Immunohistochemical and nuclear medicine analysis.

Pancreatic polypeptide cell hyperplasia (PPY-H) is a multiplication of the neuroendocrine cells producing pancreatic polypeptide (PPY). The development and role of PPY-H and its corresponding clinical and imaging findings still need to be fully elucidated. We present 12 cases of PPY-H accompanying pancreatic neuroendocrine neoplasias (NEN). PPY-H was analyzed with the help of immunohistochemistry and confocal microscopy; preoperative clinical data and imaging studies were evaluated retrospectively. We observed PPY-H emerging from pancreatic ducts, and in some cases, we observed simultaneous NKX6.1 positivity in ducts and PPY-H. Additional clinical-pathological correlations suggests that gastrointestinal symptoms (e.g., epigastric pain and cholestasis) could be more related to PPY-H than to NEN hormonal production. In particular cases, SSTR2 expression was strong in PPY-H and correlated with distinguishable accumulation of activity next to NEN on 99 mTc EDDA/Hynic-TOC SPECT/CT. In another case, 18F-FDG-PET/CT showed increased metabolic activity in the area of PPY-H surrounding NEN. Our data suggest that PPY-H originates in the lining of pancreatic ducts. Confirmation of SSTR2 in PPY-H, using immunohistochemistry, suggests the utility of 99 mTc EDDA/Hynic-TOC or 68Ga-DOTA radiotracers in clinical diagnostics; however, studies with larger cohort are needed.

Facilitating Activity and Self-management for people with Arthritic knee, hip or lower back pain (FASA): A cluster randomised controlled trial.

BACKGROUND: Chronic musculoskeletal pain including osteoarthritis (OA) can significantly limit the functional independence of individuals. The spine and hip and knee are predominantly affected; management guidelines for each recommend exercise and education to support self-management. OBJECTIVES: This study investigated the effectiveness of a generic exercise and self-management intervention for people over-50 with hip/knee OA and/or lower back pain compared to continued GP management. DESIGN: Single blind, cluster randomised controlled trial. METHOD: Participants who had previously consulted with hip/knee OA and/or chronic lower back pain were recruited from 45 GP practices in SW England. Practices were randomly allocated to receive continued GP care (control) or continued GP care and a 6-week group exercise and self-management intervention facilitated by a physiotherapist and located in a community-based physiotherapy department. The primary outcome measure was the Dysfunction Index of the Short Musculoskeletal Functional Assessment (DI-SMFA) measured at six month post-rehabilitation. RESULTS: 349 participants were recruited and allocated to the intervention (n = 170) or control (n = 179) arms; the attrition rate was 13% at the 6 month primary end-point. One minor adverse event in the intervention group that required no medical input was reported. Intervention arm participants reported better function at 6 months compared with continued GP management alone (-3.01 difference in DI-SMFA [95%CI -5.25, -0.76], p = 0.01). CONCLUSIONS: A generic exercise and self-management intervention resulted in statistically significant changes in function after six-months compared with GP management alone, but clinical significance of these findings is less clear. This may be an effective way of managing group interventions for lower limb OA and chronic lower back pain.

How to design a dose-finding study using the continual reassessment method.

INTRODUCTION: The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM's uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce. METHODS: To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM. RESULTS: An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design. CONCLUSIONS: The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.

Adaptive designs in clinical trials: why use them, and how to run and report them.

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial's course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

Platelet impedance adhesiometry: A novel technique for the measurement of platelet adhesion and spreading.

INTRODUCTION: Thrombogenesis plays an important role in today's morbidity and mortality. Antithrombotics are among the most frequently prescribed drugs. Thorough knowledge of platelet function is needed for optimal clinical care. Platelet adhesion is a separate subprocess of platelet thrombus formation; still, no well-standardized technique for the isolated measurement of platelet adhesion exists. Impedimetry is one of the most reliable, state-of-art techniques to analyze cell adhesion, proliferation, viability, and cytotoxicity. We propose impedimetry as a feasible novel method for the isolated measurement of 2 significant platelet functions: adhesion and spreading. METHODS: Laboratory reference platelet agonists (epinephrine, ADP, and collagen) were applied to characterize platelet functions by impedimetry using the xCELLigence SP system. Platelet samples were obtained from 20 healthy patients under no drug therapy. Standard laboratory parameters and clinical patient history were also analyzed. RESULTS: Epinephrine and ADP increased platelet adhesion in a concentration-dependent manner, while collagen tended to have a negative effect. Serum sodium and calcium levels and age had a negative correlation with platelet adhesion induced by epinephrine and ADP, while increased immunoreactivity connected with allergic diseases was associated with increased platelet adhesion induced by epinephrine and ADP. ADP increased platelet spreading in a concentration-dependent manner. CONCLUSION: Impedimetry proved to be a useful and sensitive method for the qualitative and quantitated measurement of platelet adhesion, even differentiating between subgroups of a healthy population. This novel technique is offered as an important method in the further investigation of platelet function.

