Development and evaluation of a spatial decision support system for malaria elimination in Bhutan

Background: Bhutan has reduced its malaria incidence significantly in the last 5 years, and is aiming for malaria elimination by 2016. To assist with the management of the Bhutanese malaria elimination programme a spatial decision support system (SDSS) was developed. The current study aims to describe SDSS development and evaluate SDSS utility and acceptability through informant interviews. Methods: The SDSS was developed based on the open-source Quantum geographical information system (QGIS) and piloted to support the distribution of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) in the two sub-districts of Samdrup Jongkhar District. It was subsequently used to support reactive case detection (RACD) in the two sub-districts of Samdrup Jongkhar and two additional sub-districts in Sarpang District. Interviews were conducted to ascertain perceptions on utility and acceptability of 11 informants using the SDSS, including programme and district managers, and field workers. Results: A total of 1502 households with a population of 7165 were enumerated in the four sub-districts, and a total of 3491 LLINs were distributed with one LLIN per 1.7 persons. A total of 279 households representing 728 residents were involved with RACD. Informants considered that the SDSS was an improvement on previous methods for organizing LLIN distribution, IRS and RACD, and could be easily integrated into routine malaria and other vector-borne disease surveillance systems. Informants identified some challenges at the programme and field level, including the need for more skilled personnel to manage the SDSS, and more training to improve the effectiveness of SDSS implementation and use of hardware. Conclusions: The SDSS was well accepted and informants expected its use to be extended to other malaria reporting districts and other vector-borne diseases. Challenges associated with efficient SDSS use included adequate skills and knowledge, access to training and support, and availability of hardware including computers and global positioning system receivers.

Mobility impairment and bad feet … who'd of guessed? The Foot Disease in Inpatients Study (FDIS)

Background Foot complications have been found to be predictors of mobility impairment and falls in community dwelling elderly patients. However, fewer studies have investigated the link between foot complications and mobility impairment in hospital in patient populations. The aim of this paper was to investigate the associations between mobility impairment and various foot complications in general inpatient populations. Methods Eligible participants were all adults admitted overnight, for any reason, into five diverse hospitals on one day; excluding maternity, mental health and cognitively impaired patients. Participants underwent a foot examination to clinically diagnose different foot complications; including foot wounds, infections, deformity, peripheral arterial disease and peripheral neuropathy. They were also surveyed on social determinant, medical history, self-care, footwear, foot complication history risk factors, and, mobility impairment defined as requiring a mobility aid for mobilisation prior to hospitalisation. Results Overall, 733 participants consented; mean(±SD) age 62(±19) years, 408 (55.8%) male, 172 (23.5%) diabetes. Mobility impairment was present in 242 (33.2%) participants; diabetes populations reported more mobility impairment than non-diabetes populations (40.7% vs 30.9%, p < 0.05). In a backwards stepwise multivariate analysis, and controlling for other risk factors, those people with mobility impairment were independently associated with increasing years of age (OR = 1.04 (95% CI) (1.02-1.05)), male gender (OR = 1.7 (1.2-2.5)), being born in Australia (OR = 1.7 (1.1-2.8), vision impairment (2.0 (1.2-3.1)), peripheral neuropathy (OR = 3.1 (2.0-4.6) and foot deformity (OR = 2.0 (1.3-3.0). Conclusions These findings support the results of other large studies investigating community dwelling elderly patients that peripheral neuropathy and foot deformity are independently associated with mobility impairment and potentially falls. Furthermore the findings suggest routine clinical diagnosis of foot complications as defined by national diabetic foot guidelines were sufficient to determine these associated foot complication risk factors for mobility impairment. Further research is required to establish if these foot complication risk factors for mobility impairment are predictors of actual falls in the inpatient environment.

Human mesenchymal stem cells retain multilineage differentiation capacity including neural marker expression after extended in vitro expansion

