Serum OPG/TRAIL ratio predicts the presence of cardiovascular disease in people with type 2 diabetes mellitus.

AIMS: Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Epidemiological studies suggest serum Osteoprotegrin (OPG)/Tumour-necrosis-factor-related-apoptosis-inducing- ligand (TRAIL) ratio may be a useful marker of cardiovascular risk. This study aimed to compare serum levels of TRAIL, OPG and OPG/TRAIL ratio in people with T2DM, with and without a history of CVD, and controls; and to determine which of these indices, if any, predict cardiovascular risk. METHODS: In this single centre observational study of 133 participants, people with T2DM, with and without a history of a cardiovascular event in the last 5 years, were recruited along with a control cohort without T2DM or CVD. Demographic information and anthropometric measurements were recorded. Blood samples were taken and OPG and TRAIL were measured using ELISA. RESULTS: People with T2DM and CVD had higher OPG/TRAIL ratios compared to controls or those with a new diagnosis of T2DM. After adjustment for potential confounding factors, OPG/TRAIL ratio was significantly associated with the presence of CVD in people with T2DM and an OPG/TRAIL ratio cut-off > 38.6 predicted the presence of CVD in this cohort with a sensitivity of 80% and specificity of 82%. CONCLUSION: This study suggests that OPG/TRAIL ratio may have a role as a biomarker of CVD in people with T2DM.

The incidence of deep vein thrombosis and pulmonary embolism following cast immobilisation and early functional bracing of Tendo Achilles rupture without thromboprophylaxis.

PURPOSE: The routine use of thromboprophylaxis during cast immobilisation for lower leg trauma is controversial. The concern involves the perceived increased risk of deep vein thrombosis (DVT) and its sequelae following leg immobilisation. However, immobilisation is used for a spectrum of trauma and for varying duration. This heterogenicity in management is reflected in the current evidence and coupled with the risks of thromboprophylaxis; no clear consensus has been made. METHODS: In this retrospective study, we report the incidence of DVT and pulmonary embolism (PE) observed following cast immobilisation and early functional management of patients with Tendo Achilles rupture. Over 12 years, 945 consecutive patients (949 tendons) were treated without additional thromboprophylaxis. RESULTS: The incidence of DVT was 1.05 % and PE was 0.32 %. Females were significantly more likely to develop a DVT but not a PE. When compared to the incidence of DVT and PE observed in the general population, DVT rate was statistically significantly higher than that observed in the general population. There was no significant difference in PE rates. The number needed to treat to reduce the DVT incidence is 106. The number needed to treat to reduce the PE incidence is 475. CONCLUSIONS: Although we can conclude that conservative treatment for Tendo Achilles does increase the incidence of symptomatic DVT from the general population, we feel that large randomised control trials are required to evaluate the efficacy, compliance and cost effectiveness of routine DVT thromboprophylaxis in the outpatient setting.

Blowback: new formal perspectives on agriculturally driven pathogen evolution and spread.

By their diversity in time, space, and mode, traditional and conservation agricultures can create barriers limiting pathogen evolution and spread analogous to a sterilizing temperature. Large-scale monocropping and confined animal feeding-lot operations remove such barriers, resulting, above agroecologically specific thresholds, in the development and wide propagation of novel disease strains. We apply a newly developed class of necessary-conditions statistical models of evolutionary process, first using the theory on an evolutionarily stable viral pathogen vulnerable to vaccine treatment: post-World War II poliomyelitis emerged in the UK and USA from sudden widespread adoption of automobile ownership and usage. We then examine an evolutionarily variable pathogen, swine influenza in North America. The model suggests epidemiological blowback from globalizing intensive husbandry and the raising and shipping of monoculture livestock across increasing expanses, is likely to be far more consequential, driving viral selection for greater virulence and lowered response to biomedical intervention.

The non-operative functional management of patients with a rupture of the tendo Achillis leads to low rates of re-rupture.

