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The RANKL-induced NF-κB signaling pathway is required for osteoclast formation and function. By screening for compounds that inhibit RANKL-induced NF-κB activation using a luciferase reporter gene assay in RAW264.7 cells, we identified triptolide (PG490), as a candidate compound targeting osteoclast differentiation and osteoclast-mediated osteolysis. Triptolide (PG490) is an active compound of the medicinal herb Tripterygium wilfordii Hook F (TWHF) or Lei Gong Teng with known anti-inflammatory properties. We found that triptolide inhibited osteoclastogenesis and bone resorption, as well as RANKL-induced NF-қB activities as monitored by luciferase reporter gene assays and the nuclear translocation of p65. In vivo studies showed that triptolide attenuates titanium-induced osteolysis and osteoclast formation in a mouse calvarial model. Considering that drugs which protect against localized bone loss are critically needed for the effective treatment of particle-induced osteolysis, our data suggest that triptolide might have therapeutic potential for the treatment of bone lytic diseases caused by prosthetic wear particles., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: This study aims to investigate, utilising micro-computed tomography (micro-CT) and histology, whether the topical application of nerve growth factor (NGF) and/or epidermal growth factor (EGF) can enhance periodontal, alveolar bone, root and pulpal tissue regeneration while minimising the risk of pulpal necrosis, root resorption and ankylosis of replanted molars in a rat model., Methods: Twelve four-week-old male Sprague-Dawley rats were divided into four groups: sham, collagen, EGF and NGF. The maxillary right first molar was elevated and replanted with or without a collagen membrane impregnated with either the growth factors EGF or NGF, or a saline solution. Four weeks after replantation, the animals were sacrificed and the posterior maxilla was assessed using histological and micro-CT analysis. The maxillary left first molar served as the control for the corresponding right first molar., Results: Micro-CT analysis revealed a tendency for all replanted molars to have reduced root length, root volume, alveolar bone height and inter-radicular alveolar bone volume. It appears that the use of the collagen membrane had a negative effect while no positive effect was noted with the incorporation of EGF or NGF. Histologically, the incorporation of the collagen membrane was found to negatively affect pulpal, root, periodontal and alveolar bone healing with pulpal inflammation and hard tissue formation, extensive root resorption and alveolar bone fragmentation. The incorporation of EGF and NGF did not improve root, periodontal or alveolar bone healing. However, EGF was found to improve pulp vascularisation while NGF-improved pulpal architecture and cell organisation, although not to the level of the control group., Conclusions: Results indicate a possible benefit on pulpal vascularisation and pulpal cell organisation following the incorporation of EGF and NGF, respectively, into the alveolar socket of replanted molars in the rat model. No potential benefit of EGF and NGF was detected in periodontal or root healing, while the use of a collagen membrane carrier was found to have a negative effect on the healing response.

Introduction: There is limited utilisation of acute stroke reperfusion treatments which have narrow therapeutic windows, with delayed hospital presentation being a major limiting factor in Singapore. Most patients who wake up with symptoms are ineligible for reperfusion treatments as duration from onset time is not known. We studied the profile of wake-up strokes, onset-to-door duration and their associated factors among ischaemic stroke patients in the context of potential new treatments., Materials and Methods: This is an observational study of consecutive ischaemic stroke patients presenting within 2 weeks of symptom onset to the Singapore General Hospital in 2012., Results: Of the 642 ischaemic stroke patients studied, 33% of the cases were wake-up strokes [median age 64 years, 88%<80 years; median NIHSS score 4, 98%<20]. The median onset-to-door duration was 14.3 hours (Interquartile range, 4.8 to 38.2 hours), 20% of them arrived <3.5 hours (considering eligibility for intravenous alteplase in the proven 4.5 hours window accounting for a one hour door-to-needle duration), 14%: ≥3.5 to <8 hours, 11%: ≥8 to <12 hours, and 56%: ≥12 hours. Most patients with known stroke risk factors including atrial fibrillation (66%), hypertension (78%) and prior stroke (81%) presented beyond 3.5 hours., Conclusion: The one- third proportion of wake-up stroke in this cohort and low prevalence of relative contraindications suggest this is a promising group for emerging thrombolysis indications. With the majority of patients presenting after 8 hours, widening of the therapeutic window with new potential reperfusion treatments would not appreciably increase treatment utilisation. This study reaffirms the urgent need for public education to improve stroke awareness in Singapore.

