Surgery with locking plate or hemiarthroplasty versus nonoperative treatment of 3-4-part proximal humerus fractures in older patients (NITEP): An open-label randomized trial.

BACKGROUND: Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking. METHODS AND FINDINGS: The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up. Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group. The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [-9.5,11.7]; p = 0.97) between nonoperative and LP, 3.78 points (95% CI [-7.0,14.6]; p = 0.69) between nonoperative and HA, and 4.84 points (95% CI [-5.7,15.4]; p = 0.53) between LP and HA. No significant differences in primary or secondary outcomes were seen in stratified age groups (60 to 70 years and 71 years and over). At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, p = 0.0004) and 16 severe pain-related adverse events. There was a revision rate of 22% in the LP group. The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely. CONCLUSIONS: In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.

Increasing incidence of surgically treated hamstring injuries: a nationwide registry study in Sweden between 2001 and 2020.

BACKGROUND AND PURPOSE: Data on incidence and on trends in treatment of hamstring injuries, including proximal hamstring tendon avulsions (PHA), is limited. We aimed to investigate the incidence, trends in operative treatment, age, and sex distribution of hamstring injuries in Sweden between 2001 and 2020. PATIENTS AND METHODS: We obtained data recorded in the National Patient Register between 2001 and 2020 on patients between 18 and 90 years of age, with the ICD-10 code S76.3, to calculate the incidence of patients treated operatively for hamstring injuries in Sweden. Patients with the NOMESCO classification NFL49 were considered as having been treated operatively. Data on quadriceps and Achilles tendon injuries were obtained for comparison. To calculate incidences, adult population data for every year were obtained from the Statistics Sweden website. RESULTS: The incidence of patients diagnosed with hamstring injuries increased from 2.2 to 7.3 per 100,000 person-years. There was a rising trend of surgical treatment per diagnosed case from 3.0% to 14.2%. Patients diagnosed in units with the highest experience of surgical treatment of hamstring injuries tended to be operated on more often (22.2%) than patients diagnosed in units with limited experience (5.1%), although the fraction of operated patients was increasing in both groups. CONCLUSION: Between 2001 and 2020 there was an increase in the proportion of operatively treated hamstring injuries.

Operative versus non-operative treatment for 2-part proximal humerus fracture: A multicenter randomized controlled trial.

BACKGROUND: Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures. METHODS AND FINDINGS: The NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant-Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group's 5-dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI -7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded. CONCLUSIONS: This trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.

Similar outcome of femoral neck fractures treated with Pinloc or Hansson Pins: 1-year data from a multicenter randomized clinical study on 439 patients.

Background and purpose - There are few reports on the efficiency of the Hansson Pinloc System (Pinloc) for fixation of femoral neck fractures. We compare Pinloc with the commonly used Hansson Pin System in a randomized clinical trial. The primary outcome measure is non-union or avascular necrosis within 2 years. We now report fracture failures and reoperations within the first year.Patients and methods - Between May 2014 and February 2017, 439 patients were included in the study. They were above 50 years of age and treated for a femoral neck fracture at 9 orthopedic departments in Sweden. They were randomized to either Pinloc or Hansson pins. The fractures were grouped as (a) non-displaced regardless of age, (b) displaced in patients < 70 years, or (c) ≥ 70 years old, but deemed unfit to undergo arthroplasty. Follow-up with radiographs and outpatient visits were at 3 and 12 months. Failure was defined as early displacement/non-union, symptomatic segmental collapse, or deep infection.Results - 1-year mortality was 11%. Of the 325 undisplaced fractures, 12% (21/169) Pinloc and 13% (20/156) Hansson pin patients had a failure during the first year. The reoperation frequencies were 10% (16/169) and 8% (13/156) respectively. For the 75 patients 50-69 years old with displaced fractures, 11/39 failures occurred in the Pinloc group and 11/36 in the Hansson group, and 8/39 versus 9/36 patients were reoperated. Among those 39 patients ≥ 70 years old, 7/21 failures occurred in the Pinloc group and 4/18 in the Hansson group. Reoperation frequencies were 4/21 for Pinloc and 3/18 for the Hansson pin patients. No statistically significant differences were found in any of the outcomes between the Pinloc and Hansson groups.Interpretation - We found no advantages with Pinloc regarding failure or reoperation frequencies in this 1-year follow-up.

