Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.

AIM: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. METHOD: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. RESULTS: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure (p < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-972, p-IRB tyr1146, and pAMPK, thereby decreasing insulin resistance. CONCLUSIONS: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.

Alpha-Lipoic Acid Protects Cardiomyocytes against Heat Stroke-Induced Apoptosis and Inflammatory Responses Associated with the Induction of Hsp70 and Activation of Autophagy.

Heat stroke (HS) is a life-threatening illness and defined as when body temperature elevates above 40°C accompanied by the systemic inflammatory response syndrome that results in multiple organ dysfunctions. α-Lipoic acid (ALA) acts as a cofactor of mitochondrial enzymes and exerts anti-inflammatory and antioxidant properties in a variety of diseases. This study investigates the beneficial effects of ALA on myocardial injury and organ damage caused by experimental HS and further explores its underlying mechanism. Male Wistar rats were exposed to 42°C until their rectal core temperature reached 42.9°C and ALA was pretreared 40 or 80 mg/kg (i.v.) 1.5 h prior to heat exposure. Results showed that HS-induced lethality and hypothermia were significantly alleviated by ALA treatment that also improved plasma levels of CRE, LDH, and CPK and myocardial injury biomarkers myoglobin and troponin. In addition, ALA reduced cardiac superoxide anion formation and protein expression of cleaved caspase 3 caused by HS. Proinflammatory cytokine TNF-α and NF-κB pathways were significantly reduced by ALA treatment which may be associated with the upregulation of Hsp70. ALA significantly increased the Atg5-12 complex and LC3B II/LC3B I ratio, whereas the p62 and p-mTOR expression was attenuated in HS rats, indicating the activation of autophagy by ALA. In conclusion, ALA ameliorated the deleterious effects of HS by exerting antioxidative and anti-inflammatory capacities. Induction of Hsp70 and activation of autophagy contribute to the protective effects of ALA in HS-induced myocardial injury.

MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations.

The objective of the study is to screen 12 MEFV gene mutations in Egyptian patients with familial Mediterranean fever (FMF) and to study the initial hypothesis that the phenotypic expression of the disease may be attributable to the existence of a particular mutation. We enrolled 136 Egyptian patients (74 males, and 62 females) with a clinical diagnosis of FMF. DNA was amplified by PCR and subjected to reverse hybridization for the detection of 12 MEFV gene mutations. The phenotypic expression of the disease was compared in two subgroups according to the presence of homozygote E148Q and M694V gene mutations. The most frequent gene mutations in the studied group were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6%, respectively. At least one of these main five founder mutations was present in 132 patients (97.1%). Thirty-two patients (23.5%) were homozygote for one of the main five founder mutations. The most common homozygote gene mutations were E148Q and M694V, each in 12 patients (8.8%). Significant increase in abdominal pain and arthritis was found in patients with homozygote M694V mutation compared to those with E148Q mutation. All patients with amyloidosis had M694V gene mutation. The increased frequency of V726A gene mutation and the rarity of amyloidosis in this study suggest that Egyptian patients may have a milder form of FMF compared to other populations. The five main founder mutations account for the vast majority of cases of FMF. M694V gene mutation may be associated with increased frequency of abdominal pain, arthritis and the presence of amyloidosis.

Reconstruction of distal tibial defects following resection of malignant tumours by pedicled vascularised fibular grafts.

The aim of this study was to evaluate the oncologic and functional outcome after wide resection of malignant tumours of the distal tibia and reconstruction of the defect by ipsilateral pedicled vascularised fibular graft and ankle arthrodesis. Thirteen patients (9 males and 4 females) with primary malignant tumours of the distal tibia were treated by wide resection. The mean age of the patients at the time of surgery was 15 years. The fibula was mobilised to fill the defect, pedicled on the peroneal vessels. The average size of the defects reconstructed was 10 cms. Patients were evaluated functionally using the Musculoskeletal Tumor Society evaluation system. The mean duration of follow-up was 27 months. Chest metastases developed in 4 patients and local recurrence in one. The mean functional score was 80% at the time of last follow-up. The average time to union of the graft both proximally and distally was 6 months. Complications were minimal and did not affect the functional outcome. Reconstruction of distal tibial defects with an ipsilateral pedicled vascularised fibular graft is a technically easy reconstructive option which offers a predictable long standing functional outcome.

Limb salvage management of pathologic fractures of primary malignant bone tumors.

