Can Clinical and Surgical Parameters Be Combined to Predict How Long It Will Take a Tibia Fracture to Heal? A Prospective Multicentre Observational Study: The FRACTING Study

Background. Healing of tibia fractures occurs over a wide time range of months, with a number of risk factors contributing to prolonged healing. In this prospective, multicentre, observational study, we investigated the capability of FRACTING (tibia FRACTure prediction healING days) score, calculated soon after tibia fracture treatment, to predict healing time. Methods. The study included 363 patients. Information on patient health, fracture morphology, and surgical treatment adopted were combined to calculate the FRACTING score. Fractures were considered healed when the patient was able to fully weight-bear without pain. Results. 319 fractures (88%) healed within 12 months from treatment. Forty-four fractures healed after 12 months or underwent a second surgery. FRACTING score positively correlated with days to healing: r = 0.63 (p < 0.0001). Average score value was 7.3 \ub1 2.5; ROC analysis showed strong reliability of the score in separating patients healing before versus after 6 months: AUC = 0.823. Conclusions. This study shows that the FRACTING score can be employed both to predict months needed for fracture healing and to identify immediately after treatment patients at risk of prolonged healing. In patients with high score values, new pharmacological and nonpharmacological treatments to enhance osteogenesis could be tested selectively, which may finally result in reduced disability time and health cost savings

Low oxygen post conditioning as an efficient non-pharmacological strategy to promote motor function after stroke

Low oxygen post conditioning (LOPC) has shown promising results in terms of neuroprotection after stroke, but the effects on motor function have not been considered. Cortical stroke targeting the motor and sensory cortex was induced by photothrombotic occlusion and after 48\ua0h allocated to LOPC (11% O) for 2\ua0weeks. Motor impairment was assessed using the cylinder and grid walk tests during the exposure period and for two further weeks upon completion of the intervention. Neuroprotection was evaluated by histological and molecular analysis at two time points. Two weeks of LOPC was sufficient to significantly reduce motor deficits and tissue loss after stroke. This functional improvement was associated with increased capillary density, enhanced levels of BDNF, decreased neuronal loss and decreased microglia activation. These improvements, in most instances, were maintained up to 2\ua0weeks after the end of the treatment. To our knowledge, this is the first study to demonstrate that LOPC induces a persistent improvement in motor function and neuroprotection after stroke, and in doing so provides evidence to support a case for considering taking LOPC forward to early stage clinical research

Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1

The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development

Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus cal-losum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke

Cost of osteoporosis-related fracture in Italy. Results of the BLOCK study

The objectives of the present study were to calculate the cost of illness of osteoporosis and to assess drug utilization patterns in postmenopausal women after a fracture-related hospitalization. The study subjects were enrolled from a large population-based administrative database. Female patients (age ≥ 65 years) who were hospitalized for a typical osteoporotic fracture between 1/1/2000 and 31/12/2005 were included. Patients were classified as exposed/unexposed to treatment according to the presence/absence of at least one prescription for an osteoporosis-related medication in the 6 months following the discharge date. Treatment adherence was calculated for patients who were exposed to bisphosphonate therapy and was defined as at least 80% of treatment coverage during the follow-up period of 18 months after the discharge date. Hospitalizations, medications, diagnostic tests, laboratory tests and specialist visits during the 18-month follow-up period were collected and classified as osteoporosis-related or non-related to osteoporosis. A total of 12,376 patients were included in the study (mean age ± SD, 79.1 ± 7.5 years), out of which 97.9% (n = 12,110) were hospitalized due to an osteoporosis-related fracture and only 2.1% (n = 266) had general osteoporosis diagnosis. Among the 12,110 women with a fracture, 15.2% (n = 1,845) had a subsequent fracture-related hospitalization (63.8% of the patients had hip fracture). Only 32.3% (n = 4,001) of all included patients was exposed to osteoporosis-related medications and out of those patients exposed to bisphosphonates (n = 860) only 34.2% (n = 294) was adherent to therapy. The average cost per patient was € 4,481, of which € 1,089 was for osteoporosis-related and € 3,392 for non-osteoporosis-related items. The average cost of a matching cohort of patients without hospitalizations for fracture was € 2,339. Among osteoporosis-related costs, 87.0% was due to hospitalizations for subsequent fractures, 1.5% was due to subsquent hospitalizations for osteoporosis, 9.0% was due to medications, 2.5% was due to laboratory or diagnostic/ instrumental tests. Osteoporosis costs after a first hospitalization for fracture were relevant (twice the costs for patients without hospitalizations for fracture), evident in the short run (within the first 24 months following the index fracture) and mostly due to re-hospitalizations for a new typical osteoporotic fracture. This is in mainly relatedto a low exposure to pharmacological therapy and to insufficient treatment adherence. This study and publication were supported by Amgen Dompe and GlaxoSmithKline.