Background: Patients with acute coronary syndrome (ACS) often present atypically. In a randomized controlled trial, we studied whether adding stress myocardial perfusion imaging (SMPI) to an evaluation strategy for emergency department (ED) patients presenting with chest pain more effectively identifies patients with ACS., Methods: Participants were randomized to standard ED chest pain protocol (clinical assessment) or standard protocol supplemented with SMPI results. During 6 hours of electrocardiogram (ECG) monitoring and serial cardiac markers (creatine kinase-MB isoenzyme, troponin), participants developing ST segment changes or elevated cardiac markers were admitted. Those with a negative observation period underwent SMPI (N = 1,004) or clinical assessment (N = 504) based on randomization, and admitted if their SMPI scan was abnormal or senior clinicians found a high or intermediate risk for ACS., Results: SMPI participants had a significantly lower admission rate than clinical assessment participants (10.16% vs 18.45%), with no significant between-group differences in risk of cardiac events (CEs) after 30 days (0.40% vs 0.79%) or 1 year (0.70% vs 0.99%)., Conclusions: When added to a standard triage strategy incorporating clinical evaluation, serial ECGs, and cardiac markers, SMPI improved clinical decision making for chest pain patients, significantly reducing the need for hospitalization without an increase in adverse CE rates at 30 days or 1 year.

Cancer chemotherapy with methotrexate (MTX) is known to cause bone loss. However, the underlying mechanisms remain unclear. This study investigated the potential role of MTX-induced pro-inflammatory cytokines and activation of NF-κB in the associated osteoclastogenesis in rats. MTX (0.75 mg/kg per day) was administered for 5 days, and bone and bone marrow specimens were collected on days 6, 9, and 14. Compared with a normal control, MTX increased the density of osteoclasts within the metaphyseal bone and the osteoclast formation potential of marrow cells on day 9. RT-PCR analysis of mRNA expression for pro-osteoclastogenic cytokines in the metaphysis indicated that, although the receptor activator of NF-κB ligand/osteoprotegerin axis was unaffected, expression of tumor necrosis factor (TNF)-α, IL-1, and IL-6 increased on day 9. Enzyme-linked immunosorbent assay analysis of plasma showed increased levels of TNF-α on day 6 and of IL-6 on day 14. Plasma from treated rats induced osteoclast formation from normal bone marrow cells, which was attenuated by a TNF-α-neutralizing antibody. Indicative of a role for NF-κB signaling, plasma on day 6 increased NF-κB activation in RAW(264.7) cells, and plasma-induced osteoclastogenesis was abolished in the presence of the NF-κB inhibitor, parthenolide. Our results demonstrate mechanisms for MTX-induced osteoclastogenesis and show that MTX induces osteoclast differentiation by generating a pro-osteoclastogenic environment in both bone and the circulation, specifically with increased TNF-α levels and activation of NF-κB., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Pathological bone destruction (osteolysis) is a hallmark of many bone diseases including tumor metastasis to bone, locally osteolytic giant cell tumor (GCT) of bone, and Paget's disease. Paclitaxel is frequently prescribed in the treatment of several malignant tumors where it has been shown to exert beneficial effects on bone lesions. However, the mechanism(s) through which paclitaxel regulates osteoclast formation and function remain ill defined. In the present study, we demonstrate that paclitaxel dose-dependently inhibits receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis in both RAW264.7 cells and mouse bone marrow macrophage (BMM) systems. In addition, paclitaxel treatment reduces the bone resorptive activity of human osteoclasts derived from GCT of bone, and attenuates lipopolysaccharide (LPS)-induced osteolysis in a mouse calvarial model. Complementary cellular and biochemical analyses revealed that paclitaxel induces mitotic arrest of osteoclastic precursor cells. Furthermore, luciferase reporter gene assays and western blot analysis indicate that paclitaxel modulates key RANKL-induced activation pathways that are essential to osteoclast formation including NF-κB and ERK. Collectively, our findings demonstrate a role for paclitaxel in the regulation of osteoclast formation and function and uncover potential mechanism(s) through which paclitaxel alleviates pathological osteolysis., (Copyright © 2011 Wiley Periodicals, Inc.)

