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Se presenta una revisión del artículo "Post-Hip Fracture Use in Prescribed Calcium Plus Vitamin D or Vitamin D Supplements and Anti-Osteoporotic Drugs Are Associated with Lower Mortality. A Nationwide Study in Finland" de varios autores, incluyendo I. Nurmi-Lüthje, R. Sund y M. Juntunen y publicado en la revista "Journal of Bone and Mineral Research" en 2011.

Background: Arthroscopic scaphotrapeziotrapezoid (STT) fusion (ASTTF) has emerged in the recent decade as an option for traditional open surgery. This retrospective study describes our technique and results of ASTTF. Methods: Medical records and radiological data of patient who had undergone ASTTF between 2014 and 2022 in two tertiary hospitals were reviewed. Results: Five ASTTF in four patients were identified. The mean age of the patients were 52.4 years. Fusion was achieved in four out of five wrists (80%). The mean postoperative radio-scaphoid angle was 48°, grip 32 kg (70% compared to contralateral hand), extension 54° (86%) and flexion 46° (93%). The mean follow-up time was 18 months (range 5 months to 4 years). One wrist (20%) developed STT non-union requiring a reoperation 2 years after index surgery. Conclusions: ASTTF is a technically challenging procedure with a long learning curve and surgery time. However, ASTTF is less invasive compared to the open procedure and our results were like the open procedures described in literature. Further studies are needed to compare the benefits and results of open and ASTTF in a prospective and randomised setup. Level of Evidence: Level IV (Therapeutic).

Competing Interests: Disclosures None.

For adipose stromal/stem cell (ASCs)-based immunomodulatory therapies, it is important to study how donor characteristics, such as obesity and type 2 diabetes (T2D), influence ASCs efficacy. Here, ASCs were obtained from 2 groups, donors with T2D and obesity (dASCs) or nondiabetic donors with normal-weight (ndASCs), and then cultured with anti-CD3/CD28-stimulated allogeneic CD4 T cells. ASCs were studied for the expression of the immunomodulators CD54, CD274, and indoleamine 2, 3 dioxygenase 1 (IDO) in inflammatory conditions. CD4 T cells cultured alone or in cocultures were assessed to evaluate proliferation, activation marker surface expression, apoptosis, the regulatory T cells (Tregs; CD4+ CD25high FOXP3+) frequency, and intracellular cytokine expression using flow cytometry. Modulation of T-cell subset cytokines was explored via ELISA. In inflammatory conditions, the expression of CD54, CD274, and IDO was significantly upregulated in ASCs, with no significant differences between ndASCs and dASCs. dASCs retained the potential to significantly suppress CD4 T-cell proliferation, with a slightly weaker inhibitory effect than ndASCs, which was associated with significantly reduced abilities to decrease IL-2 production and increase IL-8 levels in cocultures. Such attenuated potentials were significantly correlated with increasing body mass index. dASCs and ndASCs comparably reduced CD4 T-cell viability, HLA-DR expression, and interferon-gamma production and conversely increased CD69 expression, the Tregs percentage, and IL-17A production. Considerable amounts of the immunomodulators prostaglandin E2 (PGE2) and IL-6 were detected in the conditioned medium of cocultures. These findings suggest that ASCs obtained from donors with T2D and obesity are receptive to the inflammatory environment and able to modulate CD4 T cells accordingly., (© The Author(s) 2023. Published by Oxford University Press.)

The objective of this study was to evaluate whether static or 50 Hz magnetic fields (MFs) modify responses to the chemotherapeutic agent doxorubicin in human MCF-7 breast cancer cells. To this end, cells were exposed to static or 50 Hz MFs at 100 µT with or without doxorubicin for 3 h. Following the exposures, cytosolic and mitochondrial superoxide levels, DNA damage levels, and the clonogenic survival of the cells were evaluated. It was found that static MFs decreased the DNA damage level induced by doxorubicin treatment (p = 0.023), but no effects were observed for either cytosolic and mitochondrial superoxide levels or the clonogenic survival of the cells. On the other hand, 50 Hz MF increased doxorubicin-induced cytosolic superoxide levels (p = 0.016), while the mitochondrial superoxide level, DNA damage level, and clonogenic survival were unaffected. In conclusion, we found that static and 50 Hz MFs may modify responses to doxorubicin treatment, but the subsequent survival of the doxorubicin-treated cancer cells was unaffected by both types of MFs. Therefore, the present results suggest that static or 50 Hz MFs for 3 h do not modify the efficacy of doxorubicin in MCF-7 cancer cells., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Adipose stromal/stem cells (ASCs) are promising candidates for future clinical applications. ASCs have regenerative capacity, low immunogenicity, and immunomodulatory ability. The success of future cell-based therapies depends on the appropriate selection of donors. Several factors, including age, sex, and body mass index (BMI), may influence ASC characteristics. Our aim was to investigate the effect of acquired weight on ASC characteristics under the same genetic background using ASCs derived from monozygotic (MZ) twin pairs., Methods: ASCs were isolated from subcutaneous adipose tissue from five weight-discordant (WD, within-pair difference in BMI > 3 kg/m 2 ) MZ twin pairs, with measured BMI and metabolic status. The ASC immunophenotype, proliferation and osteogenic and adipogenic differentiation capacity were studied. ASC immunogenicity, immunosuppression capacity and the expression of inflammation markers were investigated. ASC angiogenic potential was assessed in cocultures with endothelial cells., Results: ASCs showed low immunogenicity, proliferation, and osteogenic differentiation capacity independent of weight among all donors. ASCs showed a mesenchymal stem cell-like immunophenotype; however, the expression of CD146 was significantly higher in leaner WD twins than in heavier cotwins. ASCs from heavier twins from WD pairs showed significantly greater adipogenic differentiation capacity and higher expression of TNF and lower angiogenic potential compared with their leaner cotwins. ASCs showed immunosuppressive capacity in direct cocultures; however, heavier WD twins showed stronger immunosuppressive capacity than leaner cotwins., Conclusions: Our genetically matched data suggest that a higher weight of the donor may have some effect on ASC characteristics, especially on angiogenic and adipogenic potential, which should be considered when ASCs are used clinically., (© 2021. The Author(s).)