The suitability of human mesenchymal stem cells (hMSCs) in regenerative medicine relies on retention of their proliferative expansion potential in conjunction with the ability to differentiate toward multiple lineages. Successful utilisation of these cells in clinical applications linked to tissue regeneration requires consideration of biomarker expression, time in culture and donor age, as well as their ability to differentiate towards mesenchymal (bone, cartilage, fat) or non-mesenchymal (e.g., neural) lineages. To identify potential therapeutic suitability we examined hMSCs after extended expansion including morphological changes, potency (stemness) and multilineage potential. Commercially available hMSC populations were expanded in vitro for > 20 passages, equating to > 60 days and > 50 population doublings. Distinct growth phases (A-C) were observed during serial passaging and cells were characterised for stemness and lineage markers at representative stages (Phase A: P+5, approximately 13 days in culture; Phase B: P+7, approximately 20 days in culture; and Phase C: P+13, approximately 43 days in culture). Cell surface markers, stem cell markers and lineage-specific markers were characterised by FACS, ICC and Q-PCR revealing MSCs maintained their multilineage potential, including neural lineages throughout expansion. Co-expression of multiple lineage markers along with continued CD45 expression in MSCs did not affect completion of osteogenic and adipogenic specification or the formation of neurospheres. Improved standardised isolation and characterisation of MSCs may facilitate the identification of biomarkers to improve therapeutic efficacy to ensure increased reproducibility and routine production of MSCs for therapeutic applications including neural repair.

Prognostic molecular factors and algorithms in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas. As DLBCL is characterized by heterogeneous clinical and biological features, its prognosis varies. To date, the International Prognostic Index has been the strongest predictor of outcome for DLBCL patients. However, no biological characters of the disease are taken into account. Gene expression profiling studies have identified two major cell-of-origin phenotypes in DLBCL with different prognoses, the favourable germinal centre B-cell-like (GCB) and the unfavourable activated B-cell-like (ABC) phenotypes. However, results of the prognostic impact of the immunohistochemically defined GCB and non-GCB distinction are controversial. Furthermore, since the addition of the CD20 antibody rituximab to chemotherapy has been established as the standard treatment of DLBCL, all molecular markers need to be evaluated in the post-rituximab era. In this study, we aimed to evaluate the predictive value of immunohistochemically defined cell-of-origin classification in DLBCL patients. The GCB and non-GCB phenotypes were defined according to the Hans algorithm (CD10, BCL6 and MUM1/IRF4) among 90 immunochemotherapy- and 104 chemotherapy-treated DLBCL patients. In the chemotherapy group, we observed a significant difference in survival between GCB and non-GCB patients, with a good and a poor prognosis, respectively. However, in the rituximab group, no prognostic value of the GCB phenotype was observed. Likewise, among 29 high-risk de novo DLBCL patients receiving high-dose chemotherapy and autologous stem cell transplantation, the survival of non-GCB patients was improved, but no difference in outcome was seen between GCB and non-GCB subgroups. Since the results suggested that the Hans algorithm was not applicable in immunochemotherapy-treated DLBCL patients, we aimed to further focus on algorithms based on ABC markers. We examined the modified activated B-cell-like algorithm based (MUM1/IRF4 and FOXP1), as well as a previously reported Muris algorithm (BCL2, CD10 and MUM1/IRF4) among 88 DLBCL patients uniformly treated with immunochemotherapy. Both algorithms distinguished the unfavourable ABC-like subgroup with a significantly inferior failure-free survival relative to the GCB-like DLBCL patients. Similarly, the results of the individual predictive molecular markers transcription factor FOXP1 and anti-apoptotic protein BCL2 have been inconsistent and should be assessed in immunochemotherapy-treated DLBCL patients. The markers were evaluated in a cohort of 117 patients treated with rituximab and chemotherapy. FOXP1 expression could not distinguish between patients, with favourable and those with poor outcomes. In contrast, BCL2-negative DLBCL patients had significantly superior survival relative to BCL2-positive patients. Our results indicate that the immunohistochemically defined cell-of-origin classification in DLBCL has a prognostic impact in the immunochemotherapy era, when the identifying algorithms are based on ABC-associated markers. We also propose that BCL2 negativity is predictive of a favourable outcome. Further investigational efforts are, however, warranted to identify the molecular features of DLBCL that could enable individualized cancer therapy in routine patient care.

