Primary Osteoma Cutis in the Interscapular Region of a Dog.

A 9-year-old neutered male Shih Tzu was presented with three contiguous firm nodules in the subcutaneous tissue of the interscapular region. Histopathological examination revealed that the nodules consisted of mature lamellar bone with a Haversian system, with no apparent lesion around the bone. Clinical examination revealed that the dog had no underlying disease and no history of trauma at the lesion site. Based on these findings and on the medical history, a diagnosis of primary osteoma cutis was made. Osteoma cutis is rare in both human and veterinary medicine, and most dogs reported to have secondary osteoma cutis. To our knowledge, this case is only the second report of primary osteoma cutis in a dog.

Intra-oral Sebaceous Gland Tumours in Two Dogs.

A 12-year-old female miniature schnauzer and a 12-year-old neutered female cocker spaniel each had a grey-yellow nodular lesion arising from the gingiva. Microscopical examination showed that both nodules were composed of varied proportions of sebocytes and basal-type reserve cells with few ducts lined by stratified squamous epithelium. Based on the histopathological findings, the cases were diagnosed as sebaceous adenoma and sebaceous epithelioma, respectively. In man, the occurrence of sebaceous neoplasms in the oral cavity has been reported to some extent, but these lesions are very rare in animals. To the best of our knowledge, this is the first report of intra-oral sebaceous neoplasms in dogs. Intra-oral sebaceous epithelioma has never been reported in animals.

Physician and nurse knowledge about patient radiation exposure in the emergency department.

BACKGROUND: Imaging methods that use ionizing radiation in emergency departments (EDs) have increased with advances in radiological diagnostic methods. Physician and nurse awareness of the radiation dose in the ED and the associated cancer risks to which the patients are exposed were surveyed with a questionnaire. METHODS: A total of 191 subjects in six EDs participated in this study. ED physicians and ED nurses were asked about the risks and the radiation doses of imaging methods ordered in the ED. The differences between the two groups were compared using Student's t-test for continuous variables. A Fisher's exact and Chi-squared tests were used for categorical variables. RESULTS: A total of 82 ED physicians and 109 ED nurses completed the questionnaire; 38 (46.3%) physicians and 8 (7.3%) nurses correctly answered the question about the chest X-ray radiation dose. A question about the number of chest X-rays that is equivalent to the dose of a pelvic X-ray was answered correctly by 5 (6.1%) physicians and 9 (8.3%) nurses (P = 0.571). Questions regarding abdominal computed tomography (CT), chest CT, brain CT, abdominal ultrasonography, and brain magnetic resonance imaging were answered correctly more frequently by the physician group than the nurse group (P < 0.05). The risk of developing cancer over a lifetime due to a brain CT was correctly answered by 21 (25.6%) physicians and 30 (27.5%) nurses (P = 0.170). A similar question regarding abdominal CT was correctly answered by 21 (25.6%) physicians and 42 (38.5%) nurses (P = 0.127). CONCLUSIONS: Knowledge of the radiation exposure of radiology examinations was lower in nurses than physicians, but knowledge was poor in both groups. ED physicians and nurses should be educated about radiation exposure and cancer risks associated with various diagnostic radiological methods.

Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition.

Twist1 is highly expressed in primary and metastatic non-small cell lung cancer (NSCLC), and thus acts as a critical target for lung cancer chemotherapy. In the current study, we investigated the underlying mechanism initiated by silencing of Twist1 that sensitizes NSCLC cells to cisplatin. Silencing of Twist1 triggered ATP depletion, leading to AMP-activated protein kinase (AMPK)-activated mammalian target of rapamycin (mTOR) inhibition in NSCLC cells. AMPK-induced mTOR inhibition, in turn, resulted in downregulation of ribosome protein S6 kinase 1 (S6K1) activity. Downregulation of mTOR/S6K1 reduced Mcl-1 protein expression, consequently promoting sensitization to cisplatin. Overexpression of Mcl-1 reduced PARP cleavage induced by cisplatin and Twist1 siRNA, suggesting that this sensitization is controlled through Mcl-1 expression. Interestingly, cells treated with Twist1 siRNA displayed upregulation of p21(Waf1/CIP1), and suppression of p21(Waf1/CIP1) with specific siRNA further enhanced the cell death response to cisplatin/Twist1 siRNA. In conclusion, silencing of Twist1 sensitizes lung cancer cells to cisplatin via stimulating AMPK-induced mTOR inhibition, leading to a reduction in Mcl-1 protein. To our knowledge, this is the first report to provide a rationale for the implication of cross-linking between Twist1 and mTOR signaling in resistance of NSCLC to anticancer drugs.

TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1.

The mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase activated in response to growth factors and nutrients. Because of frequent dysregulation of the mTOR signaling pathway in diverse human cancers, this kinase is a key therapeutic target. Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex. In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein. Redd1 and TXNIP expression was induced by a synthetic glucose analog, 2-deoxyglucose (2-DG). Moreover, Redd1 expression in response to 2-DG was regulated by activating transcription factor 4 (ATF4). Overexpression of TXNIP was associated with reduced mTOR activity mediated by an increase in Redd1 level, whereas knockdown of TXNIP using small interfering RNA resulted in recovery of mTOR activity via downregulation of Redd1 during treatment with 2-DG. Interestingly, Redd1 was additionally stabilized via interactions with N-terminal-truncated TXNIP, leading to suppression of mTOR activity. Our results collectively demonstrate that TXNIP stabilizes Redd1 protein induced by ATF4 in response to 2-DG, resulting in potentiation of mTOR suppression. To the best of our knowledge, this is the first study to identify TXNIP as a novel member of the mTOR upstream that acts as a negative regulator in response to stress signals.

A dual anteroposterior approach to the Bernese periacetabular osteotomy.

When the Bernese periacetabular osteotomy is performed through an anterior approach, the ischial and retroacetabular osteotomies and manual fracture of the incompletely osteotomized ischium are conducted with an incomplete view resulting in increased risk and morbidity. We have assessed the dual anteroposterior approach which appears to address this deficiency. We compared the results of the Bernese periacetabular osteotomy performed in 11 patients (13 osteotomies) through a single anterior approach with those in 12 patients (13 osteotomies) in whom the procedure was carried out through a dual anteroposterior approach. The estimated blood loss, the length of anaesthesia, duration of surgery and radiological parameters were measured. The mean operative time and length of anaesthesia were not significantly different in the two groups (p = 0.781 and p = 0.698, respectively). The radiological parameters improved to a similar extent in both groups after the operation but there was significantly less blood loss in the dual osteotomy group (p = 0.034). The dual anteroposterior approach provides a direct view of the retroacetabular and ischial parts of the osteotomy, within a reasonable operating time and with minimal blood loss and gives a satisfactory outcome.

Salvage of the lower extremity free flap using cross-leg venous repair.

This retrospective study was designed to evaluate a salvage technique for free flaps suffering venous congestion by using a cross-leg vein repair in patients with venous-impaired lower extremities. Four free flap reconstructions were performed using the latissimus dorsi muscle to reconstruct soft tissue defects in the lower extremity. The recipient artery was confined to the ipsilateral leg and the venous anastomosis was performed with a long saphenous vein from the contralateral side. The legs were immobilised together by means of an external fixator. All patients were males with a mean age of 31 years. The mean time of pedicle division was 8.8 days (7-10). The mean size of the free flap was 186.5 cm(2). All flaps survived after pedicle division without venous congestion. There were no complications such as joint stiffness or donor site morbidity except for a linear scar. The cross-leg venous repair is a refinement of a salvage procedure for compromised free flaps used in the reconstruction of severe soft tissue defects in vascularly compromised lower extremities.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis is dependent on activation of cysteine and serine proteases.