A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol.

BACKGROUND: Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control. METHODS/DESIGN: SPARC is a "rolling-six" design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a 'rolling-six' design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5-6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015. DISCUSSION: This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options. TRIAL REGISTRATION: ISRCTN14138956 . Funded by CRUK.

The Prognostic Value of Patient-Reported Outcome Data in Patients With Colorectal Hepatic Metastases Who Underwent Surgery.

INTRODUCTION: Patient-reported outcomes (PROs) are critical to evaluate clinically effective treatments and evidence suggests that PROs might predict survival. The prognostic value of PROs in patients with isolated liver metastases from colorectal cancer (CRC) who undergo surgery is unclear. In this study we investigated whether baseline PROs are prognostic in this patient group. PATIENTS AND METHODS: From April 2004 to May 2007, consecutive patients who underwent curative resection of CRC liver metastases completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30 and QLQ-LMC21 questionnaires before surgery. Patients were followed until death or data were censored on April 9, 2012. Cox proportional hazards models were used to assess the effect of PROs on survival controlling for predefined clinical covariates. Models were simplified using a backwards stepwise approach and model utility appraised using the Harrell C and Somers D statistics and bootstrap methods. RESULTS: Two hundred thirty-two patients underwent liver resection and 101 (43.5%) survived 5 years. Multivariate analysis controlling for relevant clinical covariates showed that a 10-point improvement in baseline global quality of life scores was associated with a 54% improvement in survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.33-0.63; P < .001), and a clinically significant weight loss was associated with 75% worse survival (HR, 1.75; 95% CI, 1.20-2.55; P = .004). Smaller effects were noted for worsening abdominal pain, taste problems, and fatigue (30%-38% poorer survival). Results of bootstrap resampling suggested that global health and weight loss most reliably predicted survival. CONCLUSION: Results of this study demonstrated that patients who reported worse baseline global quality of life and increased weight loss before liver resection for CRC liver metastases had significantly poorer survival. These findings if externally validated might be used to inform patients, and could also influence treatment planning and advise follow-up strategies and supportive care.

Tackling the urban health divide though enabling intersectoral action on malnutrition in Chile and Kenya.

As momentum grows for a sustainable urbanisation goal in the post-2015 development agenda, this paper reports on an action research study that sought to tackle the urban health divide by enabling intersectoral action on social determinants at the local level. The study was located in the cities of Mombasa in Kenya and Valparaíso in Chile, and the impact of the intervention on child nutrition was evaluated using a controlled design. The findings showed that an action research process using the social educational process known as PLA could effectively build the capacity of multisectoral teams to take coordinated action which in turn built the capacity of communities to sustain them. The impact on child nutrition was inconclusive and needed to be interpreted within the context of economic collapse in the intervention area. Four factors were found to have been crucial for creating the enabling environment for effective intersectoral action (i) supportive government policy (ii) broad participation and capacity building (iii) involving policy makers as advisors and establishing the credibility of the research and (iii) strengthening community action. If lessons learned from this study can be adapted and applied in other contexts then they could have a significant economic and societal impact on health and nutrition equity in informal urban settlements.

Clinical effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: the CoBalT randomised controlled trial.

