Collagen V deficiency during murine tendon healing results in distinct healing outcomes based on knockdown severity.

Tendon function is dependent on proper organization and maintenance of the collagen I tissue matrix. Collagen V is a critical regulator of collagen I fibrils, and while prior studies have shown a negative impact of collagen V deficiency on tendon healing outcomes, these studies are confounded by collagen V deficiency through tendon development. The specific role of collagen V in regulating healing tendon properties is therefore unknown. By using inducible Col5a1 knockdown models and analyzing gene expression, fibril and histological tendon morphology, and tendon mechanical properties, this study defines the isolated role of collagen V through tendon healing. Patellar tendon injury caused large changes in tendon gene expression, and Col5a1 knockdown resulted in dysregulated expression of several genes through tendon healing. Col5a1 knockdown also impacted collagen fibril size and shape without observable changes in scar tissue formation. Surprisingly, heterozygous Col5a1 knockdown resulted in improved stiffness of healing tendons that was not observed with homozygous Col5a1 knockdown. Together, these results present an unexpected and dynamic role of collagen V deficiency on tendon healing outcomes following injury. This work suggests a model of tendon healing in which quasi-static mechanics may be improved through titration of collagen fibril size and shape with modulation of collagen V expression and activity.

Lower limb injuries caused by improvised explosive devices: proposed 'Bastion classification' and prospective validation.

BACKGROUND: Complex lower limb injury caused by improvised explosive devices (IEDs) has become the signature wounding pattern of the conflict in Afghanistan. Current classifications neither describe this injury pattern well, nor correlate with management. There is need for a new classification, to aid communication between clinicians, and help evaluate interventions and outcomes. We propose such a classification, and present the results of an initial prospective evaluation. PATIENTS AND METHODS: The classification was developed by a panel of military surgeons whilst deployed to Camp Bastion, Afghanistan. Injuries were divided into five classes, by anatomic level. Segmental injuries were recognised as a distinct entity. Associated injuries to the intraperitoneal abdomen, genitalia and perineum, pelvic ring, and upper limbs, which impact on clinical management and resources, were also accounted for. RESULTS: Between 1 November 2010 and 20 February 2011, 179 IED-related lower limb injuries in 103 consecutive casualties were classified, and their subsequent vascular and musculoskeletal treatment recorded. 69% of the injuries were traumatic amputations, and the remainder segmental injuries. 49% of casualties suffered bilateral lower limb amputation. The most common injury was class 3 (involving proximal lower leg or thigh, permitting effective above-knee tourniquet application, 49%), but more proximal patterns (class 4 or 5, preventing effective tourniquet application) accounted for 18% of injuries. Eleven casualties had associated intraperitoneal abdominal injuries, 41 suffered genital or perineal injuries, 9 had pelvic ring fractures, and 66 had upper limb injuries. The classification was easy to apply and correlated with management. CONCLUSIONS: The 'Bastion classification' is a pragmatic yet clinically relevant injury categorisation, which describes current injury patterns well, and should facilitate communication between clinicians, and the evaluation of interventions and outcomes. The validation cohort confirms that the injury burden from IEDs in the Helmand Province of Afghanistan remains high, with most casualties sustaining amputation through or above the knee. The rates of associated injury to the abdomen, perineum, pelvis and upper limbs are high. These findings have important implications for the training of military surgeons, staffing and resourcing of medical treatment facilities, to ensure an adequate skill mix to manage these complex and challenging injuries.

Photoperiodic changes in endocannabinoid levels and energetic responses to altered signalling at CB1 receptors in Siberian hamsters.

