Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas.

Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both Tp53 and Pten in the mouse mesothelium is sufficient to rapidly drive aggressive MMs. PtenL/L ;Tp53L/L mice injected intraperitoneally or intrapleurally with adenovirus-expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt-mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when Pten and Tp53 are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to Pten loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.

Limb reconstruction after traumatic bone loss.

A variety of options exist to reconstruct limbs following traumatic bone loss. The management of these injuries is challenging and often requires prolonged and potentially painful treatment. The Ilizarov technique of bone transport using circular external fixators is widely used for limb reconstruction of large bone defects. Other techniques include vascularised fibular grafting, the use of induced pseudosynovial membranes combined with cancellous autologous bone grafts and the use of autologous, allogeneic or synthetic bone grafts on their own for smaller defects. Future directions include further research on bone tissue engineering using stem cell therapy and growth factors such as bone morphogenetic proteins. The purpose of this Continuing Medical Education article is to describe the key limb reconstructive techniques that may be employed to treat traumatic bone loss. In particular, this article is intended to serve as a revision tool for those preparing for postgraduate examinations.

Incorporation of (n-3) fatty acids in foods: challenges and opportunities.

The health benefits of long-chain (n-3) PUFA have been widely reported in the literature. Despite the potential benefits, consumption of these fatty acids continues to fall below recommendations from various health and regulatory agencies. Incorporation of long-chain PUFA in foods represents a considerable challenge due to the increased risk of lipid oxidation resulting in the development of off-flavors and reduced shelf life. As a result, new sources of (n-3) fatty acids are needed that are more efficiently converted to long-chain (n-3) fatty acids than α-linolenic acid (ALA) and can be more easily incorporated into food. Stearidonic acid [SDA, 18:4 (n-3)] is an intermediate in the desaturation of ALA to EPA. Soybeans have been modified to contain SDA. Clinical studies have demonstrated a significant increase in EPA levels when SDA is consumed. Being more stable, SDA has been added to a variety of foods and has demonstrated equal consumer acceptance compared to a regular soybean oil control. SDA-enhanced soybean oil can provide to food companies and consumers an option to increase (n-3) fatty acid consumption in foods consumers typically eat.

Promises and difficulties with the use of femoral intra-medullary lengthening nails to treat limb length discrepancies.

Limb lengthening using external fixation may be associated with problems such as pin-track infections, poor patient acceptance, muscle transfixation, secondary axial deformity and re-fractures. Intramedullary lengthening nails have been designed to address these issues. We present our results for femoral limb lengthening in adults managed by intramedullary lengthening nails. A retrospective review was undertaken for 8 femoral lengthening procedures performed in adults using intra-medullary lengthening nails over a three-year period. The average age of our patients was 34 years; the average duration of follow-up was 26.5 months (range: 8 to 40 months). An Albizzia nail was used in 5 procedures, an Intra-medullary Skeletal Kinetic Distractor (ISKD nail) in 3 procedures. Target lengthening was achieved in 6 out of 8 femurs with an average of 38.77 mm (range: 0 to 70 mm) length gained. The distraction index (length gained per day) was 0.58 on average (range: 0-1.25) and the consolidation index average was 5039 (range: 0-79) days/cm. Premature consolidation was noted in 4 cases, runaway acute lengthening in one patient; prominent metalwork--noted in 4 patients--and a bent nail were frequent obstacles and meant multiple visits to theatre. Femoral lengthening with an intramedullary lengthening nail is a reasonable alternative to external fixators, thereby avoiding problems associated with callotasis using external fixation methods. It is however, important to counsel patients regarding possibilities of significant obstacles including failure and multiple visits to theatre during the process.

Post-traumatic calcific myonecrosis of flexor hallucis longus. A case report and literature review.

Calcific myonecrosis is a rare, late complication of compartment syndrome in the lower extremity. In this condition an entire single muscle of the leg is replaced by a fusiform mass with central liquefaction and peripheral calcification. Calcific myonecrosis presents a diagnostic dilemma to the clinician; it has to be considered in the differential diagnosis of a calcifying soft tissue tumour in the lower extremity. The purpose of this report is to highlight the importance of recognition of the lesion and its key clinico-pathological presenting features leading to appropriate management. We describe the unique presentation, diagnosis and surgical management of calcific myonecrosis involving only the flexor hallucis longus muscle of the leg in a middle-age adult. We found MRI Scan as the most useful method of investigation. Diagnosis can be confirmed by yellow-brown paste like material within the lesion intra-operatively or by aspiration and further by histology. We recommend complete excision of the lesion and closure of the wound with compression dressing, to avoid secondary infection.

Cross-sectional anatomy in postdistraction osteogenesis tibia.

BACKGROUND: Although the early period of distraction osteogenesis has been extensively investigated, there are few data describing the appearance of medium-term bone regeneration. METHOD: We investigated 10 adults with magnetic resonance imaging scans. Seven of them underwent bone transport, and three had tibial lengthening. The mean follow-up was 28 months after removal of the external fixator. The values were compared with those of the contralateral tibia, which acted as a control. RESULTS: All of the cases with bone transport had an increase in the volume of the whole tibia of 15.3%-50.8%. The diameters of the regenerated segments increased significantly (P < 0.0001) in all cases. The mean signal intensity in the regenerate decreased significantly in seven cases (P < 0.0001), which suggested a rise in the content of unhydrated tissue, such as bone and collagen. The cross-sectional area of the transported segment increased in all cases (P < 0.01). Finally, in the patients who underwent bone transport, the docking site was seen to be obstructed by unhydrated tissue. CONCLUSIONS: Contrary to previous claims, the postdistraction osteogenesis of tibia consists of areas with potentially different biomechanical properties. Recognition of these changes is essential not only for appropriate preoperative counseling but also for considering treatment modalities in case of fracture.

Functional outcome following bone transport reconstruction of distal tibial defects.

BACKGROUND: Little has been written about the functional outcome of patients treated with bone transport to reconstruct a distal tibial defect. The aim of this study was to investigate the functional capabilities of patients who had undergone reconstruction with distraction osteogenesis for the treatment of a distal tibial defect in one lower limb. METHODS: At least eighteen months after completion of treatment, eight patients who had no pain and were able to walk and climb stairs without difficulty performed isometric ankle plantar flexion maximum voluntary contractions while the electromyographic activity of the tibialis anterior and triceps surae muscles was simultaneously recorded. Seven of the patients also underwent gait analysis. Data for the involved limb were compared with those collected for the contralateral limb. RESULTS: During gait, stance time (p = 0.01), the plantar flexion angular displacement and peak moment developed during the second half of stance (p < 0.046), and the amount of ankle power generated (p = 0.02) were significantly decreased in the involved limb compared with the contralateral limb. Similar decreases were observed in the plantar flexion (p = 0.01) and dorsiflexion (p = 0.01) maximum voluntary contractions and the corresponding electromyographic activity (p = 0.01). CONCLUSIONS: These results suggest that adaptive changes had occurred at the level of the transported muscles, which affected both routine and maximal effort capabilities. These findings contribute to our understanding of the functional limitations of patients who have undergone bone transport with its obligatory shortening of muscle length.