BACKGROUND: Only one-third of patients with depression respond fully to treatment with antidepressant medication. However, there is little robust evidence to guide the management of those whose symptoms are 'treatment resistant'. OBJECTIVE: The CoBalT trial examined the clinical effectiveness and cost-effectiveness of cognitive behavioural therapy (CBT) as an adjunct to usual care (including pharmacotherapy) for primary care patients with treatment-resistant depression (TRD) compared with usual care alone. DESIGN: Pragmatic, multicentre individually randomised controlled trial with follow-up at 3, 6, 9 and 12 months. A subset took part in a qualitative study investigating views and experiences of CBT, reasons for completing/not completing therapy, and usual care for TRD. SETTING: General practices in Bristol, Exeter and Glasgow, and surrounding areas. PARTICIPANTS: Patients aged 18-75 years who had TRD [on antidepressants for ≥ 6 weeks, had adhered to medication, Beck Depression Inventory, 2nd version (BDI-II) score of ≥ 14 and fulfilled the International Classification of Diseases and Related Health Problems, Tenth edition criteria for depression]. Individuals were excluded who (1) had bipolar disorder/psychosis or major alcohol/substance abuse problems; (2) were unable to complete the questionnaires; or (3) were pregnant, as were those currently receiving CBT/other psychotherapy/secondary care for depression, or who had received CBT in the past 3 years. INTERVENTIONS: Participants were randomised, using a computer-generated code, to usual care or CBT (12-18 sessions) in addition to usual care. MAIN OUTCOME MEASURES: The primary outcome was 'response', defined as ≥ 50% reduction in depressive symptoms (BDI-II score) at 6 months compared with baseline. Secondary outcomes included BDI-II score as a continuous variable, remission of symptoms (BDI-II score of < 10), quality of life, anxiety and antidepressant use at 6 and 12 months. Data on health and social care use, personal costs, and time off work were collected at 6 and 12 months. Costs from these three perspectives were reported using a cost-consequence analysis. A cost-utility analysis compared health and social care costs with quality adjusted life-years. RESULTS: A total of 469 patients were randomised (intervention: n = 234; usual care: n = 235), with 422 participants (90%) and 396 (84%) followed up at 6 and 12 months. Ninety-five participants (46.1%) in the intervention group met criteria for 'response' at 6 months compared with 46 (21.6%) in the usual-care group {odds ratio [OR] 3.26 [95% confidence interval (CI) 2.10 to 5.06], p < 0.001}. In repeated measures analyses using data from 6 and 12 months, the OR for 'response' was 2.89 (95% CI 2.03 to 4.10, p < 0.001) and for a secondary 'remission' outcome (BDI-II score of < 10) 2.74 (95% CI 1.82 to 4.13, p < 0.001). The mean cost of CBT per participant was £ 910, the incremental health and social care cost £ 850, the incremental QALY gain 0.057 and incremental cost-effectiveness ratio £ 14,911. Forty participants were interviewed. Patients described CBT as challenging but helping them to manage their depression; listed social, emotional and practical reasons for not completing treatment; and described usual care as mainly taking medication. CONCLUSIONS: Among patients who have not responded to antidepressants, augmenting usual care with CBT is effective in reducing depressive symptoms, and these effects, including outcomes reflecting remission, are maintained over 12 months. The intervention was cost-effective based on the National Institute for Health and Care Excellence threshold. Patients may experience CBT as difficult but effective. Further research should evaluate long-term effectiveness, as this would have major implications for the recommended treatment of depression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38231611.

The facile generation of two-dimensional stiffness maps in durotactic cell platforms through thickness projections of three-dimensional submerged topography.

An innovative platform that aims to facilitate studies of how adherent cells migrate in response to rigidity gradients or durotaxis has been developed. Soft polyacrylamide gel-based cell culture scaffolds are used to fabricate flat surfaces containing elasticity gradients through changes in the underlying patterned features. Moreover, this inert gel surface supports long-term cell viability and offers a tunable stiffness. By manipulating the thickness of the gel substrate through the embedded patterns, this system is also capable of directing collective cell patterning.

Applying optimal model selection in principal stratification for causal inference.

Noncompliance to treatment allocation is a key source of complication for causal inference. Efficacy estimation is likely to be compounded by the presence of noncompliance in both treatment arms of clinical trials where the intention-to-treat estimate provides a biased estimator for the true causal estimate even under homogeneous treatment effects assumption. Principal stratification method has been developed to address such posttreatment complications. The present work extends a principal stratification method that adjusts for noncompliance in two-treatment arms trials by developing model selection for covariates predicting compliance to treatment in each arm. We apply the method to analyse data from the Esprit study, which was conducted to ascertain whether unopposed oestrogen (hormone replacement therapy) reduced the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction. We adjust for noncompliance in both treatment arms under a Bayesian framework to produce causal risk ratio estimates for each principal stratum. For mild values of a sensitivity parameter and using separate predictors of compliance in each arm, principal stratification results suggested that compliance with hormone replacement therapy only would reduce the risk for death and myocardial reinfarction by about 47% and 25%, respectively, whereas compliance with either treatment would reduce the risk for death by 13% and reinfarction by 60% among the most compliant. However, the results were sensitive to the user-defined sensitivity parameter.