Genetic regulation of bone metabolism in the chicken: similarities and differences to Mammalian systems.

Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL) and expression QTL (eQTL) mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken) and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone.

A sexual ornament in chickens is affected by pleiotropic alleles at HAO1 and BMP2, selected during domestication.

Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations.

Adamts1 is highly induced in rachitic bones of FGF23 transgenic mice and participates in degradation of non-mineralized bone matrix collagen.

Transgenic mice overexpressing fibroblast growth factor 23 (FGF23) in osteoblasts have a rachitic bone phenotype. These mice display hypomineralized bones, increased expression of osteoblast markers, but osteoclast numbers are unaltered or slightly reduced. Paradoxically, they show increased serum levels of the bone resorption marker CTX, a type I collagen degradation fragment. Here we analyzed a matrix metalloproteinase- (MMP-) like secreted protease, Adamts1, that has previously been associated with osteoblastic type I collagen breakdown in vitro. Bones from FGF23 transgenic (tg) mice displayed increased Adamts1 protein upon both immunohistological staining and Western blotting. We further found Adamts1 protein together with excessively degraded type I collagen in the non-mineralized bone fraction of FGF23 tg mice. A similar degradation pattern of type I collagen was noticed upon forced expression of Adamts1 in osteoblastic cells in vitro. Importantly, these Adamts1-expressing osteoblastic cells exhibited increased release of CTX fragments when cultured on demineralized bone discs. Together, these results demonstrate for the first time that Adamts1 can be highly induced in bone tissue and that this MMP-like protease can increase osteoblastic release of CTX fragments from non-mineralized bone. Thus, Adamts1 potentially contributes to the increased serum levels of CTX in rickets/osteomalacia.

Pinloc or Hansson pins: a multicenter, randomized controlled study of 439 patients treated for femoral neck fractures.

Objectives: To compare the recently developed Hansson Pinloc system, which features 3 cylindrical parallel pins with hooks connected through a fixed-angle interlocking plate, with the Hansson Pin System (2 hook pins) for the treatment of femoral neck fractures. Design: One hundred fourteen patients with displaced femoral neck fractures and 325 patients with nondisplaced fractures from 9 orthopaedic centers were randomized to either Hansson Pinloc system or Hansson Pin System and followed for 2 years or until death. Age at inclusion was 50 years or older. Main Outcome Measurements: The primary outcome was failure (defined as early displacement, nonunion, symptomatic avascular necrosis, or deep infection). Secondary outcomes included revision surgery, Timed Up and Go (TUG) test and patient-reported outcome measures (PROMs: EQ-5D and WOMAC). Results: For nondisplaced fractures, the incidence of failure was 14% (23/169) in the Pinloc group and 16% (25/156) in the Hansson group. For displaced fractures, the analysis was stratified by age. Patients aged 50-69 years with displaced fractures showed a 2-year failure rate of 44% (17/39) in the Pinloc group versus 44% (16/36) in the Hansson group. For patients 70 years or older with displaced fractures, 33% (7/21) in the Pinloc group versus 22% (4/18) in the Hansson group failed. At 3 and 12 months, no clinically significant differences between treatment groups were found for EQ-5D-3L, WOMAC, or for the TUG in any fracture type or age group. Conclusions: There were no advantages for Pinloc in any of the studies aspects. Level of evidence: 1.

At mid- to long-term follow-up after proximal hamstring tendon avulsion; there was greater fatty infiltration, muscle atrophy and strength deficit in the hamstring muscles of the injured leg than in the uninjured leg.

