Disrupting Cu trafficking as a potential therapy for cancer.

Copper ions play a crucial role in various cellular biological processes. However, these copper ions can also lead to toxicity when their concentration is not controlled by a sophisticated copper-trafficking system. Copper dys-homeostasis has been linked to a variety of diseases, including neurodegeneration and cancer. Therefore, manipulating Cu-trafficking to trigger selective cancer cell death may be a viable strategy with therapeutic benefit. By exploiting combined in silico and experimental strategies, we identified small peptides able to bind Atox1 and metal-binding domains 3-4 of ATP7B proteins. We found that these peptides reduced the proliferation of cancer cells owing to increased cellular copper ions concentration. These outcomes support the idea of harming copper trafficking as an opportunity for devising novel anti-cancer therapies.

Engineering of Doxorubicin-Encapsulating and TRAIL-Conjugated Poly(RGD) Proteinoid Nanocapsules for Drug Delivery Applications.

Proteinoids are non-toxic biodegradable polymers prepared by thermal step-growth polymerization of amino acids. Here, P(RGD) proteinoids and proteinoid nanocapsules (NCs) based on D-arginine, glycine, and L-aspartic acid were synthesized and characterized for targeted tumor therapy. Doxorubicin (Dox), a chemotherapeutic drug used for treatment of a wide range of cancers, known for its adverse side effects, was encapsulated during self-assembly to form Dox/P(RGD) NCs. In addition, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which can initiate apoptosis in most tumor cells but undergoes fast enzyme degradation, was stabilized by covalent conjugation to hollow P(RGD) NCs. The effect of polyethylene glycol (PEG) conjugation was also studied. Cytotoxicity tests on CAOV-3 ovarian cancer cells demonstrated that Dox/P(RGD) and TRAIL-P(RGD) NCs were as effective as free Dox and TRAIL with cell viability of 2% and 10%, respectively, while PEGylated NCs were less effective. Drug-bearing P(RGD) NCs offer controlled release with reduced side effects for improved therapy.

SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα.

The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. Sirt6+/- results in significantly reduced PPARα-induced ß-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce ß-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver.

Dynamic force distribution during level walking under the feet of patients with chronic ankle instability.

OBJECTIVES: To examine changes in the pattern of force transfer between the foot and the floor associated with chronically sprained ankles by measuring the peak forces and their timing under several regions of the feet during level walking. METHODS: Twelve young male subjects (mean (SD) age 21 (2) years) with recurrent ankle sprains were studied. Seven of them had unilateral and bilateral chronic instability and laxity, and five had bilateral instability. Twelve healthy men (without orthopaedic or medical disease) served as a control group. Subjects walked at their own pace along a 7 m walkway, which included a Mini-EMED pressure distribution measuring system. The variables measured were relative peak force (fraction of body weight) and relative timing (fraction of stance time). These variables were measured under six regions of interest in each foot print: heel, midfoot, medial, central, and lateral forefoot, and toes. RESULTS: (a) A significant delay to the time of peak force under the central and lateral forefoot and toes in subjects with chronic ankle instability. (b) A significant decrease in the relative forces under the heel and toes and an increase in the relative forces under the midfoot and lateral forefoot in subjects with chronic ankle instability. (c) In the patients with unilateral instability, there were no significant differences in any of the variables between the injured and non-injured foot. CONCLUSIONS: In patients with chronic ankle instability, there is a slowing down of weight transfer from heel strike to toe off, a reduced impact at the beginning and end of the stance phase, and a lateral shift of body weight.

Subtalar distraction arthrodesis using a ramp cage.

Subtalar distraction bone block arthrodesis has been described to treat late complications of displaced calcaneal fractures. A "ramp cage" can be used to restore the talocalcaneal relationship by providing stable correction in the coronal and sagittal dimensions.

Acetabular fractures. Clinical outcome of surgical treatment.