[Multimorbidity and successful aging: the population-based KORA-Age study]. / Multimorbidität und erfolgreiches Altern: Ein Blick auf die Bevölkerung im Rahmen der KORA-Age-Studie.

BACKGROUND: The objective of the KORA-Age research consortium is to assess the determinants and consequences of multimorbidity in the elderly and to look into reasons for successful aging in the general public. PATIENTS AND METHODS: In the KORA-Age cohort study 9,197 persons were included who where born in the year 1943 or before and participants of previous KORA cohort studies conducted between 1984 and 2001 (KORA: Cooperative Health Research in the Region of Augsburg). The randomized intervention study KORINNA (Coronary infarct follow-up treatment in the elderly) tested a nurse-based case management program with 338 patients with myocardial infarct and included an evaluation in health economics. RESULTS: A total of 2,734 deaths were registered, 4,565 participants submitted a postal health status questionnaire and 4,127 participants were interviewed by telephone (response 76.2% and 68.9% respectively). A gender and age-stratified random sample of the cohort consisting of 1,079 persons took part in a physical examination (response 53.8%). CONCLUSION: The KORA-Age consortium was able to collect data in a large population-based sample and is contributing to the understanding of multimorbidity and successful aging.

Performance of statistical methods for analysing survival data in the presence of non-random compliance.

Noncompliance often complicates estimation of treatment efficacy from randomized trials. Under random noncompliance, per protocol analyses or even simple regression adjustments for noncompliance, could be adequate for causal inference, but special methods are needed when noncompliance is related to risk. For survival data, Robins and Tsiatis introduced the semi-parametric structural Causal Accelerated Life Model (CALM) which allows time-dependent departures from randomized treatment in either arm and relates each observed event time to a potential event time that would have been observed if the control treatment had been given throughout the trial. Alternatively, Loeys and Goetghebeur developed a structural Proportional Hazards (C-Prophet) model for when there is all-or-nothing noncompliance in the treatment arm only. Whitebiet al. proposed a 'complier average causal effect' method for Proportional Hazards estimation which allows time-dependent departures from randomized treatment in the active arm. A time-invariant version of this estimator (CHARM) consists of a simple adjustment to the Intention-to-Treat hazard ratio estimate. We used simulation studies mimicking a randomized controlled trial of active treatment versus control with censored time-to-event data, and under both random and non-random time-dependent noncompliance, to evaluate performance of these methods in terms of 95 per cent confidence interval coverage, bias and root mean square errors (RMSE). All methods performed well in terms of bias, even the C-Prophet used after treating time-varying compliance as all-or-nothing. Coverage of the latter method, as implemented in Stata, was too low. The CALM method performed best in terms of bias and coverage but had the largest RMSE.

The use of fixed appliances in the UK: a survey of specialist orthodontists.

OBJECTIVE: To investigate the use of fixed appliances in the UK. DESIGN: Prospective postal questionnaire. SETTING: UK. PARTICIPANTS: All members of the General Dental Council Specialist List in Orthodontics still in active practice and not in training posts. METHOD: A preemptive letter of explanation was sent inviting orthodontists to participate in the survey. The questionnaire was subsequently posted to 935 specialists. Data analysis investigated differences in clinical practice related to varying provider groups, level of operator experience and geographical region. RESULTS: The response rate achieved was 66.3%. A majority of orthodontists routinely used the 0.022 inch pre-adjusted edgewise system, standard size Siamese pattern stainless steel brackets, conventionally ligated and bonded using standard etch and light cured composite. Nickel titanium and stainless steel were the most popular archwire materials. Anchorage was supported routinely by palatal and lingual arches in up to 25% and by headgear in over a third of respondents. Newer innovations showed variable popularity. Self-etching primer was used routinely by one-third of respondents with 11% use of self-ligating brackets. Banding of first molars was preferred by over 60% of clinicians. Bone screw implants were used by only 0.2% of respondents. Clinicians with less than 10 years experience used more headgear, light curing, MBT prescription and molar bonding. Operators with over 20 years experience used more chemically cured bonding, Roth prescription, banded first molars, 0.018 inch slot size and Tip-Edge(TM), with less use of headgear. Fixed appliance use differed from that reported in the US with lower use in the UK of standard edgewise and Roth systems, aesthetic, miniaturised and 0.018 inch slot brackets and rapid maxillary expansion. CONCLUSION: Most UK orthodontic specialists routinely used the 0.022 inch pre-adjusted edgewise system with standard size Siamese steel brackets bonded using standard etch and light cured composite with conventional ligation. Variations were seen between different provider groups, types of treatment funding, levels of operator seniority and geographical regions. Differences were noted particularly in the use of bracket prescription and design, types of molar attachment and anchorage control.