BACKGROUND: Proximal hamstring tendon avulsions (PHAs) may be treated nonoperatively or operatively. Little is known about the result of the injury, and its treatment, on the quality and function of the hamstring muscle after healing and rehabilitation. We hypothesized that the injured leg would have greater fatty infiltration and atrophy than the uninjured leg at follow-up and that these findings would correlate to muscle weakness. METHODS: In a cross-sectional cohort study, 48 patients treated for PHA, either operatively or nonoperatively, were re-examined 2-11 years post-treatment. We measured muscle strength with isokinetic strength tests, and muscle volume and fatty infiltration with MRI. Primary outcomes were hamstring muscle quality, quantified by outlining the cross-sectional area slice-by-slice, and the degree of fatty infiltration estimated using the Goutallier grading method. Secondary outcome was concentric isokinetic hamstring muscle strength measured using BioDex at 60°/sec and tendon attachment assessed on MRI. Comparisons with the outcomes of the uninjured leg were made. RESULTS: The total hamstring muscle volume was on average reduced by 9% (SD ± 11%, p < 0.001) compared to that of the uninjured leg. Fatty infiltration was significantly more severe in the injured hamstrings than in the uninjured hamstrings (p < 0.001). This was also true when only analyzing operatively treated patients. The reduction in muscle volume and increase in fatty infiltration correlated significantly (r = 0.357, p = 0.013), and there was also a statistically significant correlation with muscle atrophy and reduction in isokinetic strength (r = 494, p < 0.001). CONCLUSION: PHA injuries result in fatty infiltration and muscle atrophy and the muscle quality impairment correlates with residual muscle weakness.

Over-expression of Adamts1 in mice alters bone mineral density.

ADAMTS1, a secreted multifunctional metalloproteinase with disintegrin and thrombospondin motifs, is an early response gene of parathyroid hormone (PTH) in osteoblasts. Mice engineered to lack Adamts1 are smaller compared to wild-type (WT) mice and ADAMTS1 metalloproteinase activity has been shown to increase osteoblastic growth in collagen gels. However, there are no reports investigating the consequence of Adamts1 over-expression on bone tissue in vivo. Here, we analyze bones of female and male transgenic (TG) mice over-expressing mouse Adamts1 using peripheral quantitative computed tomography to evaluate its effect on bone shape and mineral density. Western blotting of protein extracts and immunohistochemistry of bone sections reveal increased presence of Adamts1 protein in TG bones compared to WT bones. Phenotypic analyses of femur show that female TG mice have reduced metaphyseal total density, trabecular bone mineral density and trabecular mineral content. In contrast, male TG mice which were without changes in the metaphysis showed increased total density and cortical density at the mid-diaphysis cortical site. Female TG mice showed no significant changes at the cortical site compared to WT mice. Furthermore, diaphyseal endosteal compartment was only affected in male TG mice. Along these lines, Adamts1 increased blood levels of PTH only in females whereas it reduced osteocalcin levels only in males. These results reveal that Adamts1 has an impact on bone mineral density and thus further confirm Adamts1 as a potent regulator of bone remodeling.

Proximal Hamstring Tendon Avulsions: A Survey of Orthopaedic Surgeons' Current Practices in the Nordic Countries.

BACKGROUND AND PURPOSE: Evidence guiding the decision on whether to treat proximal hamstring tendon avulsions (PHA) operatively or non-operatively is very limited. The aim of this study was to identify the current practices and the rationale behind PHA treatment decisions in the Nordic countries. METHODS: A survey was sent to orthopaedic surgeons in Sweden, Norway, Finland and Denmark. The study population consisted of responding surgeons with exposure to surgical treatment of PHA (n = 125). The questions covered surgeon and unit characteristics, and surgeons' understanding of the evidence for treatment, and they explored which patient and injury factors influence treatment allocation. RESULTS: Although some surgeons indicated a preference for one of the treatments, 84% stated that the treatment decision was based on patient and injury-related factors. Severe obesity, drug abuse, a sedentary lifestyle, age > 60 years and delayed diagnosis (> 6 weeks) were considered contraindications to surgical treatment. Also, there was agreement that patients expressing a preference for non-operative treatment should not be operated. Complete avulsions with tendon dislocation ≥ 2-3 cm on MRI were relative indications for surgical treatment. The majority of surgeons did not believe that operatively treated patients did better than non-operatively treated patients and experienced that patients, generally, were satisfied with the treatment result, regardless of the type of treatment. Most surgeons had experienced significant complications to operative treatment. CONCLUSION: Current practices varied among different units, and despite the lack of evidence for their prognostic value, several factors were inconsistently being used as decision modifiers when selecting patients for surgical treatment.

Exploring the Perth Hamstring Assessment Tool and Lower Extremity Functional Scale in a Proximal Hamstring Avulsion Cohort: A Cross-sectional Study.