Siberian hamsters (Phodopus sungorus) adapt to seasonal environmental conditions with marked changes in body mass, primarily in the form of adiposity. Winter-like conditions (e.g. short days) are sufficient to decrease body mass by approximately 30% in part via reductions in food intake. The neuroendocrine mechanisms responsible for these changes are not well understood, and homeostatic orexigenic/anorexigenic systems of the hypothalamus provide little explanation. We investigated the potential role of endocannabinoids, which are known modulators of appetite and metabolism, in mediating seasonal changes in energy balance. Specifically, we housed hamsters in long or short days for 0, 3, or 9 weeks and measured endocannabinoid levels in the hypothalamus, brainstem, liver and retroperitoneal white adipose tissue (RWAT). An additional group of males housed in short days for 25 weeks were also compared with long-day controls. Following 9 weeks in short days, levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) were significantly elevated in RWAT and reduced in brainstem, although they returned to long-day levels by week 25 in short-day males that had cycled back to summer-like energy balance. Endocannabinoid levels in these tissues correlated significantly with adiposity and change in body mass. No photoperiodic changes were observed in the hypothalamus or liver; however, sex differences in 2-AG levels were found in the liver (males > females). We further tested the effects of CB(1) receptor signalling on ingestive behaviour. Five daily injections of CB(1) antagonist SR141716 significantly reduced food intake and body mass but not food hoarding. Although the CB(1) agonist arachidonyl-2-chloroethylamide did not appreciably affect either ingestive behaviour, body mass was significantly elevated following 2 days of injections. Taken altogether, these findings demonstrate that endocannabinoid levels vary with sex and photoperiod in a site-specific manner, and that altered signalling at CB(1) receptors affects energy balance in Siberian hamsters.

Pelvic ring injuries in the military environment.

Haemodynamically unstable patients with mechanically unstable pelvic ring injuries continue to present a challenge to all personnel involved. Road traffic accidents remain a significant cause of soldier morbidity and mortality in peacetime and in war. These pelvic ring disruptions are markers of high-energy transfer injuries and are associated with fatal exsanguinating haemorrhage. Identifying the ring injury and the source of bleeding remains a complex challenge. Early control of instability, both haemodynamic and mechanical is likely to produce the best results. Dealing with these issues in the military environment adds additional stress to this volatile situation. Multidisciplinary practice guidelines have been shown to reduce mortality and should be adopted by all establishments treating these causalities. A well-rehearsed ABC approach with a proactive approach to dot protection and promotion is ideal.

Forward surgery on Operation Telic--Iraq 2003.

Two Air Assault Surgical Groups (AASGs) from 16 Close Support Medical Regiment deployed to Kuwait on Operation Telic in February 2003. Each AASG was comprised of a four-table resuscitation facility, a two table FST and a twin-bedded ITU facility. An A+E Consultant and nurse, an experienced radiographer and laboratory technician with two further RGNs and CMTs provided resuscitation support. Each FST had an orthopaedic and a general surgeon, two anaesthetists and eight operating department practitioners. Further equipment consisted of a Polymobil 111 X-ray unit, a Sonosite 180 ultrasound scanner and an ISTAT gas, haematocrit and electrolyte analyser. 100 units of mixed blood were carried by each AASG. Fifty-one surgical procedures were performed on thirty one patients. Twenty one of these patients were Iraqi prisoners of war or civilians. Seventeen wound debridements, five amputations, five laparotomies, four insertions of Denham pins with Thomas splintage for femoral fracture, three external fixations and one axillary artery repair formed the basis of the major cases undertaken. The first field use of activated factor VII by the British Army was successful in the resuscitation of a patient with exsanguinating haemorrhage after an open-book (APC-III) pelvic fracture and a ruptured intrapelvic haematoma. The other cases included eleven manipulations under anaesthetic/application of plaster and four finger terminalisations. Forward military surgery has a continued role to play on the modern fast moving battlefield. 16 Close Support Medical Regiment normally supports 16 Air Assault Brigade with its remit for expeditionary operations and SF support. Its experience on Op Telic should influence planning for future deployment.

Reversal of glandular polarity in the lymphovascular compartment of breast cancer.