Prevalence of iron deficiency in children with cyanotic heart disease seen at Kenyatta National Hospital and Mater Hospital Nairobi.

OBJECTIVE: To establish the prevalence of iron deficiency among children with cyanotic heart disease. DESIGN: Cross-sectional study. SETTING: The study was carried out at Kenyatta National Hospital and Mater Hospital from August to December of 2007. A total of 112 children meeting the eligibility criteria were recruited from the wards and the cardiac clinics. SUBJECTS: These were children less than 18 years of age, with cyanotic heart disease confirmed on ECHO, presenting at the paediatric cardiac clinic of the two hospitals or admitted in the wards at Kenyatta National Hospital. These were patients who had not undergone surgical correction. RESULTS: The prevalence of iron deficiency was found to be 16.9% (95% CI 9.8-24.1%). CONCLUSION: There is a high prevalence of iron deficiency among patients with congenital heart disease with cyanosis in the two institutions. Routine screening for iron deficiency is recommended for these children and those found to be deficient should be treated.

Beta-blocker use and risk of fractures in men and women from the general population: the MONICA/KORA Augsburg cohort study.

UNLABELLED: Use of beta-blockers is associated with a reduced risk of fractures in middle-aged and older subjects from the general population. INTRODUCTION: The present prospective population-based study investigated the association between use of beta-blockers and incidence of any fracture. METHODS: The study was based on 1,793 persons 55 to 74 years of age who participated in one of the three MONICA Augsburg surveys between 1984 and 1995. Subjects were without any fracture at baseline. Incident fractures were assessed using a health questionnaire. Hazard ratios (HRs) were estimated from Cox proportional hazard models. RESULTS: During a mean follow-up of 10.7 years, there occurred 263 incident fractures. beta-blocker users were older, were significantly more likely to be obese, to drink no alcohol, to have hypertension or diabetes, to use thiazides and statins, and to be physically inactive. The use of beta-blockers was associated with a lower risk of any fracture (HR 0.57; 95% CI = 0.36-0.90) after adjustment for age, sex and survey. Further adjustment for body mass index and education years only slightly attenuated the relationship (HR 0.60; 95% CI = 0.38-0.95) and additional adjustment for a variety of further risk factors did not attenuate the association (HR 0.60; 95% CI = 0.37-0.96). CONCLUSION: Use of beta-blockers was associated with a reduced risk of fractures in middle-aged and older subjects from the general population.

One-day kinetics of myocardial engraftment after intracoronary injection of bone marrow mononuclear cells in patients with acute and chronic myocardial infarction.

OBJECTIVE: To investigate the kinetics of myocardial engraftment of bone marrow-derived mononuclear cells (BMNCs) after intracoronary injection using 99mTc-d,l-hexamethylpropylene amine oxime (99mTc-HMPAO) nuclear imaging in patients with acute and chronic anterior myocardial infarction. DESIGN: Nuclear imaging-derived tracking of BMNCs at 2 and 20 h after injection in the left anterior descending (LAD) coronary artery. SETTING: Academical cardiocentre. PATIENTS: Five patients with acute (mean (SD) age 58 (11) years; ejection fraction range 33-45%) and five patients with chronic (mean (SD) age 50 (6) years; ejection fraction range 28-34%) anterior myocardial infarction. INTERVENTIONS: A total of 24.2 x 10(8)-57.0 x 10(8) BMNCs (20% labelled with 700-1000 MBq 99mTc-HMPAO) were injected in the LAD coronary artery. RESULTS: At 2 h after BMNC injection, myocardial activity was observed in all patients with acute (range 1.31-5.10%) and in all but one patient with chronic infarction (range 1.10-3.0%). At 20 h, myocardial engraftment was noted only in three patients with acute myocardial infarction, whereas no myocardial activity was noted in any patient with chronic infarction. CONCLUSIONS: Engraftment of BMNCs shows dynamic changes within the first 20 h after intracoronary injection. Persistent myocardial engraftment was noted only in a subset of patients with acute myocardial infarction.