BACKGROUND: The goal of treatment for a proximal hamstring avulsion (PHA) is an objectively restored muscle and a subjectively satisfied, pain-free patient at follow-up. Different self-reported and performance-based outcome measures have been used to evaluate recovery, but their validity is poorly investigated. PURPOSE: To investigate (1) the correlation between the commonly used self-reported outcome measurements, the Perth Hamstring Assessment Tool (PHAT) and the Lower Extremity Functional Scale (LEFS); (2) to what extent these scores can be explained by physical dysfunction as measured by performance-based tests; (3) whether performance-based tests can discriminate between the injured and uninjured extremity; and (4) which activity limitations are perceived by patients several years after the injury. STUDY DESIGN: Cohort study (Diagnosis); Level of evidence, 3. METHODS: We included a consecutive series of patients treated for or diagnosed with PHA in our department between 2007 and 2016 having at least 2 tendons avulsed from the ischial tuberosity. Participants attended 2 study visits, answered questionnaires (PHAT, LEFS, and Patient-Specific Functional Scale [PSFS]), and performed physical performance-based tests (single-leg hop tests, single-step down test, and isometric and isokinetic strength tests). RESULTS: A total of 50 patients were included (26 men [52%], 24 women [48%]; mean age, 50.9 years [SD, 9.8 years]). The mean follow-up time was 5.5 years (SD, 2.7 years), and 74% had been surgically treated. The correlation between PHAT and LEFS was strong (r = 0.832) and statistically significant (P < .001). Seven of the performance-based tests exhibited a statistically significant but weak correlation with LEFS (0.340-0.488) and 3 of the tests to PHAT (-0.304 to 0.406). However, only peak torque could significantly discriminate between the extremities. The activity limitation most commonly mentioned in PSFS was running (16 patients [32%]). CONCLUSION: Although PHAT and LEFS correlated strongly, the correlations between functional tests and the patient-reported outcome scores were weak, and most functional tests failed to discriminate between the injured and uninjured lower extremity in patients with PHA 5 years after injury. In general, patients alleged few activity limitations, but running difficulty was a common sequela after PHA.

Osteoclast polarization is not required for degradation of bone matrix in rachitic FGF23 transgenic mice.

Hypophosphatemic transgenic (tg) mice overexpressing FGF23 in osteoblasts display disorganized growth plates and reduced bone mineral density characteristic of rickets/osteomalacia. These FGF23 tg mice were used as an in vivo model to examine the relation between osteoclast polarization, secretion of proteolytic enzymes and resorptive activity. Tg mice had increased mRNA expression levels of the osteoblast differentiation marker Runx2 and mineralization-promoting proteins alkaline phosphatase and bone sialoprotein in the long bones compared to wild type (wt) mice. In contrast, expression of alpha1(I) collagen, osteocalcin, dentin matrix protein 1 and osteopontin was unchanged, indicating selective activation of osteoblasts promoting mineralization. The number of osteoclasts was unchanged in tg compared to wt mice, as determined by histomorphometry, serum levels of TRAP 5b activity as well as mRNA expression levels of TRAP and cathepsin K. However, tg mice displayed elevated serum concentrations of C-terminal telopeptide of collagen I (CTX) indicative of increased bone matrix degradation. The majority of osteoclasts in FGF23 tg mice lacked ultrastructural morphological signs of proper polarization. However, they secreted both cathepsin K and MMP-9 at levels comparable to osteoclasts with ruffled borders. Mineralization of bone matrix thus appears essential for inducing osteoclast polarization but not for secretion of osteoclast proteases. Finally, release of CTX by freshly isolated osteoclasts was increased on demineralized compared to mineralized bovine bone slices, indicating that the mineral component limits collagen degradation. We conclude that ruffled borders are implicated in acidification and subsequent demineralization of the bone matrix, however not required for matrix degradation. The data collectively provide evidence that osteoclasts, despite absence of ruffled borders, effectively participate in the degradation of hypomineralized bone matrix in rachitic FGF23 tg mice.

Gene expression analysis of kidneys from transgenic mice expressing fibroblast growth factor-23.