Role of thrombin in coronary artery bypass grafting

Thrombin is a multifunctional protease, which has a central role in the development and progression of coronary atherosclerotic lesions and it is a possible mediator of myocardial ischemia-reperfusion injury. Its generation and procoagulant activity are greatly upregulated during cardiopulmonary bypass (CPB). On the other hand, activated protein C, a physiologic anticoagulant that is activated by thrombomodulin-bound thrombin, has been beneficial in various models of ischemia-reperfusion. Therefore, our aim in this study was to test whether thrombin generation or protein C activation during coronary artery bypass grafting (CABG) associate with postoperative myocardial damage or hemodynamic changes. To further investigate the regulation of thrombin during CABG, we tested whether preoperative thrombophilic factors associate with increased CPB-related generation of thrombin or its procoagulant activity. We also measured the anticoagulant effects of heparin during CPB with a novel coagulation test, prothrombinase-induced clotting time (PiCT), and compared the performance of this test with the present standard of laboratory-based anticoagulation monitoring. One hundred patients undergoing elective on-pump CABG were studied prospectively. A progressive increase in markers of thrombin generation (F1+2), fibrinolysis (D-dimer), and fibrin formation (soluble fibrin monomer complexes) was observed during CPB, which was further distinctly propagated by reperfusion after myocardial ischemia, and continued to peak after the neutralization of heparin with protamine. Thrombin generation during reperfusion after CABG associated with postoperative myocardial damage and increased pulmonary vascular resistance. Activated protein C levels increased only slightly during CPB before the release of the aortic clamp, but reperfusion and more significantly heparin neutralization caused a massive increase in activated protein C levels. Protein C activation was clearly delayed in relation to both thrombin generation and fibrin formation. Even though activated protein C associated dynamically with postoperative hemodynamic performance, it did not associate with postoperative myocardial damage. Preoperative thrombophilic variables did not associate with perioperative thrombin generation or its procoagulant activity. Therefore, our results do not favor routine thrombophilia screening before CABG. There was poor agreement between PiCT and other measurements of heparin effects in the setting of CPB. However, lower heparin levels during CPB associated with inferior thrombin control and high heparin levels during CPB associated with fewer perioperative transfusions of blood products. Overall, our results suggest that hypercoagulation after CABG, especially during reperfusion, might be clinically important.

Randomised Evaluation of New Technologies within the Population‐Based Cervical Cancer Screening Programme in Finland: Cross‐Sectional Performance and Validity

A randomised and population-based screening design with new technologies has been applied to the organised cervical cancer screening programme in Finland. In this experiment the women invited to routine five-yearly screening are individually randomised to be screened with automation-assisted cytology, human papillomavirus (HPV) test or conventional cytology. By using the randomised design, the ultimate aim is to assess and compare the long-term outcomes of the different screening regimens. The primary aim of the current study was to evaluate, based on the material collected during the implementation phase of the Finnish randomised screening experiment, the cross-sectional performance and validity of automation-assisted cytology (Papnet system) and primary HPV DNA testing (Hybrid Capture II assay for 13 oncogenic HPV types) within service screening, in comparison to conventional cytology. The parameters of interest were test positivity rate, histological detection rate, relative sensitivity, relative specificity and positive predictive value. Also, the effect of variation in performance by screening laboratory on age-adjusted cervical cancer incidence was assessed. Based on the cross-sectional results, almost no differences were observed in the performance of conventional and automation-assisted screening. Instead, primary HPV screening found 58% (95% confidence interval 19-109%) more cervical lesions than conventional screening. However, this was mainly due to overrepresentation of mild- and moderate-grade lesions and, thus, is likely to result in overtreatment since a great deal of these lesions would never progress to invasive cancer. Primary screening with an HPV DNA test alone caused substantial loss in specificity in comparison to cytological screening. With the use of cytology triage test, the specificity of HPV screening improved close to the level of conventional cytology. The specificity of primary HPV screening was also increased by increasing the test positivity cutoff from the level recommended for clinical use, but the increase was more modest than the one gained with the use of cytology triage. The performance of the cervical cancer screening programme varied widely between the screening laboratories, but the variation in overall programme effectiveness between respective populations was more marginal from the very beginning of the organised screening activity. Thus, conclusive interpretations on the quality or success of screening should not be based on performance parameters only. In the evaluation of cervical cancer screening the outcome should be selected as closely as possible to the true measure of programme effectiveness, which is the number of invasive cervical cancers and subsequent deaths prevented in the target population. The evaluation of benefits and adverse effects of each new suggested screening technology should be performed before the technology becomes an accepted routine in the existing screening programme. At best, the evaluation is performed randomised, within the population and screening programme in question, which makes the results directly applicable to routine use.