Effect of tuftsin and oligotuftsins on chemotaxis and chemotactic selection in Tetrahymena pyriformis.

The chemotactic properties of tuftsin (H-TKPR-OH), tuftsin derivatives (H-KPR-OH, H-TKPKG-NH(2), Ac-TKPKG-NH(2)) and TKPKG-based oligotuftsins (T20, T30, T40) were investigated in Tetrahymena pyriformis GL. In contrast to its effects on Mammalia, tuftsin elicited chemorepellent or neutral responses; truncation of the N-terminal part (KPR) led to similar results, though with more neutral effects. The significance of the C-terminal part of the molecule was revealed by the chemoattractant properties of TKPKG, which are nevertheless abolished by acylation. Among the oligotuftsins, T20 and T40 were chemoattractants at higher concentrations (10(-9)-10(-6) M), while T30 had a wide-ranging chemorepellent effect, indicating that chemotaxis is elicited in Tetrahymena only by ligands with optimal physicochemical characters (mass, conformation, etc.). The chemotactic selection data indicated that tuftsin-induced chemotaxis results from fairly short-term signalling in Tetrahymena.

[Lung resection for a non-small cell carcinoma (stage IV) with a permanent intracavitary brachytherapy 125I]. / Resekce plic pro nemalobunecný karcinom (stadium IV) s permanentní intrakavitární brachyterapií 125I.

In November 2005, the authors used the lung resection method in combination with peroperative brachytherapy125 for a non-small cell carcinoma, for the first time. The patient had an adenocarcinoma of the right lung T2N2M0, stage IIIA. During the procedure, the team diagnosed advanced stage of the process, the tumor originated in the hilus region of the middle lobe with a metastatic spread into the superior and inferior lobe. Distant unilateral lymphonodes were infiltrated simultaneously. The histological examination confirmed the diagnosis of T2N2M1, however, the original classification was re-assessed and changed to stage IV. Pneumonectomy with lymphadenectomy of all of the macroscopically detectable lymphonodes was completed. The lymphatic drainage sites in the upper and lower mediastinum were covered by seeds of a permanent gama emitter 125I with a total dose of 100 Gy. The patient recovered with no complications and was discharged on the day 8. He was included in the study and will be followed on a regular basis. On the authors' opinion, the method of the lung resection with peroperative permanent brachytherapy has a potential for decreasing the tumor relaps rates, eventually, for improving the patients survival rates and their quality of life. The authors will continue their applied research of this serious problematics, aiming to confirm or refuse the stated hypothesis.

Chemotactic-range-fitting of amino acids and its correlations to physicochemical parameters in Tetrahymena pyriformis--evolutionary consequences.

Amino acids are considered the oldest organic substances of the prebiotic evolution. Chemotactic effects of amino acid L-isomers investigated in the protozoan model Tetrahymena show that the chemotactic properties of amino acids are complex and depend on multiple physicochemical characteristics of the investigated ligands. The range of effectiveness is significantly wider for chemoattractant ligands than for chemorepellent ones. This phenomenon provides the basis of the "chemotactic-range-fitting" theory. The validity of this theory is supported by a decreased pK (-COOH), an increased pK (-NH2), and a decrease in solvent exposed areas and hydropathy indexes in chemoattractant amino acids compared to chemorepellent ones. Chemotactic selection has proven the activity of long-term (I, H, T) and short-term (P, A, Q, S) selector amino acids and their characteristic diversities in values of the pK and SEA (surface exposed area). Comprehensive studies of the chemotaxis data with the results of consensus analysis of amino acids suggests that chemotactic activity was one of the most primordial physiological activities and had a prospective significance not only in the molecular evolution of ligands, but also in the evolution of signalling.