Controversy surrounds the most appropriate treatment method for patients with a rupture of the tendo Achillis. The aim of this study was to assess the long term rate of re-rupture following management with a non-operative functional protocol. We report the outcome of 945 consecutive patients (949 tendons) diagnosed with a rupture of the tendo Achillis managed between 1996 and 2008. There were 255 female and 690 male patients with a mean age of 48.97 years (12 to 86). Delayed presentation was defined as establishing the diagnosis and commencing treatment more than two weeks after injury. The overall rate of re-rupture was 2.8% (27 re-ruptures), with a rate of 2.9% (25 re-ruptures) for those with an acute presentation and 2.7% (two re-ruptures) for those with delayed presentation. This study of non-operative functional management of rupture of the tendo Achillis is the largest of its kind in the literature. Our rates of re-rupture are similar to, or better than, those published for operative treatment. We recommend our regime for patients of all ages and sporting demands, but it is essential that they adhere to the protocol.

A negative search for a paramyxoviral etiology of Paget's disease of bone: molecular, immunological, and ultrastructural studies in UK patients.

Paget's disease of bone is a common bone disease characterized by increased and disorganized bone remodeling at focal sites throughout the skeleton. The etiology of the disease is unresolved. A persistent viral infection has long been suggested to cause the disease. Antigen and/or nucleic acid sequences of paramyxoviruses (in particular measles virus [MV], canine distemper virus [CDV], and respiratory syncytial virus [RSV]) have been reported in pagetic bone by a number of groups; however, others have been unable to confirm this and so far no virus has been isolated from patients. Here, we reexamined the question of viral involvement in Paget's disease in a study involving 53 patients with established disease recruited from seven centers throughout the United Kingdom. Thirty-seven patients showed clear signs of active disease by bone scan and/or histological assessment of the bone biopsy specimens and 12 of these had not received any therapy before samples were taken. Presence of paramyxovirus nucleic acid sequences was sought in bone biopsy specimens, bone marrow, or peripheral blood mononuclear cells using reverse-transcription polymerase chain reaction (RT-PCR) with a total of 18 primer sets (7 of which were nested), including 10 primer sets (including 3 nested sets) specifically for MV or CDV. For each patient at least one sample was tested with all primer sets by RT-PCR and no evidence for the presence of paramyxovirus RNA was found in any patient. In 6 patients, bone biopsy specimens with clear histological evidence of active disease tested negative for presence of measles and CDV using immunocytochemistry (ICC) and in situ hybridization (ISH). Intranuclear inclusion bodies, similar to those described by others previously, were seen in pagetic osteoclasts. The pagetic inclusions were straight, smooth tubular structures packed tightly in parallel bundles and differed from nuclear inclusions, known to represent MV nucleocapsids, in a patient with subacute sclerosing panencephalitis (SSPE) in which undulating, diffuse structures were found, arranged loosely in a nonparallel fashion. In the absence of amplification of viral sequences from tissues that contain frequent nuclear inclusions and given that identical inclusions are found in other bone diseases with a proven genetic, rather than environmental, etiology, it is doubtful whether the inclusions in pagetic osteoclasts indeed represent viral nucleocapsids. Our findings in this large group of patients recruited from throughout the United Kingdom do not support a role for paramyxovirus in the etiology of Paget's disease.

Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.

Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.

Organisms, organizations and interactions: an information theory approach to biocultural evolution.

The language metaphor of theoretical biology, proposed by Waddington in 1972, provides a basis for the formal examination of how different self-reproducing structures interact in an extended evolutionary context. Such interactions have become central objects of study in fields ranging from human evolution-genes and culture-to economics-firms, markets and technology. Here we use the Shannon-McMillan Theorem, one of the fundamental asymptotic relations of probability theory, to study the 'weakest' and hence most universal, forms of interaction between generalized languages. We propose that the co-evolving gene-culture structure that permits human ultra-sociality emerged in a singular coagulation of genetic and cultural 'languages', in the general sense of the word. Human populations have since hosted series of culture-only speciations and coagulations, events that, in this formulation, do not become mired in the 'meme' concept.

An audit of the combined non-operative and orthotic management of ruptured tendo Achillis.