BACKGROUND: Fibroblast growth factor-23 (FGF23), a circulating protein produced in bone, causes decreased renal inorganic phosphate (Pi) reabsorption by reducing the expression of the sodium phosphate cotransporter type 2a (Npt2a). We have previously generated transgenic mice expressing human wild-type (WT) FGF23 under the control of the alpha1 (I) collagen promoter. METHODS: In this study, we performed a large-scale gene expression study of kidneys from FGF23 transgenic mice and WT littermates. Microarray expression data of key transcripts were verified by real-time RT-PCR analysis. RESULTS: Several genes that play a role in Pi regulation revealed decreased expression levels in the transgenic mice, such as Npt2a and Pdzk1, a scaffolding protein known to interact with Npt2a. Importantly, Klotho, a suggested FGF23 receptor cofactor, was the most significantly decreased transcript and alpha2-Na(+)/K(+)-ATPase (Atp1a2), a gene isoform of alpha1-Na(+)/K(+)-ATPase (Atp1a1) which has recently been shown to interact with Klotho and regulate calcium metabolism, was the most increased transcript. In contrast, other genes proposed to regulate Pi levels, such as secreted frizzled-related protein-4 (sFrp4) and Na(+)/H(+) exchanger regulatory factor-1 (Nherf1) revealed no changes. CONCLUSIONS: FGF23 transgenic mice display differentially expressed transcript levels of several genes essential in renal Pi regulation. These findings may lead to further understanding of how FGF23 mediates its actions on renal Pi regulation.

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

BACKGROUND: Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. METHODS: Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. RESULTS: Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. CONCLUSIONS: FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.

Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells.

Fibroblast growth factor-23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate (Pi) as well as 1,25-dihydroxyvitamin D(3). Recent studies also suggest a correlation between serum levels of FGF23 and parathyroid hormone (PTH) in patients with chronic kidney disease. It is, however, unknown whether FGF23 directly modulates PTH expression, or whether the correlation is secondary to abnormalities in Pi and vitamin D metabolism. The objective of the current study was therefore to elucidate possible direct effects of FGF23 on bovine parathyroid cells in vitro. Treatment of parathyroid cells with a stabilized form of recombinant FGF23 (FGF23(R176Q)) induced a rise in early response gene-1 mRNA transcripts, a marker of FGF23 signaling. FGF23(R176Q) potently and dose-dependently decreased the PTH mRNA level within 12 h. In agreement, FGF23(R176Q) also decreased PTH secretion into conditioned media. In contrast, FGF23(R176Q) dose-dependently increased 1alpha-hydroxylase expression within 3 h. FGF23 (R176Q) did not affect cell viability nor induce apoptosis, whereas a small but significant increase in cell proliferation was found. We conclude that FGF23 is a negative regulator of PTH mRNA expression and secretion in vitro. Our data suggest that FGF23 may be a physiologically relevant regulator of PTH. This defines a novel function of FGF23 in addition to the previously established roles in controlling vitamin D and Pi metabolism.

Cranberry juice concentrate does not significantly decrease the incidence of acquired bacteriuria in female hip fracture patients receiving urine catheter: a double-blind randomized trial.

BACKGROUND: Urinary tract infection (UTI) is a common complication among patients with hip fractures. Receiving an indwelling urinary catheter is a risk factor for developing UTIs. Treatment of symptomatic UTIs with antibiotics is expensive and can result in the development of antimicrobial resistance. Cranberries are thought to prevent UTI. There is no previous research on this potential effect in patients with hip fracture who receive urinary catheters. AIM: The aim of this study is to investigate whether intake of cranberry juice concentrate pre-operatively decreases the incidence of postoperative UTIs in hip fracture patients that received a urinary catheter. DESIGN: This study employed a randomized, placebo-controlled double-blind trial. METHOD: Female patients, aged 60 years and older, with hip fracture (n=227) were randomized to receive cranberry or placebo capsules daily, from admission, until 5 days postoperatively. Urine cultures were obtained at admission, 5 and 14 days postoperatively. In addition, Euro Qual five Dimensions assessments were performed and patients were screened for UTI symptoms. RESULT: In the intention-to-treat analysis, there was no difference between the groups in the proportion of patients with hospital-acquired postoperative positive urine cultures at any time point. When limiting the analysis to patients that ingested at least 80% of the prescribed capsules, 13 of 33 (39%) in the placebo group and 13 of 47 (28%) in the cranberry group (P=0.270) had a positive urine culture at 5 days postoperatively. However, this difference was not statistically significant (P=0.270). CONCLUSION: Cranberry concentrate does not seem to effectively prevent UTIs in female patients with hip fracture and indwelling urinary catheter.