Osteolytic bone diseases including osteoporosis are commonly accompanied with enhanced osteoclast formation and bone resorption. Naringin, a natural occurring flavonoid has been found to protect against retinoic acid-induced osteoporosis and improve bone quality in rats. Here, we showed that naringin perturbs osteoclast formation and bone resorption by inhibiting RANK-mediated NF-κB and ERK signaling. Naringin suppressed gene expression of key osteoclast marker genes. Naringin was found to inhibit RANKL-induced activation of NF-κB by suppressing RANKL-mediated IκB-α degradation. In addition, naringin inhibited RANKL-induced phosphorylation of ERK. This study identifies naringin as an inhibitor for osteoclast formation and bone resorption, and provides evidence that natural compounds such as naringin might be beneficial as an alternative medicine for the prevention and treatment of osteolysis., (Copyright © 2011. Published by Elsevier B.V.)

Vesicular transport along microtubules must be strictly regulated to sustain the unique structural and functional polarization of bone-resorbing osteoclasts. However, the molecular mechanisms bridging these vesicle-microtubule interactions remain largely obscure. Rab3D, a member of the Rab3 subfamily (Rab3A/B/C/D) of small exocytotic GTPases, represents a core component of the osteoclastic vesicle transport machinery. Here, we identify a new Rab3D-interacting partner, Tctex-1, a light chain of the cytoplasmic dynein microtubule motor complex, by a yeast two-hybrid screen. We demonstrate that Tctex-1 binds specifically to Rab3D in a GTP-dependent manner and co-occupies Rab3D-bearing vesicles in bone-resorbing osteoclasts. Furthermore, we provide evidence that Tctex-1 and Rab3D intimately associate with the dynein motor complex and microtubules in osteoclasts. Finally, targeted disruption of Tctex-1 by RNA interference significantly impairs bone resorption capacity and mislocalizes Rab3D vesicles in osteoclasts, attesting to the notion that components of the Rab3D-trafficking pathway contribute to the maintenance of osteoclastic resorptive function.

Receptor activator NF-kappaB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation and survival. Caffeic acid phenethyl ester (CAPE), a natural NF-kappaB inhibitor from honeybee propolis has been shown to have anti-tumor and anti-inflammatory properties. In this study, we investigated the effect of CAPE on the regulation of RANKL-induced osteoclastogenesis, bone resorption and signaling pathways. Low concentrations of CAPE (<1 microM) dose dependently inhibited RANKL-induced osteoclastogenesis in RAW264.7 cell and bone marrow macrophage (BMM) cultures, as well as decreasing the capacity of human osteoclasts to resorb bone. CAPE inhibited both constitutive and RANKL-induced NF-kappaB and NFAT activation, concomitant with delayed IkappaBalpha degradation and inhibition of p65 nuclear translocation. At higher concentrations, CAPE induced apoptosis and caspase 3 activities of RAW264.7 and disrupts the microtubule network in osteoclast like (OCL) cells. Taken together, our findings demonstrate that inhibition of NF-kappaB and NFAT activation by CAPE results in the attenuation of osteoclastogenesis and bone resorption, implying that CAPE is a potential treatment for osteolytic bone diseases.

Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-kappaB is a set of nuclear factors that bind to consensus DNA sequences called kappaB sites, and is essential for osteoclast formation and survival. NF-kappaB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-alpha and IL-1, which differentially regulate classical and/or alternative NF-kappaB pathways in osteoclastic cells. These pathways are also modulated by NF-kappaB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin-proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-kappaB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-kappaB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-kappaB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases.

A key determinant of breast cancer outcome in any population is the degree to which cancers are detected at early stages of disease. Populations in which cancers are detected at earlier stages have lower breast cancer mortality rates. The Breast Health Global Initiative (BHGI) held its third Global Summit in Budapest, Hungary in October 2007, bringing together internationally recognized experts to address the implementation of breast healthcare guidelines for early detection, diagnosis, and treatment in low- and middle-income countries (LMCs). A multidisciplinary panel of experts specifically addressed the implementation of BHGI guidelines for the early detection of disease as they related to resource allocation for public education and awareness, cancer detection methods, and evaluation goals. Public education and awareness are the key first steps, because early detection programs cannot be successful if the public is unaware of the value of early detection. The effectiveness and efficiency of screening modalities, including screening mammography, clinical breast examination (CBE), and breast self-examination, were reviewed in the context of resource availability and population-based need by the panel. Social and cultural barriers should be considered when early detection programs are being established, and the evaluation of early detection programs should include the use of well developed, methodologically sound process metrics to determine the effectiveness of program implementation. The approach and scope of any screening program will determine the success of any early detection program as measured by cancer stage at diagnosis and will drive the breadth of resource allocation needed for program implementation., ((c) 2008 American Cancer Society.)