Sixty patients with acetabular fractures were treated surgically. All fractures were a result of high energy trauma, most with significant associated injuries. Fifty-three of the patients were followed up for at least 2 years. Clinical outcome was analyzed clinically using the Harris hip score and radiographically. In 41 (77.4%) of the patients, the surgical procedure was judged successful (Harris hip score greater than 80 points). Three factors were found to be statistically significant predictors of such an outcome: patient age younger than 40 years; simple fractures based on the classification of Letournel and Judet; and absence of damage to the femoral head. Possible influential factors that were not found to be statistically significant in this population included additional injuries, immediate complications, quality of reduction, heterotopic ossification, ipsilateral femoral fracture, and sciatic nerve damage. Open reduction and internal fixation of the displaced acetabular fracture, although a demanding procedure, can result in a satisfactory clinical outcome given a consistent approach with a dedicated team.

Fracture of the posterior body of the talus--the hidden fracture.

Fractures of the entire posterior process of the talus are rare and may be easily missed. Both the ankle joint and the subtalar joint are involved. This leads to malunion and early degenerative changes. We describe four patients with fractures of the posterior process of the talus which were initially missed. The patients were treated conservatively, and early mobilization or cast immobilization did not change the poor late results. The pitfalls in the diagnosis and imaging evaluation of such fractures are discussed.

The role of the knee brace in the prevention of anterior knee pain syndrome.

Our prospective study evaluates the use of a knee brace with a silicon patellar support ring as a method of preventing anterior knee pain from developing in young persons undergoing strenuous physical exercise. We studied 60 young athletes, who qualified for a strenuous physical training course and who had not suffered from anterior knee pain previously. Twenty-seven subjects were in the brace group and 33 were in the nonbrace control group. The incidence of anterior knee pain syndrome increased with the intensity of exertion as the study progressed; i.e., subjects ran 6 km in the 1st week, gradually increasing each week up to 42 km/week at the 8th week. Yet, there was a significant reduction in the incidence of the syndrome at the end of the study in male athletes who had applied the braces before exercise sessions and in the brace group as a whole, compared with the control group. Prophylactic use of the brace, as described, did not reduce the ability of the athletes who wore braces to improve their physical fitness parameters in response to exercise. These data indicate that the use of a brace may be an effective way to prevent the development of anterior knee pain syndromes in persons participating in strenuous and intensive physical exercise.

Concomitant medial facet and dome fractures of the talus.

Osteochondral fracture of the dome of the talus is a well known complication of an inversion injury of the ankle. Recently the authors encountered a patient having a talar dome fracture associated with intra-articular fracture of the medial facet after inversion injury of the ankle. The authors have been unable to find a medial facet intra-articular fracture reported in the English literature. The talar dome fragment was removed arthroscopically and the medial facet fragment was removed using an open surgical approach. The mechanism of injury and the operative approach are discussed.

Osteomyelitis of the pelvis.

Four cases of osteomyelitis of the pelvis are reported to demonstrate the several clinical syndromes to which this disease can give rise. Extensive surgical drainage and antibiotic treatment led to recovery in all cases.

Secondary damage to the knee after isolated injury of the anterior cruciate ligament.

Between 1978 and 1984, we examined and performed arthroscopy on 1000 consecutive patients. Ninety-eight of the 1000 had isolated ACL damage. These cases do not include patients with initial ACL injuries combined with other intraarticular damage. Diagnosis was by physical and arthroscopic examination. Examination took place an average 13.6 months after injury. Of the 98 isolated ACL injuries, 56 were complete ruptures and 42 were partial ruptures. In most cases of partial rupture, the clinical diagnosis was wrong. "Meniscal damage" was the usual diagnosis in these cases; the true diagnosis was made only by arthroscopic examination. Thirty-four of the 98 patients with isolated ACL injuries (30 men and 4 women) developed further intraarticular damage. Of these 34, 20 had complete ACL rupture and 14 had partial ACL rupture. Treatment after primary injury included physiotherapy in all patients and bracing in those whose knee was unstable during daily activities. Reconstructive surgical procedures were not performed in those patients. The time lapse from the primary to the secondary injury varied from 1 month to 20 years, with an average of 28 months. The secondary damage was caused by a secondary injury that was mild (22 cases) or developed insidiously (12 cases). Five types of secondary damage were observed: partial ACL tears that became complete--11 cases; meniscal tear--8 cases; loosening and subluxation of the anterior horn of the medial meniscus--14 cases; and fracture or damage to the articular condylar cartilage, with or without bone involvement--11 cases. It should be emphasized that the secondary damages were at times combined.