Relatively low and moderate pre-fracture serum 25-hydroxyvitamin D levels associated with the highest survival in elderly hip fracture patients in Finland: a minimum 3-year follow-up.

The association between serum 25-hydroxyvitamin D level and post-fracture mortality indicates beneficial relatively high serum 25-hydroxyvitamin D concentrations. A 1-year cohort study on 245 hip fracture patients in Finland indicated the lowest 3-year mortality and highest survival among patients with serum 25-hydroxyvitamin D level of 50-74 nmol/L. PURPOSE: To explore pre-fracture serum 25-hydroxyvitamin D level as a factor associated with post-fracture survival among a cohort of hip fracture patients in Finland. METHODS: A prospectively collected cohort of hip fracture patients (n = 245, 70% women) from two hospitals was followed for 3.2 post-hip fracture years. Serum 25-hydroxyvitamin D was measured in admission to the hospital and classified: < 50, 50-74, 75-99, and ≥ 100 nmol/L. Survival was analyzed with a Bayesian multivariate model. Relative survival was explored with the life table method according to serum 25-hydroxyvitamin D. Mortality according to serum 25-hydroxyvitamin D level and to the hospital was calculated. RESULTS: Mortality in the patients with serum 25-hydroxyvitamin D level of 50-74 nmol/L was significantly lower than in all other patients together at every post-fracture year. The most important factors for survival were age under 85 years; living in an actual/private home; serum 25-hydroxyvitamin D level of 50-74 nmol/L, followed by 75-99 nmol/L; ASA classes 1-2 and 3; and female sex. The mean age of patients with serum 25-hydroxyvitamin D level of 50-99 nmol/L was significantly higher than in other levels. Relative survival was highest in men, women, and patients in hospital B with serum 25-hydroxyvitamin D level of 50-74 nmol. CONCLUSION: The highest 3-year survival and the lowest mortality in this cohort appeared in patients with pre-fracture serum 25-hydroxyvitamin D level of 50-74 nmol/L. This result differs from similar studies and is lower than the recommended level of 25-hydroxyvitamin D among hip fracture patients. The results should be examined in future research with larger data.

Use of benzodiazepines, z-hypnotics and antidepressants among hip fracture patients in Finland. Consistency between recorded and detected benzodiazepines.

PURPOSE: We described the use of benzodiazepines (BZDs), z-hypnotics, and antidepressants; analyzed the consistency between recorded and detected BZDs among hip fracture patients admitted to two Finnish hospitals during one year; and compared the results with corresponding results from 12 years earlier. METHODS: Current use of medication was obtained from the National Prescription Register. Urine and blood samples used to detect BZD were taken during admission. The following Anatomical Therapeutic Chemical (ATC) classes were included: BZDs: N05BA, N05CD; z-hypnotics: N05CF; and antidepressants: N06A.The presence of BZDs in urine was analyzed using immunoassay. Positive BZDs were confirmed by gas chromatography mass spectrometry. BZDs in serum were analyzed using liquid chromatography. Concordance between recorded and detected BZDs was calculated with kappa (κ) and described using a Venn diagram. RESULTS: A total of 245 patients were enrolled in the study. BZD was detected in 18 %. Kappa was 0.39 (95 % CI 0.25-0.53). Overlap of detected and recorded BZDs was 59 %. According to the prescription register, 18 % used z-hypnotics, and according to both the detection of BZDs and register, 49 % used BZDs and/or z-hypnotics. 22 % used antidepressants and 15 % used combinations of the studied drugs concomitantly. CONCLUSION: Use rate of BZDs and/or z-hypnotics was similar to that 12 years ago. No difference in the consistency between our previous and present study was found either. All studied drugs and their concomitant use increase the risk for fractures. In the elderly, point prevalence of medication and appropriateness should be regularly assessed.

A 10-Year Retrospective Study of 490 Hip Fracture Patients: Reoperations, Direct Medical Costs, and Survival.