At this institution we have introduced combined non-operative and orthotic treatment for ruptured tendo Achillis. An outcome audit was performed to assess this treatment. Patients were treated in a short-leg cast in the equinus position. After a cast period of 4 weeks, the patient was placed in orthoses for a further 4 weeks, after which they returned to normal activities as was appropriate. We performed a retrospective review including visual analogue scores of patient satisfaction and physical examination. Thirty-two patients were reviewed. The average time from injury to review was 2 years (range 6 months to 5.5 years). There were no significant complications following treatment with no re-ruptures to date. Average visual analogue scores (0-10) were for casts 5.9, orthoses 8.5 and overall outcome 8.3. Of those wishing to return to sporting activities 62 per cent did so within 6.6 months (average). Clinical examination showed no significant difference (P, 0.05) between normal and injured leg in terms of ankle range of movement, tone and subtalar movement. The maximum calf circumference was significantly reduced on the affected side (36.84 cm versus 38.2 cm) as was ankle plantar flexion power. This treatment was liked by patients and is at least as effective as other established methods. Calf power and muscle bulk were reduced in the affected leg and may be improved by including a physiotherapy protocol in the treatment.

Hospital responses to a data-driven statewide quality improvement project.

BACKGROUND: The overall success of any continuous quality improvement (CQI) project lies in the ability to measure changes resulting from the project and to show that changes have resulted n improved care. METHOD: A software tool was developed to categorize hospital responses and activities implemented by hospitals as a result of the Cooperative Cardiovascular Project CCP). Information was captured regarding the hospital's acceptance of data and the educational/interventional strategies implemented. Hospital size, number of acute myocardial infarction patients treated, indicator performances, and type of presentation given (on-site versus regional visit) was entered to allow analysis of factors affecting the response. RESULT: sixty-one of 107 hospitals responded to the peer review organization. Of those, 49% planned further educational activities and 75% planned to implement some form of CQI activity. Comparison of responses in relation to the type of presentation received suggested that on-site presentations are associated with higher response rates and more intense quality improvement efforts. This also could be attributed to other factors such as hospital size, teaching environment, or number of acute myocardial infarction patients treated. CONCLUSION: The system developed allowed us to collate hospital improvement efforts as a result of CCP. The system is limited in its ability to identify those activities taking place before CCP. Further development and refinement of the tool is warranted to document quality improvement efforts and determine best strategies for peer review organization intervention.

Genetic linkage of familial expansile osteolysis to chromosome 18q.

Familial expansile osteolysis is a rare bone dysplasia which is transmitted as an autosomal dominant trait in a large kindred in Northern Ireland. The gene which causes the disease shows tight linkage with several polymorphic markers on chromosome 18q with a maximum lod score of 11.53 at a recombination fraction of 0.00 with D18S64. The gene is flanked by D18S35 and D18S61 and is located at chromosome 18q21.1-q22. Mapping a new locus for a gene involved in regulation of bone metabolism may also have implications in the study of Paget's disease of bone which is a common related bone dysplasia.

Intraoperative bupivacaine diminishes pain after lumbar discectomy. A randomised double-blind study.

A randomised double-blind study was carried out on 60 patients undergoing elective lumbar discectomy. Patients in the study group (n = 30) received an injection of 10 ml of 0.5% bupivacaine into the wound; the control group (n = 30) received none. Postoperative pain was measured by a visual analogue pain scale and by the amount of morphine administered by a patient-controlled analgesia system. Patients in the study group had lower pain scores, used less morphine, waited longer until their first demand for analgesia and reported their postoperative pain to be less severe.

Dental abnormalities associated with familial expansile osteolysis: a clinical and radiographic study.

Familial expansile osteolysis is a rare and possibly unique form of hereditary bone dysplasia with dental manifestations that has affected 42 members of a Northern Ireland family for five generations. Twenty-seven family members, aged 3 to 60 years, were examined clinically and radiographically, and it was found that cervical and/or apical root resorption is an early manifestation of the dysplasia. Of the 20 family members with skeletal manifestations of familial expansile osteolysis, 16 showed root resorption. Root resorption may therefore be a good prognosticator for later bone involvement.

Radon-222, 222Rn progeny, and 220Rn progeny levels in 70 houses.