Microglia are involved in the post-stroke immunomodulation of brain plasticity, repair, and reorganization. Here, we evaluated whether adipose-tissue-derived mesenchymal stem cells (ADMSCs) and/or rehabilitation improve behavioral recovery by modulating long-term perilesional inflammation and creating a recovery-permissive environment in a rat model of ischemic stroke., Methods: A two-way mixed lymphocyte reaction was used to assess the immunomodulatory capacity of ADMSCs in vitro. Two or 7 days after permanent middle cerebral artery occlusion (pMCAO), rats were intravenously administered ADMSCs or vehicle and housed in a standard or enriched environment (EE). Behavioral performance was assessed with a cylinder test, then we performed stereological and ImageJ/Fiji quantifications of ionized calcium-binding adaptor molecule 1 (Iba1) cells and blood-brain barrier (BBB) leakage., Results: Human ADMSCs were immunosuppressive in vitro. The cylinder test showed partial spontaneous behavioral recovery of pMCAO rats, which was further improved by combined ADMSCs and housing in EE on days 21 and 42 ( p < 0.05). We detected an ischemia-induced increase in numbers, staining intensity, and branch length of Iba1+ microglia/macrophages as well as BBB leakage in the perilesional cortex. However, these were not different among pMCAO groups., Conclusion: Combined cell therapy and rehabilitation additively improved behavioral outcome despite long-term perilesional microglia presence in stroke rats.

Stroke is a devastating neurological disorder and one of the leading causes of mortality and disability. To understand the cellular and molecular mechanisms of stroke and to develop novel therapeutic approaches, two different in vitro human cell-based stroke models were established using oxygen-glucose deprivation (OGD) conditions. In addition, the effect of adipose stem cells (ASCs) on OGD-induced injury was studied. In the present study, SH-SY5Y human neuroblastoma cells and human induced pluripotent stem cells (hiPSCs) were differentiated into neurons, cultured under OGD conditions (1% O 2 ) for 24 h, and subjected to a reperfusion period for 24 or 72 h. After OGD, ASCs were cocultured with neurons on inserts for 24 or 72 h to study the neuroprotective potential of ASCs. The effect of OGD and ASC coculture on the viability, apoptosis, and proliferation of and axonal damage to neuronal cells was studied. The results showed that OGD conditions induced cytotoxicity and apoptosis of SH-SY5Y- and hiPSC-derived neurons, although more severe damage was detected in SH-SY5Y-derived neurons than in hiPSC-derived neurons. Coculture with ASCs was protective for neurons, as the number of dead ASC-cocultured neurons was lower than that of control cells, and coculture increased the proliferation of both cell types. To conclude, we developed in vitro human cell-based stroke models in SH-SY5Y- and hiPSC-derived neurons. This was the first time hiPSCs were used to model stroke in vitro . Since OGD had different effects on the studied cell types, this study highlights the importance of using several cell types in in vitro studies to confirm the outcomes of the study. Here, ASCs exerted a neuroprotective effect by increasing the proliferation and decreasing the death of SH-SY5Y- and hiPSC-derived neurons after OGD., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Miia Juntunen et al.)

Background/Objective: Stroke is a leading global cause of adult disability. As the population ages as well as suffers co-morbidities, it is expected that the stroke burden will increase further. There are no established safe and effective restorative treatments to facilitate a good functional outcome in stroke patients. Cell-based therapies, which have a wide therapeutic window, might benefit a large percentage of patients, especially if combined with different restorative strategies. In this study, we tested whether the therapeutic effect of human adipose tissue-derived mesenchymal stem cells (ADMSCs) could be further enhanced by rehabilitation in an experimental model of stroke. Methods: Focal cerebral ischemia was induced in adult male Sprague Dawley rats by permanently occluding the distal middle cerebral artery (MCAO). After the intravenous infusion of vehicle ( n = 46) or ADMSCs (2 × 10 6 ) either at 2 ( n = 37) or 7 ( n = 7) days after the operation, half of the animals were housed in an enriched environment mimicking rehabilitation. Subsequently, their behavioral recovery was assessed by a neurological score, and performance in the cylinder and sticky label tests during a 42-day behavioral follow-up. At the end of the follow-up, rats were perfused for histology to assess the extent of angiogenesis (RECA-1), gliosis (GFAP), and glial scar formation. Results: No adverse effects were observed during the follow-up. Combined ADMSC therapy and rehabilitation improved forelimb use in the cylinder test in comparison to MCAO controls on post-operative days 21 and 42 ( P < 0.01). In the sticky label test, ADMSCs and rehabilitation alone or together, significantly decreased the removal time as compared to MCAO controls on post-operative days 21 and 42. An early initiation of combined therapy seemed to be more effective. Infarct size, measured by MRI on post-operative days 1 and 43, did not differ between the experimental groups. Stereological counting revealed an ischemia-induced increase both in the density of blood vessels and the numbers of glial cells in the perilesional cortex, but there were no differences among MCAO groups. Glial scar volume was also similar in MCAO groups. Conclusion: Early delivery of ADMSCs and combined rehabilitation enhanced behavioral recovery in an experimental stroke model. The mechanisms underlying these treatment effects remain unknown.