BACKGROUND AND AIMS: Reoperations after operative treatment of hip fracture patients may be associated with higher costs and inferior survival. We examined the acute hospital costs, long-term reoperation rates, and survival of patients with a new hip fracture. MATERIALS AND METHODS: A total of 490 consecutive new hip fracture patients treated at a single center between 31 December 2004 and 6 December 2006 were analyzed retrospectively. Fractures were classified according to Garden and AO. All medical records were checked manually. The costs of reoperations were calculated using the diagnosis-related groups (DRG)-based prices. Survival analysis was performed using the life-table method. The follow-up time was 10 years. RESULTS: In all, 70/490 patients (14.3%) needed reoperations. Of all reoperations, 34.2% were performed during the first month and 72.9% within 1 year after the primary operation. The hemiarthroplasty dislocation rate was 8.5%, and mechanical failures of osteosynthesis occurred in 6.2%. Alcohol abuse was associated with a heightened risk of reoperation. The mean direct costs of primary fracture care were lower than the mean costs of reoperations (€7500 vs €9800). The mortality rate at 10 years was 79.8% among non-reoperated patients and 62.9% among reoperated patients. CONCLUSIONS: According to our hypothesis, the cost per patient of reoperation in acute care was 31% higher than the corresponding cost of a primary operation. Reoperations increased the overall immediate costs of index fractures by nearly 20%. One-third of all reoperations were performed during the first month and almost 75% within 1 year after the primary operation.

Correction to: Remarkable improvement in serum 25-hydroxyvitamin levels among hip fracture patients over a 12-year period: a prospective study in South-eastern Finland.

The presentation of Table 4 was unclear in the original publication. The article has now been corrected in this respect.

Remarkable improvement in serum 25-hydroxyvitamin levels among hip fracture patients over a 12-year period: a prospective study in South-eastern Finland.

Hypovitaminosis D is a problem among hip fracture patients. In a 1-year cohort study comprising 245 hip fracture patients (mean age of females 81 years and males 78 years) from south-eastern Finland, the mean 25-hydroxyvitamin D [S-25(OH)D] concentration was 73(SD 31) nmol/L. Vitamin D supplementation has been integrated into our current practice. INTRODUCTION: The objectives of this study are to verify vitamin D levels among hip fracture patients and to compare the results with a similar study conducted in the same two hospitals covering the same geographic area 12 years ago. METHODS: A prospective cohort comprising 245 Caucasian hip fracture patients was enrolled in the study in two acute hospitals in south-eastern Finland (61° N) over a 12-month period in 2015-2016. The S-25(OH)D was measured using 25-hydroxyvitamin D electrochemiluminescence binding assay. The S-25(OH)D concentrations were compared with the corresponding concentrations of a similar cohort analyzed in the same two hospitals 12 years ago. RESULTS: Of the 245 patients, 70% were women with a mean age of 81 (SD 10) years, while the men had a mean age of 78 (SD 12) years (p < 0.01). The total mean S-25(OH)D concentration was 73 (SD 31.3) nmol/L. Regional differences were found: 15% in hospital A and 36% in hospital B had a S-25(OH(D level < 50 nmol/L, and the mean S-25(OH)D level was 79.2 (SD 31.7) nmol/L in hospital A and 62.4 (SD 27.5) nmol/L in hospital B (p < 0.001). No differences were found in S-25(OH)D concentrations by either the place of residence or the time of year. Overall, the percentage of patients with a sufficient vitamin D level (> 50 nmol/L) was remarkably higher in 2015-2016 (77%) than in 2003-2004 (22%). CONCLUSION: Our results indicate that vitamin D supplementation has been widely integrated into our current practice. However, regional differences were found in the S-25(OH)D concentrations for which the reasons are unknown.

An 8-year follow-up study of 221 consecutive hip fracture patients in Finland: analysis of reoperations and their direct medical costs.

BACKGROUND: Some hip fracture patients need one or more reoperations because of complications following initial operative treatment. AIMS: The aim of this study was to identify all further surgical interventions in a cohort of patients with hip fractures over a period of 8 years after index fracture. Immediate direct costs of these reoperations were also calculated. MATERIAL AND METHODS: This retrospective study investigated 221 consecutive patients with hip fractures operated on at two different hospitals in southeastern Finland. The study period in hospital A was from 1 February 2003 to 31 January 2004, and in hospital B from 1 February 2003 to 30 April 2004. About 50% were femoral neck fractures, 41% trochanteric fractures, and 9% subtrochanteric fractures. Patients' medical records were checked from the hospital records and confirmed manually. Short- and long-term complications were recorded. Survival analysis was performed using a life-table method. The actual costs for reoperations and other further procedures for each patient were calculated using diagnosis-related groups-based costs for both hospitals in 2012. RESULTS: A total of 20 patients (9%) needed reoperations. Overall, 10 patients (8.9%) with a femoral neck fracture (n = 112), 8 patients (8.7%) with trochanteric fracture (n = 92), and 2 patients (10.5%) with subtrochanteric fracture (n = 19) were reoperated on. The median interval between the primary operation of the acute hip fracture (n = 20) and the first reoperation was about 300 days (range: 2 weeks to 82 months). Among the women reoperated on, the excess mortality was lower than among those undergoing a single operation. The median costs of treatment per patient with one or more reoperations were €13,422 in hospital A (range: €1616-€61,755), €11,076 in hospital B (range: €1540-€17,866), and €12,850 in the total study group (p = 0.43). In the case of infections (3 patients), the mean costs per patient were €28,751 (range: €11,076-€61,755). CONCLUSIONS: Almost 10% of hip fracture patients required reoperations, and these reoperations caused significant direct costs to health care. However, direct costs account for only approximately 25% of the first year's total costs. These costs should be taken into account when evaluating the economics of hip fractures and the burden of health care.