AIM: To investigate the polarity of breast invasive ductal carcinoma cells by comparing the polarity of the tumour located within lymphovascular spaces with that located in the extravascular compartment. METHODS: An immunohistochemical study identifying the apical HMFG-1, basolateral AUA-1, and basal laminin polarity markers of 11 cases of invasive ductal carcinoma (grades 1 or 2) metastatic to lymph nodes, all of which contained areas of tumour within and outside of lymphovascular spaces. RESULTS: Only one of 11 tumours had a focus of apparent reversed glandular polarity in the larger extravascular tumour compartment (with AUA-1 present internally and HMFG-1 expressed externally on tumour clumps), but six of the 11 tumours showed reversed glandular polarity (either with AUA-1, or HMFG-1, or both) within the very much smaller lymphovascular space tumour compartment. Laminin was not identified in association with lymphovascular tumour. CONCLUSIONS: Reversed glandular polarity in invasive ductal breast carcinomas was identified and was significantly more frequent within vessels than outside of them. Reversal of tumour glandular polarity within lymphovascular spaces allows direct interaction between apical domain-type molecules-which are then aberrantly expressed on the external surface of tumour clumps-and lymphovascular endothelium. Such interactions may affect the establishment of metastatic disease.

Notions of reliability: considering the importance of difference in guiding patients to health care Web sites.

OBJECTIVES: This article analyzes the efforts of three organizations to provide a standard that guides Internet users to reliable health care sites. METHODS: Comparison of health Internet sites, interviews and document studies. RESULTS: In comparing these approaches, three different constructions of reliability are identified. CONCLUSIONS: The resulting possibilities and restrictions of these constructions for users that are searching for health information on the Internet are revealed.

Perianal Hodgkin's lymphoma complicating Crohn's disease.

BACKGROUND: The perianal region is a very rare location for Hodgkin's lymphoma, and clinicians may often neglect the diagnosis in patients with inflammatory bowel disease. PATIENT PRESENTATION: We present a case of perianal Hodgkin's lymphoma in patient with Crohn's disease who was on long-term immunosuppression and whose symptoms would normally be attributed to Crohn's disease. Diagnosis was based on the morphological appearance of atypical cells in the lamina propria and the immunohistochemical profile of Reed Sternberg and Hodgkin's cells, showing co-expression of CD15 and CD30. CONCLUSION: Perianal complaints in patients with inflammatory bowel disease may be a manifestation of other pathology. Hodgkin's lymphoma could be a progression in the chronically inflamed tissue in this unusual location.

Malignant mesothelioma: PAS-diastase positivity and inversion of polarity in intravascular tumour.

AIMS: Periodic acid-Schiff (PAS)-diastase-positive material was identified within pseudoglandular structures within the small intravascular component of two pleural malignant mesotheliomas. The aim of this study was to ascertain the nature of this material and to asses the polarity of the cells forming the pseudoglandular structure. METHODS AND RESULTS: Immunohistochemistry was performed using antibodies to laminin and type IV collagen and the antibody HBME-1. These demonstrated the material to be basement membrane rather than mucin. The apical polarity marker HBME-1 was not related to the internal pseudoglandular structure but stained the periphery of intravascular tumour clumps. CONCLUSIONS: Pseudoluminal PAS-diastase-positive material in malignant mesothelioma may easily be mistaken for epithelial mucin, leading to an erroneous diagnosis of adenocarcinoma. The presence of basement membrane material in pseudolumina, as defined by the presence of laminin and type IV collagen, surrounded by tumour cells whose external surface expresses the apical polarity marker HBME-1 implies inversion of polarity of tumour cells within vascular spaces.

Challenges associated with creating a pharmaceutical stockpile to respond to a terrorist event.

The Centers for Disease Control and Prevention (CDC) was called into action to develop a National Pharmaceutical Stockpile (NPS). The NPS was created to respond to terrorism events involving blast, chemical and biological agents. There are many challenges associated with creating, managing and using such an asset. This paper provides a helpful background for clinicians and those planning to develop pharmaceutical and/or medical materiel stockpiles for national use. It also describes major challenges and offers suggestions for meeting those challenges.