Adipose tissue is an attractive stem cell source for soft and bone tissue engineering applications and stem cell therapies. The adipose-derived stromal/stem cells (ASCs) have a multilineage differentiation capacity that is regulated through extracellular signals. The cellular events related to cell adhesion and cytoskeleton have been suggested as central regulators of differentiation fate decision. However, the detailed knowledge of these molecular mechanisms in human ASCs remains limited. This study examined the significance of focal adhesion kinase (FAK), Rho-Rho-associated protein kinase (Rho-ROCK), and their downstream target extracellular signal-regulated kinase 1/2 (ERK1/2) on hASCs differentiation towards osteoblasts and adipocytes. Analyses of osteogenic markers RUNX2A , alkaline phosphatase, and matrix mineralization revealed an essential role of active FAK, ROCK, and ERK1/2 signaling for the osteogenesis of hASCs. Inhibition of these kinases with specific small molecule inhibitors diminished osteogenesis, while inhibition of FAK and ROCK activity led to elevation of adipogenic marker genes AP2 and LEP and lipid accumulation implicating adipogenesis. This denotes to a switch-like function of FAK and ROCK signaling in the osteogenic and adipogenic fates of hASCs. On the contrary, inhibition of ERK1/2 kinase activity deceased adipogenic differentiation, indicating that activation of ERK signaling is required for both adipogenic and osteogenic potential. Our findings highlight the reciprocal role of cell adhesion mechanisms and actin dynamics in regulation of hASC lineage commitment. This study enhances the knowledge of molecular mechanisms dictating hASC differentiation and thus opens possibilities for more efficient control of hASC differentiation.

Despite the good performance of silicate bioactive glasses in bone regeneration, there is considerable potential to enhance their properties by chemical modifications. In this study, S53P4-based borosilicate glasses were synthesized and their dissolution profile was studied in simulated body fluid by assessing pH change, ion release and conversion to hydroxyapatite. The viability, proliferation, attachment, osteogenesis and endothelial marker expression of human adipose stem cells (hASCs) was evaluated upon direct culture on glass discs and in the extract medium. This is the first study evaluating cell behavior in response to borosilicate glasses based on S53P4 (commercially available as BonAlive®). Replacing silicate with borate in S53P4 increased the glass reactivity. Despite the good viability of hASCs under all conditions, direct culture of cells on borosilicate discs and in undiluted extract medium reduced cell proliferation. This was accompanied with changes in cell morphology. Regarding osteogenic commitment, alkaline phosphatase activity was significantly reduced by the borosilicate glass discs and extracts, whereas the expression of osteogenic markers RUNX2a, OSTERIX, DLX5 and OSTEOPONTIN was upregulated. There was also a borosilicate glass-induced increase in osteocalcin protein production. Moreover, osteogenic supplements containing borosilicate extracts significantly increased the mineral production in comparison to the osteogenic medium control. Interestingly, borosilicate glasses stimulated the expression of endothelial markers vWF and PECAM-1. To conclude, our results reveal that despite reducing hASC proliferation, S53P4-based borosilicate glasses and their dissolution products stimulate osteogenic commitment and upregulate endothelial markers, thus supporting their further evaluation for regenerative medicine., Competing Interests: The authors have declared that no competing interests exist.

The surgical reconstruction of functional neovagina is challenging and susceptible to complications. Therefore, developing tissue engineering-based treatment methods for vaginal defects is important. Our aim was to develop and test a novel supercritical carbon dioxide foamed poly-l-lactide-co-ɛ-caprolactone (scPLCL) scaffold for vaginal reconstruction. The scaffolds were manufactured and characterized for porosity (65 ± 4%), pore size (350 ± 150 µm) and elastic modulus (2.8 ± 0.4 MPa). Vaginal epithelial (EC) and stromal cells (SC) were isolated, expanded and characterized with flow cytometry. Finally, cells were cultured with scPLCL scaffolds in separate and/or co-cultures. Their attachment, viability, proliferation and phenotype were analysed. Both cell types strongly expressed cell surface markers CD44, CD73 and CD166. Strong expression of CD326 was detected with ECs and CD90 and CD105 with SCs. Both ECs and SCs attached and maintained viability on scPLCL. Further, scPLCL supported the proliferation of especially ECs, which also maintained epithelial phenotype (cytokeratin expression) during 14-day assessment period. Interestingly, ECs expressed uroplakin (UP) Ia, UPIb and UPIII markers; further, UPIa and UPIII expression was significantly higher on ECs cultured on scPLCL than on cell culture plastic. In conclusion, the scPLCL is potential scaffold for vaginal tissue engineering and the results of this study further illustrate the excellent biocompatibility of PLCL., Competing Interests: We declare we have no competing interests.

