Association Between Recurrent Fracture Risk and Implementation of Fracture Liaison Services in Four Swedish Hospitals: A Cohort Study.

Structured secondary preventions programs, called fracture liaison services (FLSs), increase the rate of evaluation with bone densitometry and use of osteoporosis medication after fracture. However, the evidence regarding the effect on the risk of recurrent fracture is insufficient. The aim of this study was to investigate if implementation of FLS was associated with reduced risk of recurrent fractures. In this retrospective cohort study, electronic health records during 2012 to 2017 were used to identify a total of 21,083 patients from four hospitals in Western Sweden, two with FLS (n = 15,449) and two without (n = 5634). All patients aged 50 years or older (mean age 73.9 [SD 12.4] years, 76% women) with a major osteoporotic index fracture (hip, clinical spine, humerus, radius, and pelvis) were included. The primary outcome was recurrent major osteoporotic fracture. All patients with an index fracture during the FLS period (n = 13,946) were compared with all patients in the period before FLS implementation (n = 7137) in an intention-to-treat analysis. Time periods corresponding to the FLS hospitals were used for the non-FLS hospitals. In the hospitals with FLSs, there were 1247 recurrent fractures during a median follow-up time of 2.2 years (range 0-6 years). In an unadjusted Cox model, the risk of recurrent fracture was 18% lower in the FLS period compared with the control period (hazard ratio = 0.82, 95% confidence interval [CI] 0.73-0.92, p = .001), corresponding to a 3-year number needed to screen of 61, and did not change after adjustment for clinical risk factors. In the hospitals without FLSs, no change in recurrent fracture rate was observed. Treatment decisions were made according to the Swedish treatment guidelines. In conclusion, implementation of FLS was associated with a reduced risk of recurrent fracture, indicating that FLSs should be included routinely at hospitals treating fracture patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Fracture Risk After Gastric Bypass Surgery: A Retrospective Cohort Study.

Gastric bypass surgery constitutes the most common and effective bariatric surgery to treat obesity. Gastric bypass leads to bone loss, but fracture risk following surgery has been insufficiently studied. Furthermore, the association between gastric bypass and fracture risk has not been studied in patients with diabetes, which is a risk factor for fracture and affected by surgery. In this retrospective cohort study using Swedish national databases, 38,971 obese patients undergoing gastric bypass were identified, 7758 with diabetes and 31,213 without. An equal amount of well-balanced controls were identified through multivariable 1:1 propensity score matching. The risk of fracture and fall injury was investigated using Cox proportional hazards and flexible parameter models. Fracture risk according to weight loss and degree of calcium and vitamin D supplementation 1-year postsurgery was investigated. During a median follow-up time of 3.1 (interquartile range [IQR], 1.7 to 4.6) years, gastric bypass was associated with increased risk of any fracture, in patients with and without diabetes using a multivariable Cox model (hazard ratio [HR] 1.26; 95% CI, 1.05 to 1.53; and HR 1.32; 95% CI, 1.18 to 1.47; respectively). Using flexible parameter models, the fracture risk appeared to increase with time. The risk of fall injury without fracture was also increased after gastric bypass. Larger weight loss or poor calcium and vitamin D supplementation after surgery were not associated with increased fracture risk. In conclusion, gastric bypass surgery is associated with an increased fracture risk, which appears to be increasing with time and not associated with degree of weight loss or calcium and vitamin D supplementation following surgery. An increased risk of fall injury was seen after surgery, which could contribute to the increased fracture risk. © 2018 American Society for Bone and Mineral Research.

Association Between Alendronate Use and Hip Fracture Risk in Older Patients Using Oral Prednisolone.