We examined the role of caspases and serine protease(s) in cell death induced by tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). After incubation of adenocarcinoma cells with TRAIL, caspase-3, -8 were activated and the cleavage of Bid induced the release of cytochrome c, from the mitochondria to the cytosol. Tetrapeptide inhibitors of caspase-1, -2, -3, and -8 suppressed DNA fragmentation and attenuated the release of cytochrome c, whereas inhibitors of caspase-5 did not. Interestingly, the general serine protease(s) inhibitor 4-(2-aminoethyl)benzylsulfonyl fluoride (AEBSF) resulted in the arrest of apoptosis. However, the AEBSF did not prevent the release of mitochondrial cytochrome c during TRAIL-induced apoptosis. From these results, we postulate that serine protease(s) may be involved in post-mitochondrial apoptotic events, that lead to the activation of the initiator, caspase-9.

Pre-expanded arterialised venous free flaps for burn contracture of the cervicofacial region.

Despite the fact that arterialised venous flaps provide thin good-quality tissue to repair defects of the face and neck, their clinical applications have been limited by an unstable postoperative course and variable flap necrosis. In an effort to resolve these problems, a tissue-expansion technique has been applied to the arterialised venous flap before flap transfer. Three pre-expanded arterialised venous free flaps have been used to treat post-burn scar contracture of the cervicofacial region. The donor site was confined to the forearm in each case. A rectangular expander was usually placed over the fascia of the flexor muscles in the proximal two-thirds of the forearm. The mean expansion period, volume and flap size were 44 days, 420 cm(3)and 147 cm(2), respectively. There were no complications caused by insertion and expansion. The cervicofacial region was successfully reconstructed, after excision of the post-burn contractures, with pre-expanded arterialised venous flaps, with no marginal necrosis or postoperative instability. Large thin arterialised venous flaps are well matched with the recipient defect in the cervicofacial area and the colour and texture match obtained with forearm tissue produced an aesthetically favourable result. Pre-expanded arterialised venous flaps are another new option for free flap reconstruction of the face and neck.

Optimizing the correction of severe postburn hand deformities by using aggressive contracture releases and fasciocutaneous free-tissue transfers.

Severe postburn hand deformities were classified into three major patterns: hyperextension deformity of the metacarpophalangeal joint of the fingers with dorsal contracture of the hand, adduction contracture of the thumb with hyperextension deformity of the interphalangeal joint, and flexion contracture of the palm. Over the past 6 years, 18 cases of severe postburn hand deformities were corrected with extensor tenotomy, joint capsulotomy, and release of volar plate and collateral ligament. The soft-tissue defects were reconstructed with various fasciocutaneous free flaps, including the arterialized venous flap (n = 4), dorsalis pedis flap (n = 3), posterior interosseous flap (n = 3), first web space free flap (n = 3), and radial forearm flap (n = 1). Early active physical therapy was applied. All flaps survived. Functional return of pinch and grip strength was possible in 16 cases. In 11 cases of reconstruction of the dorsum of the hand, the total active range of motion in all joints of the fingers averaged 140 degrees. The mean grip strength was 16.5 kg and key pinch was 3.5 kg. In palm reconstruction, the wider contact area facilitated the grasping of larger objects. In thumb reconstruction, key-pinch increased to 5.5 kg and the angle of the first web space increased to 45 degrees. Jebsen's hand function test was not possible before surgery; postoperatively, it showed more functional recovery in gross motion and in the dominant hand. Aggressive contracture release of the bone,joints, tendons, and soft tissue is required for optimal results in the correction of severe postburn hand deformities. Various fasciocutaneous free flaps used to reconstruct the defect provide early motion, appropriate thinness, and excellent cosmesis of the hand.

Implication of a small GTPase Rac1 in the activation of c-Jun N-terminal kinase and heat shock factor in response to heat shock.