Anal incontinence is a devastating condition that significantly reduces the quality of life. Our aim was to evaluate the effect of human adipose stem cell (hASC) injections in a rat model for anal sphincter injury, which is the main cause of anal incontinence in humans. Furthermore, we tested if the efficacy of hASCs could be improved by combining them with polyacrylamide hydrogel carrier, Bulkamid. Human ASCs derived from a female donor were culture expanded in DMEM/F12 supplemented with human platelet lysate. Female virgin Sprague-Dawley rats were randomized into four groups (n = 14-15/group): hASCs in saline or Bulkamid (3 × 10 5 /60 μl) and saline or Bulkamid without cells. Anorectal manometry (ARM) was performed before anal sphincter injury, at two (n = 58) and at four weeks after (n = 33). Additionally, the anal sphincter tissue was examined by micro-computed tomography (μCT) and the histological parameters were compared between the groups. The median resting and peak pressure during spontaneous contraction measured by ARM were significantly higher in hASC treatment groups compared with the control groups without hASCs. There was no statistical difference in functional results between the hASC-carrier groups (saline vs. Bulkamid). No difference was detected in the sphincter muscle continuation between the groups in the histology and μCT analysis. More inflammation was discovered in the group receiving saline with hASC. The hASC injection therapy with both saline and Bulkamid is a promising nonsurgical treatment for acute anal sphincter injury. Traditional histology combined with the 3D μCT image data lends greater confidence in assessing muscle healing and continuity. Stem Cells Translational Medicine 2018;7:295-304., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Unlabelled: Bone morphogenetic protein-2 (BMP-2) is a growth factor used to stimulate bone regeneration in clinical applications. However, there are contradicting reports on the functionality of BMP-2 in human adipose stem cells (hASCs), which are frequently used in tissue engineering. In this study, we analyzed the effects of BMP-2 on SMAD1/5 signaling, proliferation, and differentiation in hASCs. Our results indicated that BMP-2 induced dose-dependent (25-100 ng/ml) activation of SMAD signaling. Furthermore, the cell proliferation analysis revealed that BMP-2 (100 ng/ml) consistently decreased the proliferation in all the cell lines studied. However, the analysis of the differentiation potential revealed that BMP-2 (100 ng/ml) exhibited a donor-dependent dual role, inducing both osteogenic and adipogenic differentiation in hASCs. The quantitative alkaline phosphatase (qALP) activity and mineralization levels were clearly enhanced in particular donor cell lines by BMP-2 stimulus. On the contrary, in other cell lines, qALP and mineralization levels were diminished and the lipid formation was enhanced. The current study also suggests that hASCs have accelerated biochemical responsiveness to BMP-2 stimulus in human serum-supplemented culture medium compared with fetal bovine serum. The production origin of the BMP-2 growth factor is also important for its response: BMP-2 produced in mammalian cells enhanced signaling and differentiation responses compared with BMP-2 produced in Escherichia coli. These results explain the existing contradiction in the reported BMP-2 studies and indicate the variability in the functional end mechanism of BMP-2-stimulated hASCs., Significance: This study examined how bone morphogenetic protein-2 (BMP-2) modulates the SMAD signaling mechanism and the proliferation and differentiation outcome of human adipose stem cells (hASCs) derived from several donors. The results indicate that BMP-2 triggers molecular SMAD signaling mechanisms in hASCs and regulates differentiation processes in human serum-culture conditions. Importantly, BMP-2 has dual activity, inducing osteogenic and adipogenic differentiation, subject to hASC donor line studied. These findings explain contradictory previous results and highlight the importance of further studies to understand how signaling pathways guide mesenchymal stem cell functions at the molecular level., (©AlphaMed Press.)

Introduction: Adipose tissue is an attractive and abundant source of multipotent stem cells. Human adipose stem cells (ASCs) have shown to have therapeutic relevancy in diverse clinical applications. Nevertheless, expansion of ASCs is often necessary before performing clinical studies. Standard in vitro cell-culture techniques use animal-derived reagents that should be avoided in clinical use because of safety issues. Therefore, xeno- and serum-free (XF/SF) reagents are highly desirable for enhancing the safety and quality of the transplanted ASCs., Methods: In the current study, animal component-free isolation and cell-expansion protocols were developed for ASCs. StemPro MSC SFM XF medium with either CELLstart™ CTS™ coating or Coating Matrix Kit were tested for their ability to support XF/SF growth. Basic stem-cell characteristics such as immunophenotype (CD3, CD11a, CD14, CD19, CD34, CD45RO, CD54, CD73, CD80, CD86, CD90, CD105, HLA-DR), proliferation, and differentiation potential were assessed in XF/SF conditions and compared with human serum (HS) or traditionally used fetal bovine serum (FBS) cultures., Results: ASCs cultured in XF/SF conditions had significantly higher proliferation rates compared with HS/FBS cultures. Characteristic immunophenotypes of ASCs were maintained in every condition; however, cells expanded in XF/SF conditions showed significantly lower expression of CD54 (intercellular adhesion molecule 1, ICAM-1) at low passage number. Further, multilineage differentiation potential of ASCs was maintained in every culture condition., Conclusions: Our findings demonstrated that the novel XF/SF conditions maintained the basic stem cell features of ASCs and the animal-free workflow followed in this study has great potential in clinical cell therapies.