The Use of Mesenchymal Stromal Cells in the Treatment of Diseases of the Cornea

As a key component of the ocular surface required for vision, the cornea has been extensively studied as a site for cell and tissue-based therapies. Historically, these treatments have consisted of donor corneal tissue transplants, but cultivated epithelial autografts have become established over the last 15 years as a routine treatment for ocular surface disease. Ultimately, these treatments are performed with the intention of restoring corneal transparency and a smooth ocular surface. The degree of success, however, is often dependent upon the inherent level of corneal inflammation at time of treatment. In this regard, the anti-inflammatory and immuno-modulatory properties of mesenchymal stromal cells (MSC) have drawn attention to these cells as potential therapeutic agents for corneal repair. The origins for MSC-based therapies are founded in part on observations of the recruitment of endogenous bone marrow-derived cells to injured corneas, however, an increasing quantity of data is emerging for MSC administered following their isolation and ex vivo expansion from a variety of tissues including bone marrow, adipose tissue, umbilical cord and dental pulp. In brief, evidence has emerged of cultured MSC, or their secreted products, having a positive impact on corneal wound healing and retention of corneal allografts in animal models. Optimal dosage, route of administration and timing of treatment, however, all remain active areas of investigation. Intriguingly, amidst these studies, have emerged reports of MSC transdifferentiation into corneal cells. Clearest evidence has been obtained with respect to expression of markers associated with the phenotype of corneal stromal cells. In contrast, the evidence for MSC conversion to corneal epithelial cell types remains inconclusive. In any case, the conversion of MSC into corneal cells seems unlikely to be an essential requirement for their clinical use. This field of research has recently become more complicated by reports of MSC-like properties for cultures established from the peripheral corneal stroma (limbal stroma). The relationship and relative value of corneal-MSC compared to traditional sources of MSC such as bone marrow are at present unclear. This chapter is divided into four main parts. After providing a concise overview of corneal structure and function, we will highlight the types of corneal diseases that are likely to benefit from the anti-inflammatory and immuno-modulatory properties of MSC. We will subsequently summarize the evidence supporting the case for MSC-based therapies in the treatment of corneal diseases. In the third section we will review the literature concerning the keratogenic potential of MSC. Finally, we will review the more recent literature indicating the presence of MSC-like cells derived from corneal tissue.

Clinical Studies on Epidural and Spinal Postoperative Analgesia : With Special Reference to Continuous Techniques of Administration and Adjuvant Drugs

Continuous epidural analgesia (CEA) and continuous spinal postoperative analgesia (CSPA) provided by a mixture of local anaesthetic and opioid are widely used for postoperative pain relief. E.g., with the introduction of so-called microcatheters, CSPA found its way particularly in orthopaedic surgery. These techniques, however, may be associated with dose-dependent side-effects as hypotension, weakness in the legs, and nausea and vomiting. At times, they may fail to offer sufficient analgesia, e.g., because of a misplaced catheter. The correct position of an epidural catheter might be confirmed by the supposedly easy and reliable epidural stimulation test (EST). The aims of this thesis were to determine a) whether the efficacy, tolerability, and reliability of CEA might be improved by adding the α2-adrenergic agonists adrenaline and clonidine to CEA, and by the repeated use of EST during CEA; and, b) the feasibility of CSPA given through a microcatheter after vascular surgery. Studies I IV were double-blinded, randomized, and controlled trials; Study V was of a diagnostic, prospective nature. Patients underwent arterial bypass surgery of the legs (I, n=50; IV, n=46), total knee arthroplasty (II, n=70; III, n=72), and abdominal surgery or thoracotomy (V, n=30). Postoperative lumbar CEA consisted of regular mixtures of ropivacaine and fentanyl either without or with adrenaline (2 µg/ml (I) and 4 µg/ml (II)) and clonidine (2 µg/ml (III)). CSPA (IV) was given through a microcatheter (28G) and contained either ropivacaine (max. 2 mg/h) or a mixture of ropivacaine (max. 1 mg/h) and morphine (max. 8 µg/h). Epidural catheter tip position (V) was evaluated both by EST at the moment of catheter placement and several times during CEA, and by epidurography as reference diagnostic test. CEA and CSPA were administered for 24 or 48 h. Study parameters included pain scores assessed with a visual analogue scale, requirements of rescue pain medication, vital signs, and side-effects. Adrenaline (I and II) had no beneficial influence as regards the efficacy or tolerability of CEA. The total amounts of epidurally-infused drugs were even increased in the adrenaline group in Study II (p=0.02, RM ANOVA). Clonidine (III) augmented pain relief with lowered amounts of epidurally infused drugs (p=0.01, RM ANOVA) and reduced need for rescue oxycodone given i.m. (p=0.027, MW-U; median difference 3 mg (95% CI 0 7 mg)). Clonidine did not contribute to sedation and its influence on haemodynamics was minimal. CSPA (IV) provided satisfactory pain relief with only limited blockade of the legs (no inter-group differences). EST (V) was often related to technical problems and difficulties of interpretation, e.g., it failed to identify the four patients whose catheters were outside the spinal canal already at the time of catheter placement. As adjuvants to lumbar CEA, clonidine only slightly improved pain relief, while adrenaline did not provide any benefit. The role of EST applied at the time of epidural catheter placement or repeatedly during CEA remains open. The microcatheter CSPA technique appeared effective and reliable, but needs to be compared to routine CEA after peripheral arterial bypass surgery.