IMPORTANCE: Oral glucocorticoid treatment increases fracture risk, and evidence is lacking regarding the efficacy of alendronate to protect against hip fracture in older patients using glucocorticoids. OBJECTIVE: To investigate whether alendronate treatment in older patients using oral prednisolone is associated with decreased hip fracture risk and adverse effects. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using a national database (N = 433 195) of patients aged 65 years or older undergoing a health evaluation (baseline) at Swedish health care facilities; 1802 patients who were prescribed alendronate after at least 3 months of oral prednisolone treatment (≥5 mg/d) were identified. Propensity score matching was used to select 1802 patients without alendronate use from 6076 patients taking prednisolone with the same dose and treatment time criteria. Follow-up occurred between January 2008 and December 2014. EXPOSURES: Alendronate vs no alendronate use; no patients had previously taken alendronate at the time of prednisolone initiation. MAIN OUTCOMES AND MEASURES: The primary outcome was incident hip fracture. RESULTS: Of the 3604 included patients, the mean age was 79.9 (SD, 7.5) years, and 2524 (70%) were women. After a median follow-up of 1.32 years (interquartile range, 0.57-2.34 years), there were 27 hip fractures in the alendronate group and 73 in the no-alendronate group, corresponding to incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI, 21.6-34.2) fractures per 1000 person-years, with an absolute rate difference of -17.6 (95% CI, -24.8 to -10.4). The use of alendronate was associated with a lower risk of hip fracture in a multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22-0.54). Alendronate treatment was not associated with increased risk of mild upper gastrointestinal tract symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0] per 1000 person-years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7-15.5] vs 11.4 [95% CI, 8.0-16.2] per 1000 person-years; P = .86). There were no cases of incident drug-induced osteonecrosis and only 1 case of femoral shaft fracture in each group. CONCLUSIONS AND RELEVANCE: Among older patients using medium to high doses of prednisolone, alendronate treatment was associated with a significantly lower risk of hip fracture over a median of 1.32 years. Although the findings are limited by the observational study design and the small number of events, these results support the use of alendronate in this patient group.

Type 2 Diabetes and Risk of Hip Fractures and Non-Skeletal Fall Injuries in the Elderly: A Study From the Fractures and Fall Injuries in the Elderly Cohort (FRAILCO).

Questions remain about whether the increased risk of fractures in patients with type 2 diabetes (T2DM) is related mainly to increased risk of falling or to bone-specific properties. The primary aim of this study was to investigate the risk of hip fractures and non-skeletal fall injuries in older men and women with and without T2DM. We included 429,313 individuals (aged 80.8 ± 8.2 years [mean ± SD], 58% women) from the Swedish registry "Senior Alert" and linked the data to several nationwide registers. We identified 79,159 individuals with T2DM (45% with insulin [T2DM-I], 41% with oral antidiabetics [T2DM-O], and 14% with no antidiabetic treatment [T2DM-none]) and 343,603 individuals without diabetes. During a follow-up of approximately 670,000 person-years, we identified in total 36,132 fractures (15,572 hip fractures) and 20,019 non-skeletal fall injuries. In multivariable Cox regression models where the reference group was patients without diabetes and the outcome was hip fracture, T2DM-I was associated with increased risk (adjusted hazard ratio (HR) [95% CI] 1.24 [1.16-1.32]), T2DM-O with unaffected risk (1.03 [0.97-1.11]), and T2DM-none with reduced risk (0.88 [0.79-0.98]). Both the diagnosis of T2DM-I (1.22 [1.16-1.29]) and T2DM-O (1.12 [1.06-1.18]) but not T2DM-none (1.07 [0.98-1.16]) predicted non-skeletal fall injury. The same pattern was found regarding other fractures (any, upper arm, ankle, and major osteoporotic fracture) but not for wrist fracture. Subset analyses revealed that in men, the risk of hip fracture was only increased in those with T2DM-I, but in women, both the diagnosis of T2DM-O and T2DM-I were related to increased hip fracture risk. In conclusion, the risk of fractures differs substantially among patients with T2DM and an increased risk of hip fracture was primarily found in insulin-treated patients, whereas the risk of non-skeletal fall injury was consistently increased in T2DM with any diabetes medication. © 2016 American Society for Bone and Mineral Research.

Transglutaminase 4 as a prostate autoantigen in male subfertility.

Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.

Movement deviation and asymmetry assessment with three dimensional gait analysis of both upper- and lower extremity results in four different clinical relevant subgroups in unilateral cerebral palsy.

BACKGROUND: In unilateral cerebral palsy, movement pattern can be difficult to define and quantify. The aim was to assess the degree of deviation and asymmetry in upper and lower extremities during walking. METHODS: Forty-seven patients, 45 Gross Motor Function Classification Scale (GMFCS) I and 2 patients GMFCS II, mean age 17.1 years (range 13.1 to 24.0) and 15 matched controls were evaluated. Gait profile score (GPS) and arm posture score (APS) were calculated from three-dimensional gait analysis (GA). Asymmetry was the calculated difference in deviation between affected and unaffected sides. FINDINGS: The GPS was significantly increased compared to the control group on the affected side (6.93 (2.08) versus 4.23 (1.11) degrees) and on the unaffected side (6.67 (2.14)). The APS was also significantly increased on the affected side (10.39 (5.01) versus 5.52 (1.71) degrees) and on the unaffected side (7.13 (2.23)). The lower extremity asymmetry increased (significantly) in comparison with the control group (7.89 (3.82) versus 3.90 (1.01)) and correspondingly in the upper extremity (9.75 (4.62) versus 5.72 (1.84)). The GPS was not different between affected and unaffected sides, however the APS was different (statistically significant). INTERPRETATION: We calculated deviation and asymmetry of movement during walking in unilateral CP, identifying four important clinical groups: close to normal, deviations mainly in the leg, deviations mainly in the arm and those with deviation in the arm and leg. This method can be applied to any patient group, and aid in diagnosing, planning treatment, and prognosis.

Assessing chronic pelvic pain syndrome patients: blood plasma factors and cortisol saliva.

OBJECTIVE: The aim of this study was to identify changes in inflammatory molecules in the blood (plasma) of patients with chronic prostatitis/chronic pelvic syndrome (CP/CPPS) compared with controls. Altered levels indicate a systemic component by possible involvement of the prostate and/or the inner pelvic floor musculature. MATERIAL AND METHODS: In 32 patients with CP/CPPS and 37 controls, blood plasma levels of testosterone, macrophage migration inhibitory factor (MIF), tumour necrosis factor-α (TNF-α), TNF-ß, interleukin-2 (IL-2) and IL-1ß were measured by enzyme-linked immunosorbent assay. Cortisol in saliva samples was measured in the morning and late evening. All participants answered a questionnaire regarding their health profile. RESULTS: Significantly higher levels of MIF (p = 0.012) were detected in patients. The testosterone level was, contrary to other studies, little lower in patients (p = 0.014; age adjusted). When controls with health issues and patients with a parallel disease were excluded, the MIF and TNF-α levels were higher in the patients (p = 0.007, p = 0.016, respectively) than in controls, and the testosterone was slightly lower in patients (p = 0.047). CONCLUSIONS: The findings show an immune response extending to the circulatory system, in which MIF makes a significant contribution to CP/CPPS. This study also indicates TNF-α as a circulatory component when excluding subjects with concomitant diseases. Both MIF and TNF-α have previously been highlighted for other diseases related to chronic pain and here also for CP/CPPS. These results provide further insights into the immunological basis of CP/CPPS.

Pain associated with the chronic pelvic pain syndrome is strongly related to the ambient temperature.

OBJECTIVE: There are indications suggesting that the pain associated with the chronic pelvic pain syndrome (CPPS) may be related to cold. The purpose of the present study was to evaluate how the symptom intensity reported by the patient relates to the time of the year in a temperate climate, i.e. to the ambient temperature and to weather changes. MATERIAL AND METHODS: Thirty-one patients, mean age 51 years (range 35-66 years), with CPPS for 17 ± 10 years (3-42 years) were asked to complete a set of questionnaires including questions concerning how they experienced their symptom intensity during the different seasons using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire. RESULTS: The total NIH-CPSI score was 22.2 ± 8.2. There was a highly marked relationship between season and pain intensity as reported by the informants: it was experienced to be three times more intense during the winter months. All subjects reported that a temperature drop was associated with deterioration. CONCLUSION: The strong relationship between the ambient temperature, a drop in temperature and the pain experienced by men with CPPS confirms the association between cold and symptom intensity in the Scandinavian countries, where the seasonal temperature variation spans a long range and the winters are long. The cause of this relationship is still to be established. Muscular spasm/stiffness is a possibility that remains to be explored.