Acute alcohol use among patients with acute hip fractures: a descriptive incidence study in southeastern Finland.

AIM: To assess the very recent use of alcohol among patients admitted to two Finnish hospitals due to an acute hip fracture. METHOD: Very recent use of alcohol was recorded according to the patient's or the relatives' report. Ethanol was measured in blood samples taken at admission. Serum gamma-glutamyltransferase, aspartate aminotransferase and alanine aminotransferase, and vitamin D concentration were measured. Reported use of medication, vitamin D, and/or calcium supplementation was recorded. RESULTS: Complete data were obtained on 222 of 375 eligible patients; 71% of those enrolled were women. The mean age of women was 80.5 years (SD 10) and of men 73 years (SD 12) (P < 0.001). The fracture type was femoral neck in 50%, trochanteric in 41%, and subtrochanteric in 9%. The use of alcohol within 24 h before the accident leading to hip fracture was reported by 21.5% of men and 7% of women; positive serum alcohol levels were noted in 17% (19% of men and 16% of women) and 2.2% had a level of >1.0 mg/l. Recent alcohol use was more common among patients in the age group of 65-74 years than among older patients (P < 0.001). The use of alcohol was associated strongly with tobacco use (P = 0.00012) but had no association with vitamin D levels. Alcohol users used less medication than non-users (P < 0.01). Women seemed to conceal their use of alcohol more than men (P < 0.005). CONCLUSIONS: Alcohol consumption was common among patients with an acute hip fracture, being more common in younger than in older patients. Use of alcohol in the 24 h prior to the injury was reported by 21.5% of men and 7% of women. Alcohol concentration in blood was positive in 19% of men and 16% of women.

Diseases caused by nuclear genes affecting mtDNA stability.

Diseases caused by nuclear genes that affect mitochondrial DNA (mtDNA) stability are an interesting group of mitochondrial disorders, involving both cellular genomes. In these disorders, a primary nuclear gene defect causes secondary mtDNA loss or deletion formation, which leads to tissue dysfunction. Therefore, the diseases clinically resemble those caused by mtDNA mutations, but follow a Mendelian inheritance pattern. Several clinical entities associated with multiple mtDNA deletions have been characterized, the most frequently described being autosomal dominant progressive external ophthalmoplegia (adPEO). MtDNA depletion syndrome (MDS) is a severe disease of childhood, in which tissue-specific loss of mtDNA is seen. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients may have multiple mtDNA deletions and/or mtDNA depletion. Recent reports of thymidine phosphorylase mutations in MNGIE and adenine nucleotide translocator mutations in adPEO have given new insights into the mechanisms of mtDNA maintenance in mammals. The common mechanism underlying both of these gene defects could be disturbed mitochondrial nucleoside pools, the building blocks of mtDNA. Future studies on MNGIE and adPEO pathogenesis, and identification of additional gene defects in adPEO and MDS will provide further understanding about the mammalian mtDNA maintenance and the crosstalk between the nuclear and mitochondrial genomes.

Bmx tyrosine kinase has a redundant function downstream of angiopoietin and vascular endothelial growth factor receptors in arterial endothelium.

The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with the lacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype. Staining of their tissues using beta-galactosidase substrate to assess the sites of Bmx expression revealed strong signals in the endothelial cells of large arteries and in the endocardium starting between days 10.5 and 12.5 of embryogenesis and continuing in adult mice, while the venular endothelium showed a weak signal only in the superior and inferior venae cavae. Of the five known endothelial receptor tyrosine kinases tested, activated Tie-2 induced tyrosyl phosphorylation of the Bmx protein and both Tie-2 and vascular endothelial growth factor receptor 1 (VEGFR-1) stimulated Bmx tyrosine kinase activity. Thus, the Bmx tyrosine kinase has a redundant role in arterial endothelial signal transduction downstream of the Tie-2 and VEGFR-1 growth factor receptors.