Reasoning about discontinuance of information system use

While many studies have explored conditions and consequences of information systems adoption and use, few have focused on the final stages of the information system lifecycle. In this paper, I develop a theoretical and an initial empirical contribution to understanding individuals’ intentions to discontinue the use of an information system. This understanding is important because it yields implications about maintenance, retirement, and users’ switching decisions, which ultimately can affect work performance, system effectiveness, and return on technology investments. In this paper, I offer a new conceptualization of factors determining users’ intentions to discontinue the use of information systems. I then report on a preliminary empirical test of the model using data from a field study of information system users in a promotional planning routine in a large retail organization. Results from the empirical analysis provide first empirical support for the theoretical model. I discuss the work’s implications for theory on information systems continuance and dual-factor logic in information system use. I also provide suggestions for managers dealing with cessation of information systems and broader work routine change in organizations due to information system end-of-life decisions.

Sentinel lymph node biopsy as a diagnostic tool in the treatment of breast cancer

The purpose of this study was to evaluate the use of sentinel node biopsy (SNB) in the axillary nodal staging in breast cancer. A special interest was in sentinel node (SN) visualization, intraoperative detection of SN metastases, the feasibility of SNB in patients with pure tubular carcinoma (PTC) and in those with ductal carcinoma in situ (DCIS) in core needle biopsy (CNB) and additionally in the detection of axillary recurrences after tumour negative SNB. Patients and methods. 1580 clinically stage T1-T2 node-negative breast cancer patients, who underwent lymphoscintigraphy (LS), SNB and breast surgery between June 2000 - 2004 at the Breast Surgery Unit. The CNB samples were obtained from women, who participated the biennial, population based mammography screening at the Mammography Screening Centre of Helsinki 2001 - 2004.In the follow- up, a cohort of 205 patients who avoided AC due to negative SNB findings were evaluated using ultrasonography one and three years after breast surgery. Results. The visualization rate of axillary SNs was not enhanced by adjusting radioisotope doses according to BMI. The sensitivity of the intraoperative diagnosis of SN metastases of invasive lobular carcinoma (ILC) was higher, 87%, with rapid, intraoperative immunohistochemistry (IHC) group compared to 66% without it. The prevalence of tumour positive SN findings was 27% in the 33 patients with breast tumours diagnosed as PTC. The median histological tumour size was similar in patients with or without axillary metastases. After the histopathological review, six out of 27 patients with true PTC had axillary metastases, with no significant change in the risk factors for axillary metastases. Of the 67 patients with DCIS in the preoperative percutaneous biopsy specimen , 30% had invasion in the surgical specimen. The strongest predictive factor for invasion was the visibility of the lesion in ultrasound. In the three year follow-up, axillary recurrence was found in only two (0.5%) of the total of 383 ultrasound examinations performed during the study, and only one of the 369 examinations revealed cancer. None of the ultrasound examinations were false positive, and no study participant was subjected to unnecessary surgery due to ultrasound monitoring. Conclusions. Adjusting the dose of the radioactive tracer according to patient BMI does not increase the visualization rate of SNs. The intraoperative diagnosis of SN metastases is enhanced by rapid IHC particularly in patients with ILC. SNB seems to be a feasible method for axillary staging of pure tubular carcinoma in patients with a low prevalence of axillary metatastases. SNB also appears to be a sensible method in patients undergoing mastectomy due to DCIS in CNB. It also seems useful in patients with lesions visible in breast US. During follow-up, routine monitoring of the ipsilateral axilla using US is not worthwhile among breast cancer patients who avoided AC due to negative SN findings.