We analysed registry-based data on 14,915 patients treated for pertrochanteric fracture obtained from the Finnish Health Care Register during the years 1999-2009. Data on the comorbidities, residential status and deaths of the cohort were extracted from several Finnish registries using patients' unique personal identification numbers. The use of intramedullary implants increased substantially during the study period. One-year mortality was slightly higher in the patients treated with intramedullary implant (26.6% vs. 24.9%; P=0.011). In the first year after the fracture, there were more new operations on hip and thigh in patients treated with an intramedullary implant (11.1% vs. 8.9%; P<0.0001). Similarly, there were more new subtrochanteric and diaphyseal fractures of the femur in patients treated with intramedullary implants (3.2% vs. 1.05%; P<0.0001). Our findings suggest that more expensive intramedullary implants do not lead to better clinical outcomes than extramedullary implants for the treatment of pertrochanteric fractures., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The effects of bioactive glass S53P4 or beta-tricalcium phosphate; and bone morphogenetic proteins bone morphogenetic protein-2, bone morphogenetic protein-7, or bone morphogenetic protein-2 + 7 on osteogenic differentiation of human adipose stem cells were compared in control medium, osteogenic medium, and bone morphogenetic protein-supplemented osteogenic medium to assess suitability for bone tissue engineering. Cell amount was evaluated with qDNA measurements; osteogenic differentiation using marker gene expression, alkaline phosphate activity, and angiogenic potential was measured by vascular endothelial growth factor expression. As compared to beta-tricalcium phosphate, cell amount was significantly greater for bioactive glass in control medium after 7 days and in osteogenic medium after 14 days, and alkaline phosphate activity was always significantly greater for bioactive glass in control medium. However, alkaline phosphate activity increased for beta-tricalcium phosphate and decreased for bioactive glass granules in osteogenic medium. For both biomaterials, bone morphogenetic protein supplementation decreased cell amount and osteogenic differentiation of human adipose stem cells, and vascular endothelial growth factor expressions correlated with cell amounts. Effects of culture medium on human adipose stem cells are biomaterial dependent; bioactive glass in control medium enhanced osteogenic differentiation most effectively.

We previously found a positive association between calcium plus vitamin D and antiosteoporotic drugs and survival among hip fracture patients. Our aim was to verify this observation using a nationwide database. A retrospective cohort of home-discharged hip fracture patients aged 50 years or older (n = 23,615) was enrolled from the national database. Primary exposure was medical treatment for osteoporosis, and the outcome was all-cause mortality. Cumulative mortalities were calculated using the Kaplan-Meier estimator. The relationship between mortality and medication purchases was modeled using Cox's proportional hazards regression with time-dependent covariates for medication use. One in 4 women and 1 in 10 men with a hip fracture were treated for osteoporosis in Finland. Unadjusted 1-year mortality was lower among patients who purchased calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs than among those who did not purchase these medications [hazard ratio (HR) = 0.74, 95% confidence interval (CI) 0.67-0.81]. The difference in unadjusted cumulative mortality remained in favor of the drug users for at least 5 years. Among men, the use of calcium plus vitamin D or vitamin D supplements was associated with lower 1-year mortality even after adjustments for observed confounders (HR = 0.74, 95% CI 0.56-0.97). Among women, the use of antiosteoporotic drugs was associated with lower mortality (HR = 0.79, 95% CI 0.67-0.93). There was a tendency to even better survival in both genders if calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs were used simultaneously, the HR being 0.72 (95% CI 0.50-1.03) in men and 0.62 (95% CI 0.50-0.76) in women., (Copyright © 2011 American Society for Bone and Mineral Research.)

Background and Purpose: Treatment of stroke consumes a significant portion of all healthcare expenditure. We developed a system for monitoring costs from individual patient data on a national level in Finland., Methods: Multiple national administrative registers were linked to gain episode-of-care data on all hospital-treated patients with incident stroke over the years 1999 to 2007 (n = 94,316). Inpatient and specialist outpatient costs were evaluated with a cost database, long-term care costs with fixed prices, and medication costs with true retail prices., Results: For the patients of Year 2007, the mean 1-year costs after an ischemic stroke were $29 580, after an intracerebral hemorrhage $36,220, and after a subarachnoid hemorrhage $42,570, valued in Year 2008 U.S. dollars. Only part of these costs are attributable to stroke, because the annual costs prior to stroke were significant, $8900 before ischemic stroke, $7600 before intracerebral hemorrhage, and $4200 before subarachnoid hemorrhage. Older patients with ischemic stroke, and, among patients with ischemic stroke and subarachnoid hemorrhage, women, incurred higher costs. The mean estimated lifetime costs were $130,000 after ischemic stroke or intracerebral hemorrhage and $80,000 after subarachnoid hemorrhage. Annually $1.6 billion is spent in the care of Finnish patients with stroke, which equals to 7% of the national healthcare expenditure, or 0.6% of the gross domestic product. Costs of patients with stroke are increasing with prolonged survival and the aging population., Conclusions: Treatment of patients with stroke is a large national investment. Setting up a nationwide system for continuous monitoring of stroke costs is feasible. Cost data should optimally be evaluated in conjunction with effectiveness and performance indicators.

Introduction: This article in the supplement issue on the Performance, Effectiveness, and Costs of Treatment episodes (PERFECT)-project describes the PERFECT AMI (acute myocardial infarction) Database, which is developed to measure the performance of hospitals and hospital districts in Finland. We analyse annual trends and regional differences in performance indicators and whether the utilisation of services and costs of hospital care are related to improvement in survival of AMI patients., Material and Methods: The study population consists of ten annual cohorts (1998-2007) of patients hospitalised for AMI., Results: Since 1998 the treatment pattern has changed rather radically, the utilisation rate of percutaneous coronary intervention (PCI) has increased and coronary procedures have been performed earlier after myocardial infarction. Outcome measured by various measures of mortality has improved considerably. However, trends in the development of the use of services and outcomes are not similar between hospital districts. An increase in cost was positively and statistically significantly related to decrease in mortality, but the effect was not very strong., Conclusion: There is potential for decreased mortality from actions that do not increase the costs and for enhancing performance in the regions and hospitals with poor performance.

