Pigment Epithelium-Derived Factor: Inhibition of Phosphorylation of Insulin Receptor (IR)/IR Substrate (IRS), Osteogeneration from Adipocytes, and Increased Levels Due to Doxorubicin Exposure.

OBJECTIVES: Pigment epithelium-derived factor (PEDF) has been recently linked to insulin resistance and is capable of differentiating myocytes to bone. We examined in more detail the intricate signalling of the insulin pathway influenced by PEDF in skeletal myocytes. We tested whether this serpin is also capable of generating de novo bone from adipocytes in vitro and in vivo, and how the anticancer drug doxorubicin links with PEDF and cellular metabolism. METHODS AND KEY FINDINGS: We demonstrate that PEDF can inhibit phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS) in skeletal myocytes. PEDF constitutively activates p42/44 MAPK/Erk, but paradoxically does not affect mitogenic signalling. PEDF did not perturb either mitochondrial activity or proliferation in cells representing mesenchymal stem cells, cardiomyocytes, and skeletal myocytes and adipocytes. PEDF induced transdifferentiation of adipocytes to osteoblasts, promoting bone formation in cultured adipocytes in vitro and gelfoam fatpad implants in vivo. Bone formation in white adipose tissue (WAT) was better than in brown adipose tissue (BAT). The frontline anticancer drug doxorubicin increased levels of PEDF in a human breast cancer cell line, mirroring the in vivo finding where cardiac muscle tissue was stained increasingly for PEDF as the dose of doxorubicin increased in mice. PEDF also increased levels of reactive oxygen species (ROS) and glutathione (GSH) in the breast cancer cell line. CONCLUSIONS: PEDF may be used to regenerate bone from adipose tissue in cases of trauma such as fractures or bone cancers. The increased presence of PEDF in doxorubicin-treated tumour cells need further exploration, and could be useful therapeutically in future. The safety of PEDF administration in vivo was further demonstrated in this study.

Doxorubicin Action on Mitochondria: Relevance to Osteosarcoma Therapy?

BACKGROUND: The mitochondria may very well determine the final commitment of the cell to death, particularly in times of energy stress. Cancer chemotherapeutics such as the anthracycline doxorubicin perturb mitochondrial structure and function in tumour cells, as evidenced in osteosarcoma, for which doxorubicin is used clinically as frontline therapy. This same mechanism of cell inhibition is also pertinent to doxorubicin's primary cause of side-effects, that to the cardiac tissue, culminating in such dire events as congestive heart failure. Reactive oxygen species are partly to blame for this effect on the mitochondria, which impact the electron transport chain. OBJECTIVE: As this review highlights that, there is much more to be learnt about the mitochondria and how it is affected by such effective but toxic drugs as doxorubicin. CONCLUSION: Such information will aid researchers who search for cancer treatment able to preserve mitochondrial number and function in normal cells.

Spinal cord injury in the emergency context: review of program outcomes of a spinal cord injury rehabilitation program in Sri Lanka.

BACKGROUND: The final months of the conflict in Sri Lanka in 2009 resulted in massive displacement of the civilian population and a high volume of orthopedic trauma including spinal cord injury. In response to this need, Médecins Sans Frontières implemented a multidisciplinary rehabilitation program. METHODS: Patients were admitted to the program if they had a spinal cord injury, a stable spine and absence of a high-grade pressure ulcer. All patients were assessed on admission with a standardized functional scale the Spinal Cord Independence Measure II (SCIM) and the American Spinal Injury Association Impairment Scale (ASIA). A multidisciplinary team provided nursing care, physiotherapy, bowel and bladder training, mental health care, and vocational rehabilitation. Patients were discharged from the program when medically stable and able to perform activities of daily living independently or with assistance of a caregiver. The primary outcome measures were discharge to the community, and change in SCIM score on discharge. Secondary outcome measures were measured at 6-12 weeks post-discharge, and included SCIM score and presence of complications (pressure ulcers, urinary tract infections and bowel problems). RESULTS: 89 patients were admitted. The majority of injuries were to the thoracic region or higher (89%). The injuries were classified as ASIA grade A in 37 (43%), grade B in 17(20%), grade C in 15 (17%) and grade D in 17(20%). 83.2% met the criteria for discharge, with a further 7.9% patients requiring transfer to hospital for surgical care of pressure ulcers. There was a significant change in SCIM score from 55 on admission to 71 on discharge (p < 0.01). 79.8% and 66.7% achieved a clinically significant and substantially significant SCIM score improvement, respectively. Amongst those with follow up data, there was a reduction in post spinal cord injury complications from those experienced either at or during admission. A further 79% of SCIM scores were stable or improved compared to the score on discharge. CONCLUSIONS: Provision of effective rehabilitation for spinal cord injury is possible in complex humanitarian emergency situations. A multidisciplinary approach, including psychological support along with partnerships with local and international organizations with specialized expertise, was key to the program's success.

Physiotherapy in Afghanistan: an analysis of current challenges.

INTRODUCTION: Afghanistan has high levels of disability due to prolonged conflict. An important part of the reconstruction process in Afghanistan is strengthening health service capacity and, within this, rehabilitation services. AIMS: To identify training needs of, and key issues affecting, Afghan physiotherapists. METHODS: 20 interviews and clinical accompaniment of 15 physiotherapists/physiotherapy assistants (APA) carried out in the second quarter of 2003. Analysis was using a grounded theory approach. RESULTS: Five themes emerged: (1) Low professional profile of physiotherapy; (2) Difficult working conditions; (3) Difficulty identifying personal training needs; (4) Difficulty with clinical reasoning at undergraduate level; (5) Variable levels of clinical competence. DISCUSSION: Many of the challenges facing Afghan physiotherapists are not unique to Afghanistan but are exacerbated by a lack of government recognition of the profession. War has isolated Afghan physiotherapists from completed professional links and consequently the undergraduate curriculum had not matched developments in other comparable countries. This has contributed to the difficulties therapists' experience with current clinical reasoning and accessing new practice developments. Culture also influences attitudes towards training and has restricted female travel and access to education. CONCLUSIONS: Core training needs include disability sensitization, reflective practice and clinical reasoning. The physiotherapy curriculum needs updating and links with ongoing research need to be established to keep abreast of new developments.

Perspectives on disability in Afghanistan and their implications for rehabilitation services.

Twenty years of conflict has severely disrupted the infrastructure and economy of Afghanistan. Disability levels are high and much of the population has little access to health facilities. Re-establishing and strengthening rehabilitation services is therefore an important country priority. The aims of this study were to explore perceptions of the nature of disability in Afghanistan and to identify implications for the development of rehabilitation services. Over a 4-week period, interviews and focus groups, supplemented by field observations, were held with a range of service users and other stakeholders (including physiotherapist service providers and representatives of the Afghan Disability Committee) in the districts of Kabul and Herat. Data analysis identified three core themes in discussions with respondents: the nature of disability, causes of disability and rehabilitation priorities for people with disability (PWD). Afghan society distinguishes between traumatic and congenital disability, but disability awareness is much greater for persons with traumatic disability. This group enjoys much greater representation in disabled people's organizations. There is a strong cultural responsibility to care and provide for PWD rather than to encourage independence. Healthcare professionals reflect a medical model in their attitudes towards PWD. A key priority of PWD is economic. There is a low understanding of rehabilitation practice by PWD and medical staff. Training for rehabilitation workers and wider health professionals needs to reflect greater emphasis on a social model of disability. Public awareness and enablement of people with congenital disability needs to be raised.