Arm posture score and arm movement during walking: a comprehensive assessment in spastic hemiplegic cerebral palsy.

Patients with hemiplegic cerebral palsy often have noticeably deviant arm posture and decreased arm movement. Here we develop a comprehensive assessment method for the upper extremity during walking. Arm posture score (APS), deviation of shoulder flexion/extension, shoulder abduction/adduction, elbow flexion/extension and wrist flexion/extension were calculated from three-dimensional gait analysis. The APS is the root mean square deviation from normal, similar to Baker's Gait Profile Score (GPS) [1]. The total range of motion (ROM) was defined as the difference between the maximum and minimum position in the gait cycle for each variable. The arm symmetry, arm posture index (API) was calculated by dividing the APS on the hemiplegic side by that on the non-involved side, and the range of motion index (ROMI) by dividing the ROM on the hemiplegic side by that on the non-involved side. Using the APS, two groups were defined. Group 1 had minor deviations, with an APS under 9.0 and a mean of 6.0 (95% CI 5.0-7.0). Group 2 had more pronounced deviations, with an APS over 9.0 and a mean of 13.1 (CI 10.8-15.5) (p=0.000). Total ROM was 60.6 in group 1 and 46.2 in group 2 (p=0.031). API was 0.89 in group 1 and 1.70 in group 2 (p<0.001). ROMI was 1.15 in group 1 and 0.69 in group 2 (p=0.003). APS describes the amount of deviation, ROM provides additional information on movement pattern and the indices the symmetry. These comprehensive objective and dynamic measurements of upper extremity abnormality can be useful in following natural progression, evaluating treatment and making prognoses in several categories of patients.

Vitamin D and prostate cancer: the role of membrane initiated signaling pathways in prostate cancer progression.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been demonstrated to mediate both genomic and non-genomic responses in prostate cancer (CaP) cells. Here, we give an overview of membrane initiated 1,25(OH)2D3 signaling in prostate cancer cell progression. The presence of PDIA3 was investigated and homologous modeling of the putative PDIA3 receptor complex was conducted. Furthermore, the cellular distribution of nVDR was analyzed. We could show that both nVDR and PDIA3 are expressed in the prostate cancer cell lines investigated. The homologous modeling of PDIA3 showed that the receptor complex exists in a trimer formation, which suggests for allosteric activity. Our findings support previous reports and suggest that 1,25(OH)2D3 is an important therapeutic agent in inhibiting prostate cancer progression. Furthermore, our data show that 1,25(OH)2D3 regulate prostate cell biology via multiple pathways and targeting specific pathways for 1,25(OH)2D3 might provide more effective therapies compared to the vitamin D therapies currently clinically tested.

A fold-recognition approach to loop modeling.

A novel approach is proposed for modeling loop regions in proteins. In this approach, a prerequisite sequence-structure alignment is examined for regions where the target sequence is not covered by the structural template. These regions, extended with a number of residues from adjacent stem regions, are submitted to fold recognition. The alignments produced by fold recognition are integrated into the initial alignment to create an alignment between the target sequence and several structures, where gaps in the main structural template are covered by local structural templates. This one-to-many (1:N) alignment is used to create a protein model by existing protein-modeling techniques. Several alternative approaches were evaluated using a set of ten proteins. One approach was selected and evaluated using another set of 31 proteins. The most promising result was for gap regions not located at the C-terminus or N-terminus of a protein, where the method produced an average RMSD 12% lower than the loop modeling provided with the program MODELLER. This improvement is shown to be statistically significant.

