Fracture haematoma formation is the first and foremost important stage of fracture healing. It orchestrates the inflammatory and cellular processes leading to the formation of callus and the restoration of the continuity of the bone. Evidence suggests that blocking this initial stage could lead to an impairment of the overall bone healing process. This review aims to analyse the existing evidence of molecular contributions to bone healing within fracture haematoma and to determine the potential to modify the molecular response to fracture in the haematoma with the aim of improving union times. A comprehensive search of literature documenting fracture haematoma cytokine content was performed. Suitable papers according to prespecified criteria were identified and analysed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 89 manuscripts formed the basis of this analysis. Low oxygen tension, high acidity, and high calcium characterised initially the fracture haematoma micro-environment. In addition, a number of cytokines have been measured with concentrations significantly higher than those found in peripheral circulation. Growth factors have also been isolated, with an observed increase in bone morphogenetic proteins, platelet-derived growth factor, and transforming growth factor. Although molecular modification of fracture haematoma has been attempted, more research is required to determine a suitable biological response modifier leading to therapeutic effects. The cytokine content of fracture haematoma gives insight into processes occurring in the initial stages of fracture healing. Manipulation of signalling molecules represents a promising pathway to target future therapies aiming to upregulate the osteogenesis.

Background and ObjectiveEpidural corticosteroid injections (ESIs) have been used for several decades and now represent the most common intervention performed for the management of back pain with a radicular component. However, several reports have presented devastating complications and adverse effects, which fuelled concerns over the risk versus clinical effectiveness. The authors offer a comprehensive review of the available literature and analyse the data derived from studies and case reports.MethodsStudies were identified by searching PubMed MEDLINE, Ovid MEDLINE, EMBASE, Scopus, Google Scholar and the Cochrane Library to retrieve all available relevant articles. Publications from the last 20 years (September 1994 to September 2014) were considered for further analysis. Studies selected were English-language original articles publishing results on complications related to the technique used for cervical and lumbar ESIs. The studies had to specify the approach used for injection. All studies that did not fulfil these eligibility criteria were excluded from further analysis.ResultsOverall, the available literature supports the view that serious complications following injections of corticosteroid suspensions into the cervical and lumbar epidural space are uncommon, but if they occur they can be devastating.ConclusionsThe true incidence of such complications remains unclear. Direct vascular injury and/or administration of injectates intra-arterially represent a major concern and could account for the vast majority of the adverse events reported. Accurate placement of the needle, use of a non-particulate corticosteroid, live fluoroscopy, digital subtraction angiography, and familiarisation of the operator with contrast patterns on fluoroscopy should minimise these risks. The available literature has several limitations including incomplete documentation, unreported data and inherent bias. Large registries and well-structured observational studies are needed to determine the true incidence of adverse events and address the safety concerns.

SUMMARYThere is a controversy as to whether the increase in heart rate in response to stimulation of atrial receptors is mediated solely by the sympathetic or by both the sympathetic and vagal nerves to the heart. In dogs anaesthetized with chloralose the activity in vagal efferent nerve fibres from the cardiac branches of the right vagus nerve was recorded. The effects of distension of small balloons at the right pulmonary vein-atrial junctions on this activity was investigated. Distension of the small balloons caused an increase in heart rate in all dogs. Distension of the small balloons had no effect on vagal efferent fibres whether these were affected by carotid occlusion or not (seven dogs), or whether they were affected by changes in the pressure or nature of the blood perfusing the vascularly isolated carotid sinuses or not (nine dogs). It is concluded that the increase in heart rate seen in response to stimul,tion of left atrial receptors by distension of small balloons at the pulmonary vein-atrial junctions does not involve vagal efferent nerves.

The effect of distension of the urinary bladder on the activity in the efferent cardiac sympathetic nerves which responded to stimulation of atrial receptors or those which responded to stimulation of carotid baroreceptors or chemoreceptors, was studied in dogs anaesthetized with chloralose; the urinary bladder was distended with warm saline, small balloons were positioned at the right pulmonary vein-atrial junctions and distended with 1 cm3 saline, and the carotid sinuses were vascularly isolated and perfused with blood at constant flow. The efferent cardiac sympathetic nerve fibres which responded to stimulation of carotid baroreceptors and chemoreceptors by a decrease in activity always responded with an increase in activity in response to distension of the urinary bladder. In contrast, in those efferent cardiac sympathetic nerve fibres which did not respond to an increase in carotid sinus pressure, but responded to stimulation of atrial receptors by an increase in activity, distension of the urinary bladder neither caused a significant change in activity nor produced a reproducible pattern of response. It is concluded that the efferent cardiac sympathetic nerve fibres which respond to stimulation of atrial receptors are separate from those which respond to distension of the urinary bladder.