It has been postulated that venous thrombosis in free flap surgery necessitates the use of 2 venous anastomoses into different venous systems. We retrospectively analyzed a single surgeon's 10-year experience (August 1993 to August 2003) in primary free flap reconstruction for malignant tumors of the head and neck. Of 492 primary reconstructions that did not need a vein graft, vein loop, or cephalic turnover procedure, 251 used the internal jugular venous system as venous outflow, 140 used the subclavian system as outflow, and 101 used both. Two hundred thirty-eight of 251 (95%) of flaps utilizing the internal jugular venous system for outflow were successful compared with 129 of 140 (92%) of flaps utilizing the subclavian system. Where both venous systems were used the success rate was 101 of 101 (100%) (P < 0.05). Where possible, a second venous anastomosis should be performed utilizing both venous drainage systems.

Background: Successful free flap surgery in the head and neck is dependent on the successful anastomosis of both artery and vein. The success of all free flaps was analyzed to determine the necessity for performing 2 venous anastomoses., Methods: We retrospectively analyzed a single surgeon's 10-year experience (August 1993-August 2003) in free flap reconstruction for malignant tumors of the head and neck. Four hundred ninety-two free flaps were primary reconstructions that did not require a vein graft, vein loop, or cephalic turnover procedure. Three hundred forty-five flaps had 1 venous anastomosis, and 147 flaps had 2 venous anastomoses., Results: Overall, flap success was 468 of 492 (95.1%). Successful flap reconstruction in patients undergoing 2 venous anastomoses was 145 of 147 (98.6%) compared with 323 of 345 (93.6%) in patients undergoing 1 anastomosis (p < .05)., Conclusion: Where possible, a second venous anastomosis should be performed in head and neck free flap reconstruction.

Calcium/calmodulin-dependent protein kinase (CaMK) is a major down stream mediator of Ca(2+) signaling in a wide range of cellular functions, including ion channel and cell cycle regulation and neurotransmitter synthesis and release. Here we have investigated the role of the CaMK signaling pathway in osteoclast differentiation and bone resorption. We observed that the CaMKI, CaMKII gamma isoforms were present in both bone-marrow derived macrophages and RAW264.7 murine macrophage cell line, and that expression persisted during osteoclast differentiation in the presence of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL). RANKL-induced differentiation was accompanied by increased cyclic AMP response element transcriptional activity, and ERK phosphorylation, which are both downstream targets of CaMK. Two selective inhibitors of CaMKs, KN-93 and KN-62, inhibited osteoclastogenesis in a time and concentration-dependent manner. This was accompanied by suppression of cathepsin K expression and osteoclastic bone resorption, which are markers for differentiated osteoclast function. KN-93 and KN-62 both inhibited RANKL-induced ERK phosphorylation and CREB transcriptional activity. These findings imply a role for CaMK in osteoclast differentiation and bone resorption.

We have developed a bioreactor vessel design which has the advantages of simplicity and ease of assembly and disassembly, and with the appropriately determined flow rate, even allows for a scaffold to be suspended freely regardless of its weight. This article reports our experimental and numerical investigations to evaluate the performance of a newly developed non-perfusion conical bioreactor by visualizing the flow through scaffolds with 45 degrees and 90 degrees fiber lay down patterns. The experiments were conducted at the Reynolds numbers (Re) 121, 170, and 218 based on the local velocity and width of scaffolds. The flow fields were captured using short-time exposures of 60 microm particles suspended in the bioreactor and illuminated using a thin laser sheet. The effects of scaffold fiber lay down pattern and Reynolds number were obtained and correspondingly compared to results obtained from a computational fluid dynamics (CFD) software package. The objectives of this article are twofold: to investigate the hypothesis that there may be an insufficient exchange of medium within the interior of the scaffold when using our non-perfusion bioreactor, and second, to compare the flows within and around scaffolds of 45 degrees and 90 degrees fiber lay down patterns. Scaffold porosity was also found to influence flow patterns. It was therefore shown that fluidic transport could be achieved within scaffolds with our bioreactor design, being a non-perfusion vessel. Fluid velocities were generally same of the same or one order lower in magnitude as compared to the inlet flow velocity. Additionally, the 90 degrees fiber lay down pattern scaffold was found to allow for slightly higher fluid velocities within, as compared to the 45 degrees fiber lay down pattern scaffold. This was due to the architecture and pore arrangement of the 90 degrees fiber lay down pattern scaffold, which allows for fluid to flow directly through (channel-like flow)., ((c) 2007 Wiley Periodicals, Inc.)