Preterm delivery and selected biomarkers : phosphorylated insulin-like growth factor-binding protein-1 and matrix metalloproteinase-8 – in cervical fluid

Premature delivery is a major cause of neonatal morbidity and mortality. The incidence of premature deliveries has increased around the world. In Finland 5.3%, or about 3,000 children per year are born prematurely, before 37 weeks of gestation. The corresponding figure in the United States is about 13%. The morbidity and mortality are highest among infants delivered before 32 weeks of gestation - about 600 children each year in Finland. Approximately 70% of premature deliveries are unexplained. Preterm delivery can be caused by an asympto-matic infection between uterus and the fetal membranes, such can begin already in early pregnancy. It is difficult to predict preterm delivery, and many patients are therefore unnecessarily admitted to hospital for observation and exposed to medical treatments. On the other hand, the high risk women should be identified early for the best treatment of the mother and preterm infant. --- In the prospective study conducted at the Department of Obstetric and Gynecology, Helsinki University Central Hospital two biochemical inflammation related markers were measured in the lower genital tract fluids of asymp-tomatic women in early and mid pregnancy in an order to see whether these markers could identify women with an increased risk of preterm delivery. These biomarkers were phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and matrix metalloproteinase-8 (MMP-8). The study involved 5180 asymptomatic pregnant women, examined during the first and second ultrasound screening visits. The study samples were taken from the vagina and cervicix. In addition, 246 symptomatic women were studied (pregnancy weeks 22 – 34). The study showed that increased phIGFBP-1 concentration in cervical canal fluid in early pregnancy increased the risk for preterm delivery. The risk for very premature birth (before 32 weeks of gestation) was nearly four-fold. Low MMP-8 concentration in mid pregnancy increased the risk of subsequent premature preterm rupture of fetal membranes (PPROM). Significantly high MMP-8 concentrations in the cervical fluid increased the risk for prema-ture delivery initiated by preterm labour with intact membranes. Among women with preterm contractions the shortened cervical length measured by ultrasound and elevated cervical fluid phIGFBP-1 both predicted premature delivery. In summary, because of the relatively low sensitivity of cervical fluid phIGFBP-1 this biomarker is not suitable for routine screening, but provides an additional tool in assessing the risk of preterm delivery. Cervical fluid MMP-8 is not useful in early or mid pregnancy in predicting premature delivery because of its dual role. Further studies on the role of MMP-8 are therefore needed. Our study confirms that phIGFBP-1 testing is useful in predicting pre-term delivery.

Cyclins in Breast Cancer

Breast cancer is the most common malignancy in women in Western countries. It is a heterogeneous disease with varying biological characteristics and aggressiveness. Family history is one of the strongest predisposing factors for breast cancer. The known susceptibility genes explain only around 25% of all familial breast cancers. At least part of the unknown familial aggregation may be caused by several low-penetrance variants that occur commonly in the general population. Cyclins are cell cycle-regulating proteins. Cyclin expression oscillates during the cell cycle and is under strict control. In cancer cells, cyclin expression often becomes deregulated, leading to uncontrolled cell division and proliferation, one of the hallmarks of cancer. In this study, we investigated the role of cyclins in breast cancer predisposition, pathogenesis, and tumor behavior. Cyclin A immunohistochemistry was evaluated both on traditional large sections and on tissue microarrays (TMA). The concordance of the results was good, indicating that TMA is a reliable method for studying cyclin expression in breast cancer. The expression of cyclins D1, E, and B1 was studied among 1348 invasive breast cancers on TMA. Familial BRCA1/2-mutation negative tumors had significantly more often low cyclin E and high cyclin D1 expression than BRCA1/2 related or sporadic tumors. Unique cyclin E and D1 expression patterns among familial non-BRCA1/2 breast cancers may reflect different predisposition and pathogenesis in these groups and help to differentiate mutation-positive from mutation-negative familial cancers. High cyclin E expression was associated with an aggressive breast cancer phenotype and was an independent marker of poor metastasis-free survival. High cyclin D1 was associated with high grade and high proliferation among estrogen receptor (ER)-positive but with low grade and low proliferation among ER-negative breast cancers. Among ER-positive cancers not treated with chemotherapy, high cyclin D1 showed a trend towards shorter metastasis-free survival. These results suggest that different mechanisms may drive proliferation in ER-negative and -positive breast cancers and that cyclin D1 has a particularly important role in tumorigenesis of hormone receptor-positive breast cancer. High cyclin B1 expression was associated with aggressive breast cancer features and had an independent impact on survival. The results suggest that cyclin B1 immunohistochemistry is a method that could easily be adapted for routine use and is an independent prognostic factor, adding specificity to prognostic evaluation conducted with traditional markers. A commonly occurring cyclin D1 gene polymorphism A870G was associated with increased breast cancer risk in a large material of Finnish and Canadian breast cancer patients. The interaction of the high-activity alleles of cyclin D1 gene and estrogen metabolism gene COMT conferred an even higher risk. These results show that cyclin D1 and COMT act synergistically to contribute to breast cancer progression and that individual risk for breast cancer can be altered by the combined effect of polymorphisms with low-penetrance alleles. By investigating critical cell cycle regulator protein cyclins, we revealed new aspects of breast cancer predisposition, pathogenesis, and clinical course.