BACKGROUND: Little is known about oncologic outcomes of patients with primary bone tumors complicated by a pathologic fracture and treated by limb salvage. METHODS: Our study included 17 men and 14 women aged 6 to 61 years (average age 17 years). All 31 patients had primary bone tumors complicated by a pathologic fracture. Diagnoses included osteosarcoma (17 patients), Ewing's sarcoma (10), malignant fibrous histiocytoma (3), and lymphoma (1). All received preoperative chemotherapy. The distal femur was affected in 13 patients, the proximal femur in 6, mid shaft femur in 4, the proximal humerus in 4, the proximal tibia in 3, and the fibula in 1. All patients underwent limb salvage and achieved a wide resection margin. RESULTS: The average follow-up period was 18 months (range 8 to 51 months). Two patients required amputation due to local recurrence. Six patients developed pulmonary metastases and eventually died. CONCLUSIONS: A pathologic fracture of primary bone tumor is not always a contraindication for limb salvage since the oncologic outcome appears acceptable.

Anterior versus posterior approach in reconstruction of infected nonunion of the tibia using the vascularized fibular graft: potentialities and limitations.

The potentialities, limitations, and technical pitfalls of the vascularized fibular grafting in infected nonunions of the tibia are outlined on the basis of 14 patients approached anteriorly or posteriorly. An infected nonunion of the tibia together with a large exposed area over the shin of the tibia is better approached anteriorly. The anastomosis is placed in an end-to-end or end-to-side fashion onto the anterior tibial vessels. To locate the site of the nonunion, the tibialis anterior muscle should be retracted laterally and the proximal and distal ends of the site of the nonunion debrided up to healthy bleeding bone. All the scarred skin over the anterior tibia should be excised, because it becomes devitalized as a result of the exposure. To cover the exposed area, the fibula has to be harvested with a large skin paddle, incorporating the first septocutaneous branch originating from the peroneal vessels before they gain the upper end of the flexor hallucis longus muscle. A disadvantage of harvesting the free fibula together with a skin paddle is that its pedicle is short. The skin paddle lies at the antimesenteric border of the graft, the site of incising and stripping the periosteum. In addition, it has to be sutured to the skin at the recipient site, so the soft tissues (together with the peroneal vessels), cannot be stripped off the graft to prolong its pedicle. Vein grafts should be resorted to, if the pedicle does not reach a healthy segment of the anterior tibial vessels. Defects with limited exposed areas of skin, especially in questionable patency of the vessels of the leg, require primarily a fibula with a long pedicle that could easily reach the popliteal vessels and are thus better approached posteriorly. In this approach, the site of the nonunion is exposed medial to the flexor digitorum muscle and the proximal and distal ends of the site of the nonunion debrided up to healthy bleeding bone. No attempt should be made to strip the scarred skin off the anterior aspect of the bone lest it should become devitalized. Any exposed bone on the anterior aspect should be left to granulate alone. This occurs readily when stability has been regained at the fracture site after transfer of the free fibula. The popliteal and posterior tibial vessels are exposed, and the microvascular anastomosis placed in an end-to-side fashion onto either of them, depending on the length of the pedicle and the condition of the vessels themselves. To obtain the maximal length of the pedicle of the graft, the proximal osteotomy is placed at the neck of the fibula after decompressing the peroneal nerve. The distal osteotomy is placed as distally as possible. After detaching the fibula from the donor site, the proximal part of the graft is stripped subperiosteally, osteotomized, and discarded. Thus, a relatively long pedicle could be obtained. To facilitate subperiosteal stripping, the free fibula is harvested without a skin paddle. In this way, the use of a vein graft could be avoided. Patients presenting with infected nonunions of the tibia with extensive scarring of the lower extremity, excessively large areas of skin loss, and with questionable patency of the anterior and posterior tibial vessels are not suitable candidates for the free vascularized fibular graft. Although a vein graft could be used between the recipient popliteal and the donor peroneal vessels, its use decreases flow to the graft considerably. These patients are better candidates for the Ilizarov bone transport method with or without free latissimus dorsi transfer.

Shoulder reconstruction after tumor resection by pedicled scapular crest graft.

The current authors present and evaluate a technique for reconstructing proximal humeral defects that result after resection of malignant bone tumors. Sixteen patients were included in this study with an average followup of 3 years (range, 12-76 months). Twelve patients had intraarticular resections, two had extraarticular resections, and two had intercalary resections. Reconstruction was done at the lateral border of the scapula (based on the circumflex scapular vessels) that was osteotomized and mobilized to bridge the resultant defect. Shoulder arthrodesis was done in 14 patients and the shoulder was spared in the two patients who had intercalary resections. Function was evaluated according to the Musculoskeletal Tumor Society scoring system. The average time for union of the graft proximally and distally was 6 months after which the graft started to hypertrophy. The average functional score was 22.5 points (75%) with a minimum score of 18 points (60%) and a maximum score of 27 points (90%). Nonunion of the distal host-graft junction occurred in two patients; both patients required iliac crest bone grafting and both achieved clinical and radiographic union without additional intervention. In three patients, the proximal fixation became loose but had no effect on function. The authors conclude that this technique is inexpensive, effective, and a durable reconstructive option for proximal humeral defects that are less than 15 cm. It has a predictable functional outcome (60%-90%) that is comparable with other reconstructive options.