Role of adenine nucleotide translocator 1 in mtDNA maintenance.

Autosomal dominant progressive external ophthalmoplegia is a rare human disease that shows a Mendelian inheritance pattern, but is characterized by large-scale mitochondrial DNA (mtDNA) deletions. We have identified two heterozygous missense mutations in the nuclear gene encoding the heart/skeletal muscle isoform of the adenine nucleotide translocator (ANT1) in five families and one sporadic patient. The familial mutation substitutes a proline for a highly conserved alanine at position 114 in the ANT1 protein. The analogous mutation in yeast caused a respiratory defect. These results indicate that ANT has a role in mtDNA maintenance and that a mitochondrial disease can be caused by a dominant mechanism.

Drainage is of no use in primary uncomplicated cemented hip and knee arthroplasty for osteoarthritis: a prospective randomized study.

In a prospective, randomized study, 58 patients with primary cemented hip arthroplasty and 39 patients with primary cemented knee arthroplasty were divided into groups with postoperative closed-suction drainage and without drainage. There was no difference in healing of the wounds, postoperative blood transfusions, complications, or range of motion. Although there was more soaked dressing requiring reinforcements in the groups without drainage, as a result of this study, we no longer use drains in uncomplicated cemented primary hip and knee arthroplasties for osteoarthritis.

MR imaging in suspected acute trauma of wrist bones.

OBJECTIVE: The purpose of this study was to evaluate the findings of MR imaging compared to plain radiography in acute wrist trauma. METHODS: Radiography and MR imaging (obtained at 1.5 T) of 67 patients (38 female, 29 male, aged 15-80 years) were analysed by three senior radiologists in a blinded random fashion. RESULTS: One-third (n= 13) of the 37 fractures observed on MR images were missed on the radiographs. The McNemar test indicated significant differences in diagnoses between radiography and MR. CONCLUSION: We recommend that MR imaging should be considered in the diagnosis of acute wrist trauma when: 1) There is a clear discrepancy between the clinical status and a negative radiography and when splint treatment would increase cost by causing occupational restrictions; and 2) Healing of trauma diagnosed as contusion or distension does not occur within the expected time.

Human Emt tyrosine kinase is specifically expressed both in mature T-lymphocytes and T-cell associated hematopoietic malignancies.

The pattern of expression of the human Emt tyrosine kinase was established in healthy individuals and hematological malignancies by RT-PCR from bone marrow and blood samples, fractionated into T-cells, B-cells, monocytes, granulocytes and thrombocytes. Previously studied mostly in murine samples or established human cell lines, the in vivo correlation was here further clarified. In hematopoietic cells, expression of the EMT gene was associated with T-cell fractions, but Emt was not detected in cord blood CD34+ cells. In fetal tissues, Emt mRNA was strongly expressed in thymus, no expression could be detected in non-hematopoietic tissues. The expression pattern of the 48 malignant bone marrow samples (23 ALL, 1 PLL, 9 AML, 7 CLL and 8 CML cases) paralleled the findings from normal hematopoietic cells: 9/11 T cell associated ALLs, as well as one T-PLL sample, but only 1/12 samples of B-ALL expressed Emt markedly. Only minor signs of Emt expression could be shown in the AML samples, while CML and CLL samples were totally devoid of expression. In addition the Emt protein could be detected by Western blotting from T-lymphocytes and T-cell associated ALL, corresponding to mRNA expression. In conclusion, Emt (Itk) is T-cell associated both in normal and leukemic cells, but is not expressed in cord blood CD34+ cells, suggesting that Emt expression is switched on only later in T-cell development. In addition, an association between Emt and CD2 expression remains even in malignancies.

Localization of the APECED protein in distinct nuclear structures.