Neurons of the cerebral neocortex in mammals, including humans, are generated during fetal life in the proliferative zones and then migrate to their final destinations by following an inside-to-outside sequence. The present study examined the effect of ultrasound waves (USW) on neuronal position within the embryonic cerebral cortex in mice. We used a single BrdU injection to label neurons generated at embryonic day 16 and destined for the superficial cortical layers. Our analysis of over 335 animals reveals that, when exposed to USW for a total of 30 min or longer during the period of their migration, a small but statistically significant number of neurons fail to acquire their proper position and remain scattered within inappropriate cortical layers and/or in the subjacent white matter. The magnitude of dispersion of labeled neurons was variable but systematically increased with duration of exposure to USW. These results call for a further investigation in larger and slower-developing brains of non-human primates and continued scrutiny of unnecessarily long prenatal ultrasound exposure.

The aim of this study was to establish the long-term biomechanical and histological properties of 2-octylcyanoacrylate-assisted microvascular anastomosis over conventional suture-only anastomosis in the laboratory rat model. The biomechanical and histological properties of three groups of vessels were compared: 1) vessels with 2-octylcyanoacrylate-assisted anastomoses (study group); 2) vessels with suture-only anastomoses (control group); and 3) normal unoperated vessels (sham group). In total, 144 adult rats were used, and these were studied at 1 week, 1 month, 3 months, and 6 months postanastomosis. At 6 months, the tensile strength of study vessels was significantly higher than control vessels. The stiffness of study and control vessels was similar at all time intervals. Histologically, there was no evidence that 2- octylcyanoacrylate caused toxicity to vessel walls, and there was less perivasacular foreign-body giant-cell reaction in the study group compared to the control group. Long-term follow-up showed that microvascular anastomosis with 2-octylcyanoacrylate in rat femoral arteries had superior tensile strength and similar stiffness to vessels anastomosed with sutures only, without adverse effects to surrounding tissues., (Copyright 2004 Wiley-Liss, Inc.)

Objective: Our aim was to evaluate the feasibility of acquiring an MR signal intensity-time renographic curve and dynamic serial images in a way similar to that of acquiring radionuclide renograms, with a dynamic gradient-echo sequence and a low-dose gadopentetate dimeglumine technique, using a commonly available 1.5-T MR scanner. SUBJECTS AND METHODS. Patients who underwent both radionuclide and MR renographic studies within a 3-month period were included in the analysis. This yielded 21 studies from 19 patients. Nineteen of the 21 studies were available for analysis. Two studies were excluded because of technical errors during MR renographic acquisition. Serial MR renograms were obtained using a dynamic two-dimensional spoiled gradient-echo fast low-angle shot T1-weighted sequence. Low-dose IV furosemide and gadopentetate dimeglumine (0.025 mmol/kg of body weight) were administered. Intensity-time curves were obtained from the manually selected regions of interest over the renal parenchyma and whole kidney for calculation of split renal function and assessment of urinary excretion, respectively. Results were compared with those obtained with radionuclide renography., Results: Good correlation (Pearson's correlation coefficient, r = 0.97, p < 0.001) was observed when the volume-corrected split renal function acquired with MR renography was compared with that obtained with radionuclide renography. There was also good agreement in the excretory curve patterns (weighted kappa(observer 1) = 0.77 and kappa(observer 2) = 0.81) between the two techniques., Conclusion: Dynamic MR gradient-echo imaging with a low-dose gadopentetate dimeglumine technique can produce an intensity-time curve and serial dynamic images of the urinary system, in a way similar to that of radionuclide renography. This technique allows assessment of split renal function and urinary excretory status and is a feasible alternative to radionuclide renography.