Introduction: This article in the supplement on the PERFormance, Effectiveness, and Costs of Treatment episodes (PERFECT)-project aims to measure the performance and quality of hip fracture treatment by analysing annual trends and regional differences in developed performance indicators., Material and Methods: The PERFECT Hip Fracture Database contains all hip fracture patients identified from the Hospital Discharge Register in Finland since 1999. Follow-up data from several administrative registers were also linked to the database. Several risk-adjusted performance indicators were developed., Results: In 2007 (compared with 1999), 4.1 percentage points fewer patients had died and 7.5 percentage points more patients were at home four months after fracture. The mean length of treatment had shortened from about 50 to about 45 days, and the mean costs of treatment per patient during the year following hip fracture had increased from about €18,000 to almost €20,000. There was extensive variation between the hospitals in the proportion of patients with an operative delay longer than two days and clear differences between hospital districts in several performance indicators., Conclusions: Outcomes of hip fracture treatment in Finland have been improved in recent years, but regional variation exists. Register-based data are useful for performance assessment of hip fracture treatment.

Introduction: This article in this supplement issue on the Performance, Effectiveness, and Costs of Treatment episodes (PERFECT) project describes trends in Finnish stroke treatment and outcome., Material and Methods: The PERFECT Stroke study uses multiple national registry linkages at individual patient level to produce a national stroke database with comprehensive follow-up of all hospital-treated stroke patients in Finland., Results: There were 94,316 incident stroke patients treated in Finnish hospitals from 1999 to 2007. Lengths-of-stays decreased after ischemic stroke (IS), and increased after intracerebral (ICH) and subarachnoid (SAH) hemorrhage. Ten-year survival improved in IS (hazard ratio 0.75; 95% CI 0.71-0.79) and ICH patients (0.88; 0.79-0.97), increasing median survival by 2 and 1 life-years respectively. This has translated into more days spent home among IS patients, but not among ICH patients. Treatment by neurologists improved the survival of IS (odds ratio [OR] 1.77; 95% CI 1.70-1.84) and ICH patients (OR 1.55; 95% CI 1.40-1.69), and treatment by neurosurgeons of SAH patients (OR 2.66; 95% CI 2.25-3.16), the effects were further improved by care in specialized stroke centers., Discussion: The survival of Finnish IS and ICH patients has improved. Specialized acute care was associated with improved outcome.

Introduction: In health care, measures of performance are needed at producer level for improving the treatment processes and at system level for steering purposes. In addition, measures that enable reliable comparisons of producers with respect to each other should encourage them to develop their treatment processes to attain better positioning in benchmarking., Methods: The main innovation of the Performance, Effectiveness, and Costs of Treatment episodes (PERFECT) project is to measure performance using existing linkable information available from registers within well-defined care episodes in a whole population. Finnish health care and related registers are used for constructing the disease-specific databases, with rich content on treatment processes and complete follow-up data., Results: The PERFECT project has developed numerous performance indicators that can be used to evaluate health policy actions as well as to create regional and hospital-level benchmarking data. In PERFECT, the idea is to eliminate individual-level variation from the performance indicators by using individual-level data and proper risk adjustment methods. The focus of our interest is in the variation at the producer or regional level., Conclusions: Our experience shows that the utilization of population-level health care registers with an episode-of-care approach enables a continual system and producer-level performance measurement.

Background and Purpose: Stroke databases are established to systematically evaluate both the treatment and outcome of stroke patients and the structure and processes of stroke services. Comprehensive data collection on this common disease is resource-intensive, and national stroke databases often include only patients from selected hospitals. Here we describe an alternative national stroke database., Methods: We established a nationwide stroke database with multiple administrative registry linkages at the individual-patient level. Information on comorbidities; treatments before, during, and after stroke; living status; recurrences; case fatality; and costs were collected for each hospital-treated stroke patient., Results: The current database includes 94 316 patients with incident stroke between January 1999 and December 2007, with follow-up until December 2008. Annually, 10 500 new patients are being added. One-year recurrence was 13% and case fatality was 27% during the study period. In 2007, 86% of patients survived 1 month and 77% were living at home at 3 months, but the proportion treated in stroke centers (62%) or with nationally recommended secondary preventive medication after ischemic stroke (49%) was still suboptimal., Conclusions: In comparison with other national stroke databases, our method enables higher coverage and more thorough follow-up of patients. Information on long-term recurrences, case fatality, or costs is not often included in national stroke databases. Our database has low maintenance costs, but it lacks detailed data on in-hospital processes. Use of national administrative data, where such linkage is possible, saves resources, achieves high rates of long-term follow-up, and allows for comprehensive monitoring of the burden of the disease.

Background and Purpose: Previous studies show better outcomes for patients with stroke receiving care in stroke units, but many different stroke unit criteria have been published. In this study, we explored whether stroke centers fulfilling standardized Brain Attack Coalition criteria produce better patient outcomes than hospitals without stroke centers., Methods: We did an observational register-linkage study of all patients with ischemic stroke treated in Finland between 1999 and 2006. After exclusion of recurrent strokes and nonanalyzable patients, we included 61 685 consecutive patients treated in 333 hospitals classified in national audits either as Comprehensive Stroke Centers, Primary Stroke Centers, or General Hospitals according to Brain Attack Coalition criteria. Primary outcome measures were case-fatality and being in institutional care 1 year after stroke., Results: Care in stroke centers was associated with lower 1-year case-fatality and reduced institutional care compared with General Hospitals. The number-needed-to-treat to prevent 1 death or institutional care at 1 year was 29 for Comprehensive Stroke Centers and 40 for Primary Stroke Centers versus General Hospitals. Patients treated in stroke centers had lower mortality during the entire follow-up of up to 9 years and their median survival was increased by 1 year., Conclusions: This study shows a clear association between the level of acute stroke care and patient outcome and supports use of published criteria for primary and comprehensive stroke centers.