Structural and functional characterization of AtPTR3, a stress-induced peptide transporter of Arabidopsis.

A T-DNA tagged mutant line of Arabidopsis thaliana, produced with a promoter trap vector carrying a promoterless gus (uidA) as a reporter gene, showed GUS induction in response to mechanical wounding. Cloning of the chromosomal DNA flanking the T-DNA revealed that the insert had caused a knockout mutation in a PTR-type peptide transporter gene named At5g46050 in GenBank, here renamed AtPTR3. The gene and the deduced protein were characterized by molecular modelling and bioinformatics. Molecular modelling of the protein with fold recognition identified 12 transmembrane spanning regions and a large loop between the sixth and seventh helices. The structure of AtPTR3 resembled the other PTR-type transporters of plants and transporters in the major facilitator superfamily. Computer analysis of the AtPTR3 promoter suggested its expression in roots, leaves and seeds, complex hormonal regulation and induction by abiotic and biotic stresses. The computer-based hypotheses were tested experimentally by exposing the mutant plants to amino acids and several stress treatments. The AtPTR3 gene was induced by the amino acids histidine, leucine and phenylalanine in cotyledons and lower leaves, whereas a strong induction was obtained in the whole plant upon exposure to salt. Furthermore, the germination frequency of the mutant line was reduced on salt-containing media, suggesting that the AtPTR3 protein is involved in stress tolerance in seeds during germination.

Characterisation of a T-DNA-tagged gene of Arabidopsis thaliana that regulates gibberellin metabolism and flowering time.

A gene (At4g20010) involved in regulating flowering time in Arabidopsis thaliana (L.) Heynh. was identified by promoter trap T-DNA tagging. Plants containing a T-DNA insert in the 3'-UTR of At4g20010 flowered later under both long- and short-day conditions compared with control plants. Histochemical assays of the mutant plants showed that the promoterless gus gene is expressed predominantly in the shoot apex, but it is also expressed in root tips, stem nodes and in the abscission zone of developing siliques. Measurement of endogenous gibberellin (GA) showed that bioactive GA4 levels in mutant plants were reduced compared with wild type (WT) plants. Like other known mutants defective in GA biosynthesis, the late-flowering phenotype observed in our T-DNA-tagged line could be largely repressed by application of exogenous GA3. The T-DNA-tagged gene At4g20010 encodes a previously uncharacterised protein belonging to the DUF731 family. Sequence analysis showed similarity to a single-stranded binding domain and to an RNA-binding protein of Chlamydomonas reinhardtii. Considering the above results (sequence similarity, mutant phenotype and level of endogenous GA), we propose that At4g20010 is an RNA-binding protein involved in regulating GA biosynthesis, possibly at the post-transcriptional level.

Functional prediction of a T-DNA tagged gene of Arabidopsis thaliana by in silico analysis.

We have employed a gene-knockout approach using T-DNA tagging and in vivo gene fusion in Arabidopsis thaliana for identification and isolation of specific plant genes. Screening of about 3,000 T-DNA tagged lines resulted in identification of a mutant line (no. 197) exhibiting a significant delay in flowering. From this line a 600-bp plant DNA fragment downstream of the left T-DNA junction was cloned by inverse PCR. BLAST searching in the A. thaliana genomic database indicated a putative gene, frf (flowering regulating factor), with unknown function downstream of the T-DNA insert. Bioinformatic tools were used to predict possible protein structure and function. The protein structure predicted by fold recognition indicates that frf is a transcriptional regulator, a ligand-binding receptor responsive to steroids and hormones. Analyzing the predicted results and the phenotype of the T-DNA tagged plant we hypothesized that FRF might be involved in hormone response in A. thaliana. For verification of this hypothesis we exposed the plants of line no. 197 to gibberellic acid (GA3), a potential growth regulator in higher plants. This treatment resulted in an earlier onset of flowering, almost similar to that in wild type control plants.