Autoimmune-polyendocrinopathy-candidiasis-ecto-dermaldystrophy (APECED) is the only systemic autoimmune disease with a monogenic background known so far revealing no association with the major histocompatibility complex region. We have recently isolated the gene defective in this syndrome and characterized several different mutations in individuals with the disorder. The novel gene, AIRE, contains a putative bipartite nuclear targeting signal predicting a nuclear location of the corresponding protein. The presence of two PHD-type zinc finger domains as well as the newly described putative DNA-binding domain, SAND, in the amino acid sequence of the APECED protein implies that it may be involved in the regulation of gene expression. Using transient expression of AIRE cDNA in mammalian cells we demonstrate here the nuclear location of the APECED protein. Immunohistochemical staining of transfected cells revealed that most of the recombinant 58 kDa APECED protein is present in the form of nuclear dots. By double immuno-fluorescence labelling we further show that these APECED-containing structures and the previously described PML nuclear bodies are largely non-overlapping. The AIRE protein was also visualized in multiple human tissues: a subset of the cells in thymus, in spleen and in lymph node showed nuclear staining with APECED antiserum. Immunofluorescence labelling of peripheral blood mononuclear leukocytes also revealed a nuclear body-like staining pattern in a fraction of these cells. These data from both in vitro and ex vivo systems, together with the predicted structural features of the APECED protein, suggest that this protein is most probably involved in the regulation of gene expression.

Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation.

VEGF-C is a recently characterised endothelial growth factor structurally related to vascular endothelial growth factor (VEGF). We studied the expression of VEGF-C and VEGF in the cells of peripheral blood and in the umbilical cord blood CD 34+ cells, representing haematopoietic progenitor cells. Expression of VEGF-C was detected in the CD34+ cells. In peripheral blood VEGF-C mRNA was restricted to platelets and T-cells. In contrast to the expression pattern of VEGF-C, VEGF mRNA was detected in all peripheral blood cell fractions studied, and also in CD34+ cells. VEGF-C mRNA was also detected in fresh bone marrow samples of acute leukaemia patients, but the expression did not show lineage specificity. VEGF-C and VEGF polypeptides were present in platelets and they were released from activated platelets together with the release of beta-thromboglobulin, suggesting that VEGF-C and VEGF reside in the alpha-granules of platelets. VEGF-C and VEGF, released from activated platelets, may have a role in angiogenesis during wound healing, and possibly also in other pathological conditions, such as atherosclerosis, tumour growth, and metastasis formation.

Genomic organization of human and mouse genes for vascular endothelial growth factor C.

We report here the cloning and characterization of human and mouse genes for vascular endothelial growth factor C (VEGF-C), a newly isolated member of the vascular endothelial growth factor/platelet-derived growth factor (VEGF/PDGF) family. Both VEGF-C genes comprise over 40 kilobase pairs of genomic DNA and consist of seven exons, all containing coding sequences. The VEGF homology domain of VEGF-C is encoded by exons 3 and 4. Exons 5 and 7 encode cysteine-rich motifs of the type C6C10CRC, and exon 6 encodes additional C10CXCXC motifs typical of a silk protein. A putative alternatively spliced rare RNA form lacking exon 4 was identified in human fibrosarcoma cells, and a major transcription start site was located in the human VEGF-C gene 523 base pairs upstream of the translation initiation codon. The upstream promoter sequences contain conserved putative binding sites for Sp-1, AP-2, and NF-kappaB transcription factors but no TATA box, and they show promoter activity when transfected into cells. The VEGF-C gene structure is thus assembled from exons encoding propeptides and distinct cysteine-rich domains in addition to the VEGF homology domain, and it shows both similarities and distinct differences in comparison with other members of the VEGF/PDGF gene family.

Analysis of Tie receptor tyrosine kinase in haemopoietic progenitor and leukaemia cells.

We generated a panel of monoclonal antibodies against the extracellular domain of the Tie receptor tyrosine kinase and studied its expression in human haemopoietic and tumour cell lines and in samples from leukaemia patients. Most of the erythroblastic/megakaryoblastic (6/8), 2/7 myeloid and 3/6 B-lymphoblastic leukaemia cell lines were Tie-positive. The erythroblastic/megakaryoblastic leukaemia cell lines also expressed the related Tie-2/Tek gene and, surprisingly, its recently cloned ligand gene angiopoietin-1, which was located in chromosome 8q23.1. In addition, 16% of freshly isolated leukaemia samples were Tie positive. Peripheral blood mononuclear cells were Tie negative, but a few Tie positive cells were found in immunoperoxidase staining of mobilized peripheral blood stem cells. Long-term culture of isolated umbilical cord blood CD34+ Tie+ and CD34+ Tie- cells indicated that the Tie+ fraction contained a slightly higher frequency of cobblestone area forming cells (CAFC). Thus, Tie is expressed on haemopoietic progenitor cells and some leukaemic blasts. The coexpression of Tie-2 and angiopoietin-1 in megakaryoblastic leukaemia cell lines suggests the existence of an autocrine ligand/receptor signalling loop in these cells.