A year-long, multipollutant, indoor air quality study involving 70 occupied houses in four states was completed in 1987. All of the houses included in the study had a partial or complete basement with a concrete slab floor and block walls. On an approximately quarterly schedule, integrating monitors for short-lived Rn progeny, nitrogen dioxide, formaldehyde, and water vapor were exposed for 1 wk in each house on both the basement and main floors. At the beginning of the study, a pair of alpha-track detectors were placed on top of the refrigerator in the kitchen (or some other sampling location on the main floor) and at a location in the basement. One detector at each location was left in place for a year while the other detector was retrieved and replaced once every 3-mo period. In addition, short-term measurements of Rn and 222Rn progeny were made at all sampling locations once per quarter. In this study, comparisons were made between: (1) seasonal and annual averages, (2) summer and winter averages, (3) living-area and basement results, (4) 222Rn and 220Rn progeny, and (5) short- and long-term measurements. The Rn and Rn progeny concentrations in houses near Huntsville, AL were found to be well above recommended action levels (150 Bq m-3). For houses near Birmingham, AL, summer Rn concentrations were found to exceed winter concentrations, whereas for the other houses in the study, winter concentrations exceeded summer concentrations. Potential alpha energy concentrations (PAEC) from 220Rn progeny were found to be generally less than PAEC from 222Rn.

The radiographic features of familial expansile osteolysis.

The radiographic features of a unique autosomal dominant bone dysplasia are presented. The features are classified as generalised and/or focal. Generalised features are either altered trabecular pattern or modelling abnormalities. Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla. Almost 90% of these lesions occur in the appendicular skeleton. Clinically, hearing loss is the earliest manifestation of the disease, presenting sometimes as early as 4 years of age. Apical and cervical resorption of teeth is extremely common, resulting in premature loss of teeth. Radiologically, the differential diagnosis refers to Paget's disease, polyostotic fibrous dysplasia, and osteofibrous dysplasia. The progressive destruction of the bone is similar to massive osteolysis (Gorham's disease). The radiographic features in combination with the histopathology render the condition unique.

Familial expansile osteolysis.

Familial expansile osteolysis (FEO) is a unique bone dysplasia, which has, over five generations, affected 42 members of a Northern Ireland family. The disease follows a classic autosomal dominant pattern of inheritance. The condition is distinct enough in its clinical features and natural history to be recognized as a new and unique disease. There are both general and focal skeletal changes, the latter having a predominantly peripheral distribution and an onset from the second decade. Progressive osteoclastic resorption accompanied by medullary expansion leads to severe and painful disabling deformities with a tendency to pathologic fracture. Most affected members of the family have an associated early-onset deafness and loss of dentition as a result of unique middle ear and dental abnormalities. The serum alkaline phosphatase and urinary hydroxyproline are elevated to a variable degree, whereas other biochemical indices are normal. The response of the disease to a therapeutic trial using parenteral dichloro-methylene-diphosphonate (dichloro-MDP) produced an initial rapid biochemical response, which was not sustained.

Pain-free cutting of split skin grafts by application of a percutaneous local anaesthetic cream.

The use of a novel percutaneous anaesthetic preparation for the pain-free cutting of split skin grafts has been assessed in a series of 80 patients, age range 12 to 96 years. The technique was completely successful in 80% of these cases, with complete analgesia established within one hour of initial application. Duration of anaesthesia was such that pain-free cutting of the skin was possible up to 5 hours after initial application of the preparation. Failures of the technique were largely attributed to a loss of anaesthetic potency in the preparation, application of an inadequate amount to the site or patient anxiety. The use of the percutaneous anaesthetic preparation was found to offer considerable advantages over conventional infiltration anaesthesia for this type of surgery. Several additional surgical applications of percutaneous anaesthesia are also considered.

Familial expansile osteolysis. A new dysplasia.

We report 40 cases in one family of an autosomal dominant bone dysplasia, which, though similar in some aspects to Paget's disease, seems unique in some features and in its natural history. The disease shows both general and focal skeletal changes, the latter being mainly in the limbs with an onset from the second decade. Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture. The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal. Most patients had an associated deafness of early onset and loss of dentition. No previous description of this disease has been found in the literature.