Heat shock induces c-Jun N-terminal kinase (JNK) activation as well as heat shock protein (HSP) expression through activation of the heat shock factor (HSF), but its signal pathway is not clearly understood. Since a small GTPase Rac1 has been suggested to participate in the cellular response to stresses, we examined whether Rac1 is involved in the heat shock response. Here we show that moderate heat shock (39-41 degrees C) induces membrane translocation of Rac1 and membrane ruffling in a Rac1-dependent manner. In addition, Rac1N17, a dominant negative mutant of Rac1, significantly inhibited JNK activation by heat shock. Since Rac1V12 was able to activate JNK, it is suggested that heat shock may activate JNK via Rac1. Similar inhibition by Rac1N17 of HSF activation in response to heat shock was observed. However, inhibitory effects of Rac1N17 on heat shock-induced JNK and HSF activation were reduced as the heat shock temperature increased. Rac1N17 also inhibited HSF activation by l-azetidine-2-carboxylic acid, a proline analog, and heavy metals (CdCl)), suggesting that Rac1 may be linked to HSF activation by denaturation of polypeptides in response to various proteotoxic stresses. However, Rac1N17 did not prevent phosphorylation of HSF1 in response to these proteotoxic stresses. Interestingly, a constitutively active mutant Rac1V12 did not activate the HSF. Therefore, Rac1 activation may be necessary, but not sufficient, for heat shock-inducible HSF activation and HSP expression, or otherwise a signal pathway(s) involving Rac1 may be indirectly involved in the HSF activation. In sum, we suggest that Rac1 may play a critical role(s) in several aspects of the heat shock response.

Antimalarial, antiproliferative, and antitumor activities of artemisinin-derived, chemically robust, trioxane dimers.

Nine C-10 non-acetal derivatives of the natural trioxane artemisinin (1) were prepared as dimers using some novel chemistry. As designed, each dimer was stable chemically. C-10 Olefinic dimers 7 and C-10 saturated dimers 8-13 all showed good to excellent antimalarial and antiproliferative activities in vitro. Dimers 8, 10, and 12 were especially potent and selective at inhibiting growth of some human cancer cell lines in the NCI in vitro 60-cell line assay.

Microsurgical reconstruction of partial thumb defects.

We have reconstructed thumb defects using microsurgical techniques in 43 patients. The flap survival was 100% and functional improvement with near normal appearance was obtained in the reconstructed thumbs. In order to obtain satisfactory results, donor sites were confined to the great toe and its adjacent structures and adventitia was removed from the vascular pedicle, which was transferred by subcutaneous tunnelling to minimize scar formation in the reconstructed thumb. The width of transferred nail and pulp volume were matched to the defect in the thumb before transfer.

KR025, a new cytotoxic compound from Myxococcus fulvus.

A new bithiazole, KR-025 (1), was isolated from Myxococcus fulvus. Its structure was elucidated by spectroscopic analysis. In addition to 1, the strain produced relatively large quantities of a second, closely related antibiotic, myxothiazol. These compounds demonstrated potent cytotoxicity against human tumor cells.

Classification of the first web space free flap of the foot and its applications in reconstruction of the hand.

Owing to its unique anatomic arterial supply and dual nerve innervation, the first web space of the foot can be used to harvest various sizes and shapes of flaps, which the authors have classified into four types according to their usage in hand reconstruction. This in turn depends on the site, shape, and size of the soft-tissue defect in the hand. Web skin flaps (n = 8) were used in prevention of contracture in the first web space and for proximal finger reconstruction. Two-island skin flaps (n = 4) were used to resurface the pulp defect in two adjacent fingers. In severe adduction contracture of the first web space, fill-up web flaps (n = 10) were used to replace the volume defect after a release procedure in the hand. Adjuvant web flaps (n = 9) were used in wrap-around procedures, in dorsalis pedis flap transfer, and in vascularized joint transfer to supplement the main flaps and to restore sensation in the reconstructed area. In the past 10 years up to February of 1998, a total of 31 patients with soft-tissue defects in the hand and fingers were reconstructed using the web space free flap with flap survival rate of 100 percent. The mean static 2-point discrimination was 8.5 (7.2 to 10) mm, and the mean first web angle was 86 degrees. The advantage of the first web space flap from the foot is that it can easily be harvested to match various sizes and shapes of defects in the hand and fingers. In addition, because of the anatomic similarity in contour, thickness, texture, and nerve innervation with the hand, the sensory restoration is excellent with minimal morbidity at the donor site. By classifying the flaps into four types according to various sizes, shapes, and the site from which the flap are harvested, clinical usefulness in various types of hand and finger reconstruction was confirmed.