We have used time-lapse multiphoton microscopy to map the migration and settling pattern of GABAergic interneurons that originate in the ganglionic eminence of the ventral forebrain and incorporate into the neocortex of the cerebral hemispheres. Imaging of the surface of the cerebral hemispheres in both explant cultures and brains of living mouse embryos revealed that GABAergic interneurons migrating within the marginal zone originate from three different sources and migrate via distinct and independent streams. After reaching their areal destination, interneurons descend into the underlying cortex to assume positions with isochronically generated, radially derived neurons. The dynamics and pattern of cell migration in the marginal zone (see movies, available at www.jneurosci.org) suggest that the three populations of interneurons respond selectively to distinct local cues for directing their migration to the appropriate areas and layers of the neocortex. This approach opens a new avenue for study of normal and abnormal neuronal migration in their native environment and indicate that interneurons have specific programs for their areal and laminar deployment.

This paper reviews the role of free flap reconstruction following surgical resection of head and neck tumours. The process of selection of the various types of flaps for each specific defect is discussed. Challenges facing the reconstructive surgeon are reiterated.

Purpose: A small 6-cm colonic J-pouch improves stool frequency and continence, without stool evacuation problems. However, the reservoir function is not improved on physiologic studies. Hence, a scintigraphy technique was devised to study the transit of solid and liquid colonic contents in these patients., Methods: Patients were randomly assigned to straight or colonic J-pouch anal anastomoses after ultralow anterior resection. At 1 year after surgery, they were studied by bowel questionnaire, anorectal manometry, and technetium TC 99m tin-colloid liquid test meal/I-131 microcapsule scintigraphy. In the latter, technetium TC 99m tin-colloid was ingested orally to image the colonic liquids. I-131 microcapsules taken simultaneously imaged the solid stools. After ingestion of the radioisotopes, imaging was performed at intervals of 7 to 8, 24, and 56 hours later. Two independent observers noted the presence of technetium TC 99m tin-colloid liquid and I-131 microcapsules in various areas of interest drawn over the colon., Results: There were six patients (5 males, mean age, 61.5 (SE mean, 1.9) years) in the straight, and six patients (5 males, mean age, 63.2 (4.5) years) in the colonic J-pouch group. Stool frequency was more in the straight group (4.8 (0.4) vs. 3 (0.2) stools/day; P <.001). Continence, evacuation problems, and anorectal physiologic findings were not different. Technetium TC 99m tin-colloid (imaging liquids) transited significantly faster than I-131 microcapsules (imaging solids), at various areas of interest in the colon. In the colonic J-pouch patients, technetium TC 99m tin-colloid liquid was retained significantly longer in the descending colon at 24 hours (P <.05). Stool frequency was higher when technetium TC 99m tin-colloid was not retained in the descending colon at 56 hours (3.3 (0.5) vs. 4.3 (0.4) stools/day) but this did not reach statistical significance. There were no significant differences in the distribution of the ingested I-131 microcapsules between colonic J-pouch and straight groups., Conclusions: Reduced stool frequency after colonic J-pouch may be related to factors causing better retention of liquid stools in the distal colon. No difference in solid stool transit could possibly account for minimal evacuation problems in small pouches.

Primary osteosarcoma of the sphenoid bone is an extremely rare condition. This paper presents a case of a lady with recurrent oesteosarcoma of the sphenoid bone who had resection of the tumour via a combined neurosurgical and craniofacial procedure and reconstruction with a free flap and bone graft. It details the diagnosis, treatment and follow-up of this unusual condition.

Gastrointestinal haemorrhage is a rare but well-recognised complication of extensive burns, the site of haemorrhage usually being in the upper gastrointestinal tract. The case of an 18-year old female patient who developed sudden massive rectal bleeding 1 month after suffering 45% body surface area burns is presented. The source of the haemorrhage was a Dieulafoy-type lesion at the anorectal junction associated with mucosal ulceration, a cause of bleeding not previously described in a patient with major burns. Angiographic embolisation failed to control the haemorrhage and surgical arrest was required, following which the patient made a complete recovery with no recurrence of bleeding. Haemorrhage from the lower gastrointestinal tract is rarely associated with major burns but may be significant when it occurs. The aetiology is unclear but sepsis, mucosal ischaemia and ulceration may be implicated.