We assessed the determinants of onset of hypertension in a large, prospective population-based study of perimenopausal women from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The data collection started in 1989, when a baseline postal inquiry was sent to all women aged 47-56 years (n=14 220) residing in the Kuopio Province in Eastern Finland. Names, social security numbers and addresses were obtained from the Population Register Centre of Finland. A total of 11 798 women responded at baseline and at 5-year follow-up in 1994. After the exclusion of 1777 women with prevalent hypertension at baseline and women with missing height or weight information, the study population consisted of 9485 without established hypertension at baseline. New cases of established hypertension during the follow-up (n=908) were ascertained with the Registry of Specially Refunded Drugs of the Finnish Social Insurance Institution (SII). According to the National Health Insurance, the SII granted 90% reimbursement for drug costs in defined chronic illnesses necessitating continuous medication, like arterial hypertension. Weight and weight gain both raised the risk by 5% per kg (P<0.001). Weight gain of 4-6 kg increased the risk of hypertension 1.25 times and a gain of more than 7 kg 1.65 times compared with the control (zero) group. To conclude, the onset of hypertension in peri- and early postmenopausal women was related to an increase in body weight despite controlling for initial body weight, reported physical activity and use of HRT. Therefore, preventing weight gain by dietary means and exercise is of great importance at menopausal age.

Bisphenol A (BPA), an environmental estrogen derived from the plastic industry, was given orally via incorporation into the food of 30 male and female polecats at 3 different doses (10, 50, or 250 mg/kg body weight/day) for 2 wk with 10 animals acting as controls. Several hormone levels in the plasma were determined as well as the activities of the phase I and II biotransformation enzymes 7-ethoxyresorufin O-deethylase (EROD), cytosolic glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT). BPA did not cause any macroscopic effects on body mass or the health of the animals. UDPGT and GST activities increased significantly in direct correlation with increasing BPA exposure in females and UDPGT increased in a dose-related manner in males. There was no change in the plasma T4 and testosterone concentrations of the males with increasing BPA exposure. Discriminant analysis indicated that the group receiving 10 mg BPA/kg body weight/d was not different from the control group but the groups receiving 50 and 250 mg/kg body weight/d were different from the control group. This suggests physiological changes in the groups receiving 50 or 250 mg BPA/kg body weight/d.

The aim of this study was to evaluate the effectiveness of vocationally oriented medical rehabilitation (VOMR) carried out in institutions with regard to the use of health-care services, work absenteeism, leisure-time physical activity, musculoskeletal symptoms and physical performance during 112 years of follow-up. The prospective cohort study consisted of 265 patients from four different occupational groups (loggers, hairdressers, police officers and female farmers) who took part in VOMR courses in three inhouse phases, financed by the Finnish Social Insurance Institution, and who had chronic musculoskeletal symptoms in their back and neck. The subjective physical and mental strain of work, subjective neck-shoulder and low-back pain, use of health-care services and leisure-time physical activity were assessed with a questionnaires. The muscle strength of the upper and lower extremities and trunk was determined and maximal VO2 was measured using the direct maximal bicycle ergometer test. The subjective physical and mental strain of work, subjective neck-shoulder and low-back pain and physical performance showed positive significant development and improvement. The changes in the use of health-care services and work absenteeism were minor or insignificant. The general finding was that the results from the second phase of the VOMR courses did not differ from those of the third phase. VOMR courses had a beneficial effect on physical performance and subjective pain caused by neck and back musculoskeletal diseases of farmers, loggers, police officers and hairdressers within 112 years of follow-up, but VOMR courses did not decreased the use of health-care services.

Aim: To evaluate the effect of maternal diabetes on the concentrations of free and bound leptin at birth and during postnatal adaptation., Methods: Total, bound, and free leptin concentrations and the percentage of free leptin were measured in cord plasma and plasma at 3 days of age of 13 term infants of mothers with gestational diabetes mellitus (GDM) and 13 term infants of healthy mothers. Gestational age was 40.2 (1.4) weeks, and birth weight was 3693 (549) g (means (SD))., Results: At birth, infants of mothers with GDM had significantly higher concentrations of total, bound, and free leptin and a higher percentage of free leptin (all p < 0.05). In all infants, these concentrations were significantly lower at 3 days of age than at birth (all p < 0.003), and the differences in concentrations of total, bound, and free leptin between the two groups were no longer significant. In infants of mothers with GDM, the percentage of free leptin remained unchanged, and was higher (p<0.05) than in infants of healthy mothers; in the latter group the percentage of free leptin significantly declined (p = 0.02)., Conclusions: GDM appears to influence fetoplacental leptin metabolism. This effect may be mediated through altered maternal glucose metabolism, or insulinaemia, or both.

The concentration of fecal mucin and the adhesion of specific probiotics and their combinations in the intestinal mucus of infants during and after rotavirus diarrhea and in healthy children were determined. Mucus was prepared from fecal samples from 20 infants during and after rotavirus diarrhea and from 10 healthy age-matched children. Mucin concentration was determined, and the adhesion of five probiotics-Lactobacillus rhamnosus GG, Lactobacillus casei Shirota, Lactobacillus paracasei F19, Lactobacillus acidophilus LA5, and Bifidobacterium lactis Bb12-and their combinations was tested in vitro. The mean concentrations of fecal mucin during and after rotavirus diarrhea, 15.2 and 14.1 mg/g, were comparable to that in healthy children, 14.9 mg/g. The adherence of probiotics ranged from 1 to 34% in healthy subjects as indicated for the following strains: L. rhamnosus GG, 34%; B. lactis Bb12, 31%; L. acidophilus LA5, 4%; L. paracasei F19, 3%; and L. casei Shirota, 1% (P = 0.0001). The distinctive pattern of probiotic adherence was not influenced by rotavirus diarrhea. The adhesion of Bb12 in the presence of GG increased from 31 to 39% in healthy infants (P = 0.018) and in episodes of diarrhea increased from 26 to 44% (P = 0.001). Rotavirus diarrhea does not decrease the production of fecal mucin or with respect to the adhesion of probiotic bacteria tested in vitro. Combination of specific probiotic strains may enhance adherence in a synergistic manner. Optimal clinical application of these interactions may offer novel therapeutic guidelines for the treatment and prevention of gastrointestinal infections.