Individualized immunosuppression after renal transplantation in childhood

Pediatric renal transplantation (TX) has evolved greatly during the past few decades, and today TX is considered the standard care for children with end-stage renal disease. In Finland, 191 children had received renal transplants by October 2007, and 42% of them have already reached adulthood. Improvements in treatment of end-stage renal disease, surgical techniques, intensive care medicine, and in immunosuppressive therapy have paved the way to the current highly successful outcomes of pediatric transplantation. In children, the transplanted graft should last for decades, and normal growth and development should be guaranteed. These objectives set considerable requirements in optimizing and fine-tuning the post-operative therapy. Careful optimization of immunosuppressive therapy is crucial in protecting the graft against rejection, but also in protecting the patient against adverse effects of the medication. In the present study, the results of a retrospective investigation into individualized dosing of immunosuppresive medication, based on pharmacokinetic profiles, therapeutic drug monitoring, graft function and histology studies, and glucocorticoid biological activity determinations, are reported. Subgroups of a total of 178 patients, who received renal transplants in 1988 2006 were included in the study. The mean age at TX was 6.5 years, and approximately 26% of the patients were <2 years of age. The most common diagnosis leading to renal TX was congenital nephrosis of the Finnish type (NPHS1). Pediatric patients in Finland receive standard triple immunosuppression consisting of cyclosporine A (CsA), methylprednisolone (MP) and azathioprine (AZA) after renal TX. Optimal dosing of these agents is important to prevent rejections and preserve graft function in one hand, and to avoid the potentially serious adverse effects on the other hand. CsA has a narrow therapeutic window and individually variable pharmacokinetics. Therapeutic monitoring of CsA is, therefore, mandatory. Traditionally, CsA monitoring has been based on pre-dose trough levels (C0), but recent pharmacokinetic and clinical studies have revealed that the immunosuppressive effect may be related to diurnal CsA exposure and blood CsA concentration 0-4 hours after dosing. The two-hour post-dose concentration (C2) has proved a reliable surrogate marker of CsA exposure. Individual starting doses of CsA were analyzed in 65 patients. A recommended dose based on a pre-TX pharmacokinetic study was calculated for each patient by the pre-TX protocol. The predicted dose was clearly higher in the youngest children than in the older ones (22.9±10.4 and 10.5±5.1 mg/kg/d in patients <2 and >8 years of age, respectively). The actually administered oral doses of CsA were collected for three weeks after TX and compared to the pharmacokinetically predicted dose. After the TX, dosing of CsA was adjusted according to clinical parameters and blood CsA trough concentration. The pharmacokinetically predicted dose and patient age were the two significant parameters explaining post-TX doses of CsA. Accordingly, young children received significantly higher oral doses of CsA than the older ones. The correlation to the actually administered doses after TX was best in those patients, who had a predicted dose clearly higher or lower (> ±25%) than the average in their age-group. Due to the great individual variation in pharmacokinetics standardized dosing of CsA (based on body mass or surface area) may not be adequate. Pre-Tx profiles are helpful in determining suitable initial CsA doses. CsA monitoring based on trough and C2 concentrations was analyzed in 47 patients, who received renal transplants in 2001 2006. C0, C2 and experienced acute rejections were collected during the post-TX hospitalization, and also three months after TX when the first protocol core biopsy was obtained. The patients who remained rejection free had slightly higher C2 concentrations, especially very early after TX. However, after the first two weeks also the trough level was higher in the rejection-free patients than in those with acute rejections. Three months after TX the trough level was higher in patients with normal histology than in those with rejection changes in the routine biopsy. Monitoring of both the trough level and C2 may thus be warranted to guarantee sufficient peak concentration and baseline immunosuppression on one hand and to avoid over-exposure on the other hand. Controlling of rejection in the early months after transplantation is crucial as it may contribute to the development of long-term allograft nephropathy. Recently, it has become evident that immunoactivation fulfilling the histological criteria of acute rejection is possible in a well functioning graft with no clinical sings or laboratory perturbations. The influence of treatment of subclinical rejection, diagnosed in 3-month protocol biopsy, to graft function and histology 18 months after TX was analyzed in 22 patients and compared to 35 historical control patients. The incidence of subclinical rejection at three months was 43%, and the patients received a standard rejection treatment (a course of increased MP) and/or increased baseline immunosuppression, depending on the severity of rejection and graft function. Glomerular filtration rate (GFR) at 18 months was significantly better in the patients who were screened and treated for subclinical rejection in comparison to the historical patients (86.7±22.5 vs. 67.9±31.9 ml/min/1.73m2, respectively). The improvement was most remarkable in the youngest (<2 years) age group (94.1±11.0 vs. 67.9±26.8 ml/min/1.73m2). Histological findings of chronic allograft nephropathy were also more common in the historical patients in the 18-month protocol biopsy. All pediatric renal TX patients receive MP as a part of the baseline immunosuppression. Although the maintenance dose of MP is very low in the majority of the patients, the well-known steroid-related adverse affects are not uncommon. It has been shown in a previous study in Finnish pediatric TX patients that steroid exposure, measured as area under concentration-time curve (AUC), rather than the dose correlates with the adverse effects. In the present study, MP AUC was measured in sixteen stable maintenance patients, and a correlation with excess weight gain during 12 months after TX as well as with height deficit was found. A novel bioassay measuring the activation of glucocorticoid receptor dependent transcription cascade was also employed to assess the biological effect of MP. Glucocorticoid bioactivity was found to be related to the adverse effects, although the relationship was not as apparent as that with serum MP concentration. The findings in this study support individualized monitoring and adjustment of immunosuppression based on pharmacokinetics, graft function and histology. Pharmacokinetic profiles are helpful in estimating drug exposure and thus identifying the patients who might be at risk for excessive or insufficient immunosuppression. Individualized doses and monitoring of blood concentrations should definitely be employed with CsA, but possibly also with steroids. As an alternative to complete steroid withdrawal, individualized dosing based on drug exposure monitoring might help in avoiding the adverse effects. Early screening and treatment of subclinical immunoactivation is beneficial as it improves the prospects of good long-term graft function.