Topoisomerase II inhibition by aporphine alkaloids.

The aporphine alkaloids (+)-dicentrine and (+)-bulbocapnine are non-planar molecules lacking features normally associated with DNA binding by intercalation or minor groove binding. Surprisingly, dicentrine showed significant activity as a topoisomerase II (EC 5.99.1.3) inhibitor and also was active in a DNA unwinding assay. The DNA unwinding suggests DNA intercalation, which could explain the inhibition of topoisomerase II. Bulbocapnine, which differs from dicentrine only by the presence of a hydroxyl group at position 11 and the absence of a methoxyl group at position 9, was inactive in all assays. Molecular modeling showed that dicentrine can attain a relatively planar conformation, whereas bulbocapnine cannot, due to steric interaction between the 11-hydroxyl group and an oxygen of the methylenedioxy ring. These observations suggest that dicentrine is an "adaptive" DNA intercalator, which can bind DNA only by adopting a somewhat strained planar conformation. The requirement of a suboptimal conformation to achieve DNA binding appears to make dicentrine a weaker topoisomerase II inhibitor than the very planar oxoaporphine alkaloid liriodenine. These results suggest that it may be possible to modulate DNA binding and biologic activity of drugs by modifications affecting their ability to adopt planar conformations.

DNA polymerase and topoisomerase II inhibitors from Psoralea corylifolia.

An ethanol extract of Psoralea corylifolia caused strong DNA polymerase inhibition in a whole cell bioassay specific for inhibitors of DNA replication enzymes. Bioassay-directed purification of the active compounds led to the isolation of the new compound corylifolin (1) and the known compound bakuchiol (2) as DNA polymerase inhibitors. On the basis of the structures of 1 and 2, resveratrol (3) was tested and found to be active as a DNA polymerase inhibitor in this bioassay. Neobavaisoflavone (4) was isolated as a DNA polymerase inhibitor, daidzein (5) as a DNA polymerase and topoisomerase II inhibitor, and bakuchicin (6) as a topoisomerase II inhibitor.

Effects of blood flow and venous network on the survival of the arterialized venous flap.

The purpose of this study was to evaluate further factors that could explain the survival mechanism in the arterialized venous flap. The authors used 16 canines to investigate the survival rate and pattern of the arterialized venous flap and compared the results with those of the conventional saphenous flap. The number and distribution of draining veins in the arterialized venous flap group were varied to observe their impact on the survival rate and pattern. Gross examination of venous network, blood gas, venogram, blood pressure, and histologic study were also carried out. Although there was no significant difference in final survival rate between conventional flap and arterialized venous flap with two efferent veins (p > 0.01), that of the arterialized venous flap increased significantly as the number of draining veins increased. Blood gas analysis showed that more effective oxygen consumption took place when the number of draining veins increased. By measuring the blood flow and volume at 8 hours after the operation with a laser Doppler flowmeter, it was possible to predict the necrosis of the arterialized venous flap. Attachment to a high pressure arterial blood flow system induced smooth muscle proliferation and neogrowth of elastic fibers in the veins. Furthermore, progressive narrowing of the lumen hastened the development of a collateral circulation, demonstrated on a venogram by the tortuous vessels and neovascularization up to the flap margin. To make it possible to predict and achieve complete survival of the arterialized venous flap, the following criteria must be considered: (a) an arterialized venous flap should be designed to contain most of the venous network in the center, (b) the arterial inflow has to be anastomosed to one afferent vein, (c) two or more efferent veins should drain the arterialized venous flap.