In a clinical follow-up case series study, the test-retest reliability of an outcome measure questionnaire was tested. The study group consisted of 48 patients who had taken part in a vocational rehabilitation programme. Test-retest reliability of a questionnaire was evaluated with the reliability index two years after entering the programme. It was found that the test-retest reliability of demographic data was rather good, although the questions concerning basic and occupational training showed instability over time. The answers concerning general health symptoms, mental working capacity and perceived changes in life during the past 12 months showed particularly high variability. The respondents' opinions on their general outlook of life seemed rather stable. Opinions about the perceived benefits from the intervention were marginally stable. The respondents' opinions about the benefits perceived from the physicians' work were more stable than the opinions about the perceived help from the other members of the rehabilitative team. It was concluded that an outcome analysis questionnaire is a useful tool to document the respondents' general and present perception of life and their present health situation as well as the rehabilitation process. The further development of generally applicable outcome measures for health promotion programmes will require unified, long-term efforts.

In 1991 the Social Insurance Institution Rehabilitation Act introduced a working capacity sustaining and improving training programme (TYK). The goal of this programme is to sustain the physio-psycho-social competences of older workers and employees by creating a chain of in-house rehabilitation phases and training phases at the workplace. We describe the programme in its early state of implementation. Two years after entering the programme 17 patients were working, six were on sick leave, three were out of work, 16 were on pension, and six patients could not be retrieved.

The inverse problem of the depth dose curve is formulated and a proposition for its solution is presented. The solution is based on the approximation of the observation equation with a numerical quadrature operator and the regularization of this inverse problem with a smoothness side constraint. The problem formulation is applicable for both the electron and the photon depth dose curve estimation. Moreover, the method is equivalent for, for example, all energies, field sizes and source-to-phantom distances. Simulations show that the estimation error is smaller with the proposed method than with direct linear interpolation. The main result of the paper, however, is the formulation of the problem that allows feasible extensions and modifications for different measurement situations.

To determine the effect of a human Lactobacillus strain (Lactobacillus casei sp strain GG, Gefilac) on recovery from acute diarrhea (82% rotavirus), 71 well-nourished children between 4 and 45 months of age were studied. After oral rehydration, the patients randomly received either Lactobacillus GG-fermented milk product, 125 g (10(10-11) colony-forming units) twice daily (group 1); Lactobacillus GG freeze-dried powder, one dose (10(10-11) colony-forming units) twice daily (group 2); or a placebo, a pasteurized yogurt (group 3) 125 g twice daily; each diet was given for 5 days, in addition to normal full diet otherwise free of fermented dairy products. The mean (SD) duration of diarrhea after commencing the therapy was significantly shorter in group 1 (1.4 [0.8] days) and in group 2 (1.4 [0.8] days) than in group 3 (2.4 [1.1] days); F = 8.70, P less than 0.001. After rehydration, each dietary group maintained a positive weight trend. The urinary lactulose-mannitol recovery ratios (means [95% confidence intervals]) on admission were 0.09 (0.03, 0.24) in group 1, 0.12 (0.07, 0.22) in group 2, and 0.08 (0.04, 0.18) in group 3; no significant alterations in intestinal permeability were observed at retesting after 2 days of realimentation. The result indicates that early nutritional repletion after rehydration causes no mucosal disruption and is beneficial for recovery from diarrhea. It is further suggested that Lactobacillus GG in the form of fermented milk or freeze-dried powder is effective in shortening the course of acute diarrhea.

The effects of early home management of acute diarrhea followed by rapid in-hospital realimentation on intestinal permeability were studied in 41 children aged 3-25 months with acute gastroenteritis (73% rotavirus). After oral rehydration, a 100 ml oral load containing 4 g of lactulose and 0.8 g of mannitol was administered, and an aliquot of urine excreted in the subsequent 5 h was analyzed with gas-liquid chromatography. The mean lactulose/mannitol recovery ratio was significantly higher than in 28 nondiarrheal controls, which was due to decreased mannitol excretion. The gastroenteritis patients who had received uninterrupted feeding in addition to adequate fluid replacement before hospitalization had a normal urinary lactulose/mannitol ratio, with a mean of 0.04, and a 95% confidence interval (CI) of [0.03, 0.07], whereas in fasted children with inadequate or adequate fluid replacement, the respective mean ratios were 0.24, 95% CI of [0.14, 0.43], and 0.14, 95% CI of [0.09, 0.20] (F = 12.63, p less than 0.001). The fasting-associated rise was caused by increased lactulose excretion. At retesting of gastroenteritis patients after 2 days of in-hospital realimentation, the lactulose/mannitol ratios did not differ significantly from the level on admission. The study indicated that fasting maintains the increased intestinal permeability associated with acute gastroenteritis whereas early feeding at home may promote reduction of permeability and hasten recovery.