The angiogenins: an emerging family of ribonuclease related proteins with diverse cellular functions.

Angiogenin is a member of the ribonuclease superfamily, which shows an ever expanding collection of molecules being identified and cloned. It was initially isolated from the conditioned medium of cultured tumour cells. Its angiogenic activity appears to be critical for the maintenance and support of tumour growth. Angiogenin also plays a role in a number of non-malignant vasculoproliferative pathological conditions. Along with other related molecules, it has been identified in a wide variety of somatic tissues in adult and embryonic stages of vertebrate development. This suggests that angiogenin and related molecules are likely to play a vital role in normal physiology. Angiogenin is detectable in serum and to date has been implicated as a mitogen for vascular endothelial cells, an immune modulator with suppressive effects on polymorphonuclear leukocytes, an activator of certain protease cascades such as matrix metalloproteases and plasminogen-activated plasmin pathways, as well as an adhesion molecule. However, the role of the angiogenin family in both normal and abnormal physiology and in development will only fully be realised by genetic approaches involving gene deletion.

Digestion of 125I-labelled plasmin-derived fibrin degradation products by neutrophil lysosomal enzymes.

The cellular components of the blood, which become associated with fibrin through specific cellular adhesive processes, play a significant role in the breakdown of fibrin. Fibrinolysis by neutrophil elastase and cathepsin G occurs in a manner distinct from that produced by plasmin. This study demonstrates that neutrophil lysosomal enzyme activity further degrades the end products of plasmic fibrin degradation into low-molecular-weight material, followed by reassembly of higher-molecular-weight products in a process dependent on calcium and factor XIII. Although one of the reformed products has a similar molecular weight to D-dimer and is recognized by a monoclonal antibody raised against D-dimer, its isoelectric point indicates it to be distinctly different from plasmin-derived D-dimer. Processing of the end products of plasmic fibrin degradation by neutrophils may have the potential for modulating the immune response as well as compromising the predictive value of tests measuring D-dimer.

The scalability of the Rivermead Motor Assessment in acute stroke patients.

OBJECTIVE: To examine the scalability of the Rivermead Motor Assessment with hospitalized acute stroke patients. DESIGN: This was a prospective study of hospitalized stroke patients. SUBJECTS: Fifty-one selected stroke patients, including those over the age of 65, were assessed at one, three and six weeks post-stroke using the Rivermead Motor Assessment. Coefficients of scalability and reproducibility were calculated for each of the three sections of the Rivermead Motor Assessment at each assessment. RESULTS: The items in the gross function and arm sections met scaling criteria at all three assessments which meant that they were in appropriate order of difficulty. There was an overall increase in the proportion of subjects passing each item at successive assessments, suggesting that patients in the study were recovering. The leg and trunk section did not meet scale criteria with these acute stroke patients. CONCLUSIONS: We recommend that only the gross function and arm sections should be used as hierarchical scales with selected acute stroke patients. The leg and trunk section should only be used as an assessment checklist.

The scalability of the Rivermead Motor Assessment in nonacute stroke patients.

OBJECTIVE: To examine the scalability of the Rivermead Motor Assessment (RMA) with nonacute stroke patients in the community. DESIGN: This was a prospective study of the patients after discharge from hospital. All subjects were assessed on the RMA at six and 12 months after discharge home from hospital. Coefficients of scalability and reproducibility were calculated for each of the three sections of the RMA at each assessment. SUBJECTS: Subjects were nonacute stroke patients aged 65 years and over, nonacute stroke patients aged under 65 years, and a selected group of those aged under 65 years. RESULTS: Only the items in the gross function section met scaling criteria with nonacute strokes in both age groups, which suggests that the items in this section were in appropriate order of difficulty. The items in the leg and trunk section were not in hierarchical order and were in fact closer to scaling if the present order were reversed. CONCLUSIONS: The clinical and research value of the RMA, as an ordered scale, are questioned. Changes in treatment styles and philosophies may mean that some of the items themselves are out-dated.