Objective: In the light of a reported 30-40% prevalence of pulmonary embolism (PE) in intermediate probability lung scans (IPLS) based on results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, we examined the frequency of documented PE in 82 patients with IPLS, the management strategy employed in these patients with regards to additional imaging (e.g. further evaluation with venous sonography or spiral computed tomographic angiography (CTA)), anticoagulation therapy, and subsequent follow-up outcomes., Method: Retrospective review of the medical records of 82 patients with intermediate probability ventilation-perfusion (V/Q) lung scans from January 1998 to July 1999., Results: 14.1% of V/Q scans were reported as having an intermediate probability of PE. 72% of IPLS were subject to further evaluation with venous Doppler ultrasound and/or CTA, and 39% of these patients had evidence of thrombo-embolic disease. All patients with imaging evidence of thromboembolic disease were started on anticoagulation therapy. In addition, 19 patients were treated based on clinical judgement. Amongst the 35 patients who were not treated, 17 (49%) were based on clinical findings without further imaging. There was no mortality on follow-up of 28 cases of untreated IPLS., Conclusion: The majority of IPLS will have further imaging, out of which over one-third will have thrombo-embolic disease. Approximately half of IPLS cases will receive anticoagulation therapy. No mortality or PE was found on follow-up of patients who were not treated.

Standard microvascular anastomosis using only sutures is a well-established and successful technique; however, it is time-consuming and may cause vessel narrowing, needle trauma, and tissue reaction. The authors' hypothesis was that 2-octylcyanoacrylate could simplify microvascular anastomosis and reduce wall trauma and reaction. End-to-end anastomoses of the femoral arteries were performed in 20 adult rats. Each animal served as its own control. The time taken for each anastomosis (from first stitch to release of clamps) was noted, and the patency assessed. At day 7, the anastomoses were reassessed for patency, and the vessels evaluated histologically. 2-octylcyanoacrylate reduced the need to insert more sutures. Anastomotic time in the study group was statistically significantly shorter (p < 0.001), and the patency rate was 90 percent, compared to 85 percent with the standard suture technique. There was also less intense inflammatory reaction, with fewer foreign-body granulomata. This is the first report on the use of 2-octylcyanocrylate, currently approved for cutaneous use, for vessel anastomosis. Further work on the biomechanics and long-term histologic effects will be carried out. 2-octylcyanoacrylate has the potential for simplifying and improving the patency rates of arterial microanastomosis.

Context: Moist exposed burn ointment (MEBO), from China, has been said to revolutionize burn management., Objective: Our study was conducted to compare MEBO with conventional management (C) with respect to the rate of wound healing, antibacterial and analgesic effect, and hospital costs., Design: This is a prospective, randomized, controlled clinical trial conducted between 1 March 1997 and 24 October 1998., Setting: The trial was conducted in a specialized burn facility located in a tertiary referral hospital in a developed and industrialized island-state in Southeast Asia., Patients: We randomly assigned 115 consecutive patients between the ages of 12 and 80 who had partial-thickness thermal burns covering less than 40% of body surface area (BSA) to receive either MEBO or C. Fifty-seven patients were assigned to MEBO and 58 patients to C. The latter group received twice-daily dressing changes; MEBO patients received MEBO every 4 hours., Main Outcome Measures: Patients were hospitalized until 75% BSA had healed. BSA was determined by visual inspection and charted on Lund and Browder charts regularly. Wound healing rate, bacterial infection rate, pain score, and hospitalization costs were recorded., Results: The median time to 75% healing was 17.0 and 20.0 days with MEBO and C, respectively (HR = 0.67, 95% CI = 0.41-1.11, P =.11), suggesting similar efficacy between the 2 modalities. Bacterial infection rates were similar between the 2 groups (HR = 1.10, 95% CI = 0.59-2.03, P =.76). MEBO imparted a greater analgesic effect in the first 5 days of therapy and reduced hospital costs by 8%., Conclusions: MEBO is as effective as conventional management but is not the panacea for all burn wounds. The use of MEBO eases the management of face and neck burns and facilitates early institution of occupational therapy in hand burns. It confers better pain relief such that fewer opiates are used during the first 5 days after burn injury.