1 The pharmacokinetics of cilazapril and its active metabolite, cilazaprilat, were investigated in a three-part crossover study in 12 healthy male volunteers aged 19-38 years, excluding one subject who withdrew from the study. 2 Single 2.5 mg oral doses of cilazapril, and equivalent oral and intravenous doses of cilazaprilat were administered as aqueous solutions to the fasted subjects. There was an interval of 1 week between treatments. Concentrations of cilazapril and cilazaprilat in plasma and urine, and activities of angiotensin converting enzyme (ACE) in plasma were measured by radioenzymatic methods.3 After 10 min infusion of cilazaprilat, the mean plasma concentration was 194 ng ml-', and ACE inhibition was almost 100%. The decline in concentrations was polyphasic, with mean half-lives for the periods 1-4 h and 24-168 h of 0.90 h and 46 h, respectively. Between 4 and 24 h the decline was non-linear, and ACE inhibition decreased from 91% to 67%. Urinary recovery of cilazaprilat averaged 91% of dose. 4 After oral cilazapril, the parent drug was rapidly absorbed and rapidly eliminated, with a mean maximum plasma concentration of 82 ng ml-' at 0.83 h and a single elimination half-life of 1.3 h. Cilazaprilat peaked at 36 ng ml-' about 1.7 h after dosing and the decline in concentrations was biphasic, with half-lives of 1.8 h and 45 h. After oral cilazaprilat, plasma concentrations were considerably lower, and the peak later (2.2 h). 5 Urinary recovery data indicated an absolute bioavailability for cilazaprilat of 57% (range 45-75%) from oral cilazapril, but only 19% (range 8-40%) from oral cilazaprilat.6 The plasma data for cilazaprilat suggest that the first phase of the kinetics after oral cilazapril is controlled by the rate of hydrolysis of the parent drug, whereas the terminal phase is controlled by tight binding to ACE. Clearance of cilazaprilat is almost exclusively renal.

SUMMARY1. Urinary responses to stimulation of atrial receptors have been found to be greater in dogs with a high blood volume than in dogs with a low blood volume. Two groups of dogs with different blood volume were examined by distending a large balloon in the left atrium, to stimulate atrial receptors and find out whether the increase in atrial receptor discharge was different in the two groups of dogs.2. The relationship between atrial receptor discharge and left atrial pressure was determined in twenty-six fibres studied in four dogs with a high blood volume and sixteen fibres studied in three dogs with a low blood volume.3. The slope of the relationship representing the increase in atrial receptor activity during increases in left atrial pressure, and the activity at each left atrial pressure, were significantly greater in dogs with a high blood volume than in dogs with a low blood volume.4. This study has shown that the atrial receptor discharge and their responses to increases in left atrial pressure are greater in dogs with a high blood volume than in those with a low blood volume.

Fracture haematoma forms immediately after fracture and is considered essential for the bone healing process. Its molecular composition has been briefly investigated with our current understanding being based on animal studies. This study aims to analyse the inflammatory cytokine content of fracture haematoma in humans and determine its effect on osteoprogenitor cells. Twenty-three patients were recruited following informed consent. Peripheral blood, fracture haematoma and bone were collected. A Luminex assay on the levels of 34 cytokines was performed and autologous peripheral blood samples served as control. Mesenchymal Stem Cells (MSCs) were isolated following collagenase digestion and functional assays were performed. Gene expression analysis of 84 key osteogenic molecules was performed. Thirty-three inflammatory cytokines were found to be significantly raised in fracture haematoma when compared to peripheral serum (p < 0.05). Amongst the most raised molecules were IL-8, IL-11 and MMP1, -2 and -3. Fracture haematoma did not significantly affect MSC proliferation, but ALP activity and calcium deposition were significantly increased in the MSCs undergoing osteogenic differentiation. Medium supplementations with fracture haematoma resulted in a statistically significant upregulation of osteogenic genes including the EGF, FGF2 and VEGFA. This seems to be the pathway involved in the osteogenic effect of fracture haematoma on bone cells. In conclusion, fracture haematoma is found to be a medium rich in inflammatory and immunomodulatory mediators. At the same time, it contains high levels of anti-inflammatory molecules, regulates osteoclastogenesis, induces angiogenesis and the production of the extracellular matrix. It appears that fracture haematoma does not affect osteoprogenitor cells proliferation as previously thought, but induces an osteogenic phenotype.

SUMMARYIn dogs anaesthetized with chloralose, the effect of distension of the urinary bladder on the activity in efferent vagal nerves was studied; the urinary bladder was distended with warm saline, and the carotid sinuses were vascularly isolated and perfused with blood at constant flow. In one group of efferent vagal nerve fibres distension of the bladder always caused a decrease in activity. These fibres also responded to stimulation of receptors in the carotid region by an increase in activity and to stimulation of superficial branches of the left radial nerve by a decrease in activity. Another group of vagal nerve fibres which did not respond to stimulation of receptors in the carotid region, also did not respond to distension of the urinary bladder. It is concluded that distension of the urinary bladder results in the response of a decrease in activity in efferent cardiac vagal nerve fibres, onto which converge the effects of stimulating receptors in the carotid region and the somatic nerves.