Fractional damping: Stochastic origin and finite approximations

Fractional-order derivatives appear in various engineering applications including models for viscoelastic damping. Damping behavior of materials, if modeled using linear, constant coefficient differential equations, cannot include the long memory that fractional-order derivatives require. However, sufficiently great rnicrostructural disorder can lead, statistically, to macroscopic behavior well approximated by fractional order derivatives. The idea has appeared in the physics literature, but may interest an engineering audience. This idea in turn leads to an infinite-dimensional system without memory; a routine Galerkin projection on that infinite-dimensional system leads to a finite dimensional system of ordinary differential equations (ODEs) (integer order) that matches the fractional-order behavior over user-specifiable, but finite, frequency ranges. For extreme frequencies (small or large), the approximation is poor. This is unavoidable, and users interested in such extremes or in the fundamental aspects of true fractional derivatives must take note of it. However, mismatch in extreme frequencies outside the range of interest for a particular model of a real material may have little engineering impact.

The development and preliminary evaluation of an education intervention to prevent driveway run-over incidents

Objective While driveway run-over incidents continue to be a cause of serious injury and deaths among young children in Australia, few empirically evaluated educational interventions have been developed which address these incidents. Addressing this gap, this study describes the development and evaluation of a paper-based driveway safety intervention targeting caregivers of children aged 5 years or younger. Design Cross-sectional survey. Method and setting Informed by previous research, the intervention targeted key caregiver safety behaviours that address driveway risks. To assess the impact of the intervention, 137 Queensland (Australia) caregivers (95.0% women; mean age = 34.97 years) were recruited. After receiving the intervention, changes to a number of outcomes such as caregiver risk perception, safety knowledge and behavioural intentions were measured. Results Findings indicated that the intervention had increased general and specific situational risk awareness and safety knowledge among a substantial proportion of participants. Close to one-quarter of the sample strongly agreed that the intervention had increased these outcomes. In addition, 71.6% of the sample reported that they intended to make changes to their routine in and around the driveway, as a result of reading the intervention material and a further, quarter of the participants strongly agreed that the information provided would be a help both to themselves (26.5%) and other caregivers (33.8%) to keep their children safe in the driveway. Conclusion: While the educational intervention requires further validation, findings from this study suggest that intervention content and format increases driveway safety.