Do Orthogeriatric Inpatients Have a Correct Medication List? A Pharmacist-Led Assessment of 254 Patients in a Swedish University Hospital.

INTRODUCTION: Comorbidities and polypharmacy complicate the treatment of geriatric patients with acute orthopedic injuries. A correct medication history and an updated medication list are a prerequisite for safe treatment of these debilitated patients. Published evidence suggests favorable outcomes with comanaged care. The aim of this study was to assess the accuracy of the inpatient medication lists generated at admission and investigate the efficacy of a dedicated ward-based pharmacist to find and correct mistakes in these lists. METHODS: A total of 254 patients were enrolled. The ward-based pharmacist performed the assessment regarding the accuracy of the medication list generated at admission by the method of medication reconciliation. Number of discrepancies and types of discrepancy were noted. RESULTS: The 254 patients (176 women) had a mean age of 85 years (standard deviation 7.4 years, range 42-100 years). The most common reason for orthopedic admission was hip fracture. The mean number of discrepancies was 2.1 for all patients (range 0-13). Omission of a prescribed drug was the most common mistake. Fifty-six (22%) of the 254 assessed patients had a correct medication list. DISCUSSION: The many discrepancies in our study may have several explanations but highlight the difficulties in taking a correct medication history of patients in a stressful environment with an extremely high workload. Moreover, electronic medication lists create challenges. Implementing new electronic tools for health care requires feedback, redesign, and adaptation to meet various needs of the users. CONCLUSION: In conclusion, orthogeriatric patients have an unsatisfactory high number of discrepancies in their medication lists. Clinical pharmacists can accurately identify many of these mistakes.

Increased Bone Mass in Female Mice Lacking Mast Cell Chymase.

Here we addressed the potential impact of chymase, a mast-cell restricted protease, on mouse bone phenotype. We show that female mice lacking the chymase Mcpt4 acquired a persistent expansion of diaphyseal bone in comparison with wild type controls, reaching a 15% larger diaphyseal cross sectional area at 12 months of age. Mcpt4-/- mice also showed increased levels of a bone anabolic serum marker and higher periosteal bone formation rate. However, they were not protected from experimental osteoporosis, suggesting that chymase regulates normal bone homeostasis rather than the course of osteoporosis. Further, the absence of Mcpt4 resulted in age-dependent upregulation of numerous genes important for bone formation but no effects on osteoclast activity. In spite of the latter, Mcpt4-/- bones had increased cortical porosity and reduced endocortical mineralization. Mast cells were found periosteally and, notably, bone-proximal mast cells in Mcpt4-/- mice were degranulated to a larger extent than in wild type mice. Hence, chymase regulates degranulation of bone mast cells, which could affect the release of mast cell-derived factors influencing bone remodelling. Together, these findings reveal a functional impact of mast cell chymase on bone. Further studies exploring the possibility of using chymase inhibitors as a strategy to increase bone volume may be warranted.

Quantitative Trait Locus and Genetical Genomics Analysis Identifies Putatively Causal Genes for Fecundity and Brooding in the Chicken.

Life history traits such as fecundity are important to evolution because they make up components of lifetime fitness. Due to their polygenic architectures, such traits are difficult to investigate with genetic mapping. Therefore, little is known about their molecular basis. One possible way toward finding the underlying genes is to map intermediary molecular phenotypes, such as gene expression traits. We set out to map candidate quantitative trait genes for egg fecundity in the chicken by combining quantitative trait locus mapping in an advanced intercross of wild by domestic chickens with expression quantitative trait locus mapping in the same birds. We measured individual egg fecundity in 232 intercross chickens in two consecutive trials, the second one aimed at measuring brooding. We found 12 loci for different aspects of egg fecundity. We then combined the genomic confidence intervals of these loci with expression quantitative trait loci from bone and hypothalamus in the same intercross. Overlaps between egg loci and expression loci, and trait-gene expression correlations identify 29 candidates from bone and five from hypothalamus. The candidate quantitative trait genes include fibroblast growth factor 1, and mitochondrial ribosomal proteins L42 and L32. In summary, we found putative quantitative trait genes for egg traits in the chicken that may have been affected by regulatory variants under chicken domestication. These represent, to the best of our knowledge, some of the first candidate genes identified by genome-wide mapping for life history traits in an avian species.