Cost of osteoporosis-related fracture in Italy. Results of the BLOCK study

The objectives of the present study were to calculate the cost of illness of osteoporosis and to assess drug utilization patterns in postmenopausal women after a fracture-related hospitalization. The study subjects were enrolled from a large population-based administrative database. Female patients (age ≥ 65 years) who were hospitalized for a typical osteoporotic fracture between 1/1/2000 and 31/12/2005 were included. Patients were classified as exposed/unexposed to treatment according to the presence/absence of at least one prescription for an osteoporosis-related medication in the 6 months following the discharge date. Treatment adherence was calculated for patients who were exposed to bisphosphonate therapy and was defined as at least 80% of treatment coverage during the follow-up period of 18 months after the discharge date. Hospitalizations, medications, diagnostic tests, laboratory tests and specialist visits during the 18-month follow-up period were collected and classified as osteoporosis-related or non-related to osteoporosis. A total of 12,376 patients were included in the study (mean age ± SD, 79.1 ± 7.5 years), out of which 97.9% (n = 12,110) were hospitalized due to an osteoporosis-related fracture and only 2.1% (n = 266) had general osteoporosis diagnosis. Among the 12,110 women with a fracture, 15.2% (n = 1,845) had a subsequent fracture-related hospitalization (63.8% of the patients had hip fracture). Only 32.3% (n = 4,001) of all included patients was exposed to osteoporosis-related medications and out of those patients exposed to bisphosphonates (n = 860) only 34.2% (n = 294) was adherent to therapy. The average cost per patient was € 4,481, of which € 1,089 was for osteoporosis-related and € 3,392 for non-osteoporosis-related items. The average cost of a matching cohort of patients without hospitalizations for fracture was € 2,339. Among osteoporosis-related costs, 87.0% was due to hospitalizations for subsequent fractures, 1.5% was due to subsquent hospitalizations for osteoporosis, 9.0% was due to medications, 2.5% was due to laboratory or diagnostic/ instrumental tests. Osteoporosis costs after a first hospitalization for fracture were relevant (twice the costs for patients without hospitalizations for fracture), evident in the short run (within the first 24 months following the index fracture) and mostly due to re-hospitalizations for a new typical osteoporotic fracture. This is in mainly relatedto a low exposure to pharmacological therapy and to insufficient treatment adherence. This study and publication were supported by Amgen Dompe and GlaxoSmithKline

VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology that are associated with an aberrant mucosal immune response. Neoangiogenesis and vascular injury are observed in IBD along with increased lymphangiogenesis. While the pathogenic role of angiogenesis in IBD is well characterized, it is not clear how or if increased lymphangiogenesis promotes disease. Here, we determined that enhancing lymphangiogenesis and lymphatic function reduces experimental IBD. Specifically, we demonstrated that adenoviral induction of prolymphangiogenic factor VEGF-C provides marked protection against the development of acute and chronic colitis in 2 different animal models. VEGF-C-dependent protection was observed in combination with increased inflammatory cell mobilization and bacterial antigen clearance from the inflamed colon to the draining lymph nodes. Moreover, we found that the VEGF-C/VEGFR3 pathway regulates macrophage (Mφ) plasticity and activation both in cultured Mφs and in vivo, imparting a hybrid M1-M2 phenotype. The protective function of VEGF-C was meditated by the so-called resolving Mφs during chronic experimental colitis in a STAT6-dependent manner. Together, these findings shed light on the contribution of lymphatics to the pathogenesis of gut inflammation and suggest that correction of defective lymphatic function with VEGF-C has potential as a therapeutic strategy for IBD

Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms

Cognitive impairment is a common and disruptive outcome for stroke survivors, which is recognized to be notoriously difficult to treat. Previously, we have shown that low oxygen post-conditioning (LOPC) improves motor function and limits secondary neuronal loss in the thalamus after experimental stroke. There is also emerging evidence that LOPC may improve cognitive function post-stroke. In the current study we aimed to explore how exposure to LOPC may improve cognition post-stroke. Experimental stroke was induced using photothrombotic occlusion in adult, male C57BL/6 mice. At 72 h post-stroke animals were randomly assigned to either normal atmospheric air or to one of two low oxygen (11% O2) exposure groups (either 8 or 24 h/day for 14 days). Cognition was assessed during the treatment phase using a touchscreen based paired-associate learning assessment. At the end of treatment (17 days post-stroke) mice were euthanized and tissue was collected for subsequent histology and biochemical analysis. LOPC (both 8 and 24 h) enhanced learning and memory in the 2nd week post-stroke when compared with stroke animals exposed to atmospheric air. Additionally we observed LOPC was associated with lower levels of neuronal loss, the restoration of several vascular deficits, as well as a reduction in the severity of the amyloid-beta (Aβ) burden. These findings provide further insight into the pro-cognitive benefits of LOPC