The transcription factor DeltaFosB is induced in the hippocampus and other brain regions by repeated electroconvulsive seizures (ECS), an effective antidepressant treatment. The unusually high stability of this protein makes it an attractive candidate to mediate some of the long-lasting changes in the brain caused by ECS treatment. To understand how DeltaFosB might alter brain function, we examined the gene expression profiles in the hippocampus of inducible transgenic mice that express DeltaFosB in this brain region by the use of cDNA expression arrays that contain 588 genes. Of the 430 genes detected, 20 genes were consistently upregulated, and 14 genes were downregulated, by >50%. One of the upregulated genes is cyclin-dependent kinase 5 (cdk5). On the basis of its purported role in regulating neuronal structure, we studied directly whether cdk5 is a true target for DeltaFosB. Upregulation of cdk5 immunoreactivity in the hippocampus was confirmed by Western blotting in the DeltaFosB-expressing transgenic mice as well as in rats treated chronically with ECS. Chronic ECS treatment also increased, in the hippocampus, the phosphorylation state of tau, a microtubule-associated protein that is a known substrate for cdk5. A 1.6 kb fragment of the cdk5 promoter was cloned, and activity of the promoter was found to be increased after overexpression of DeltaFosB in cell culture. Moreover, mutation of the single consensus activator protein-1 site contained within the cdk5 promoter fragment completely abolished activation of the promoter by DeltaFosB. Together, these results suggest that cdk5 is one target by which DeltaFosB produces some of its physiological effects in the hippocampus and thereby mediates certain long-term consequences of chronic ECS treatment.

Introduction: The aim of this study was to evaluate the usefulness of technetium-99m (Tc-99m) ciprofloxacin in imaging inflammation/infection. The ciprofloxacin for labelling, as a kit, was obtained from St Bartholomew's Hospital in London., Materials and Methods: Patients were injected intravenously with Tc-99m ciprofloxacin and imaging was done at 10 minutes, 4 hours and 24 hours if necessary. Tomographic images (SPECT) were obtained in a few patients. Ninety-six patients were studied using Tc-99m ciprofloxacin. Forty-eight patients had bone scans and 22 had Tc-99m IgG scans. Eight patients were imaged using Tc-99m HMPAO labelled white blood cell, and bacteriological culture results were available in 24 patients. Organisms cultured included Acinetobacter baumanii, Streptococcus, Staphylococcus aureus, Pseudomonas, Klebsiella, Blastococidia, Methicillin-resistant S. aureus, Salmonella and Candida., Results: Findings were evaluated against microbiology, alternative imaging modalities and clinical outcome. There were 47 true positives, 33 true negatives, 5 false positives and 11 false negatives, giving a sensitivity of 81% and specificity of 87%. The positive and negative predictive values were 90% and 75%, respectively. There were no side effects and the scan was particularly useful in the evaluation of painful joint prosthesis to exclude infection. Repeat studies on 8 patients given antibiotics over a long period were very useful in deciding on termination of the antibiotic treatment.

Introduction: Reperfusion therapy with either thrombolysis or angioplasty has been shown to be beneficial in acute myocardial infarction. Tc-99m sestamibi is a myocardial tracer that can be used to assess myocardial salvage because of its property of very limited redistribution., Materials and Methods: To assess the feasibility of this technique locally, Tc-99m sestamibi was injected before and after reperfusion therapy with angioplasty (n = 11) or streptokinase (n = 18) in 29 patients with acute myocardial infarction (anterior = 25, inferior = 4). Single-photon emission computed tomography (SPECT) was performed within 4 hours of reperfusion and repeated 5 to 7 days later., Results: Initial perfusion defect size ranged from 6% to 78% (mean 36.3 +/- 18.7%), and final defect size from 0% to 50% of the left ventricle (mean 23.7 +/- 14.8%, P < 0.001). Patients with proximal left anterior descending artery (LAD) lesions had larger defects compared to those with mid LAD lesions (mean defect size 52% for pLAD versus 28% for mLAD, P < 0.013). However, there were wide variations in initial defect size (myocardium at risk) for a given infarct-related artery location. The mean decrease in defect size was 12% in the 28 patients with patent arteries compared to only 2% in the patient with an occluded artery (47% to 45%). There was no significant difference in amount of salvage between patients who had thrombolysis (mean 13%, P = 0.0003) and patients who had percutaneous transluminal coronary angioplasty (PTCA) (mean 12%, P = 0.005)., Conclusions: Assessment of myocardial salvage is feasible using Tc-99m sestamibi SPECT imaging. It allows for quantitation of myocardium at risk and the amount of myocardial salvage, which is not possible by angiography alone.

Introduction: Conventional management of partial thickness facial burn wounds includes the use of silver sulphadiazine dressings. Silver sulphadiazine forms an overlying slough that makes wound healing assessment difficult. Moist exposed burn ointment (MEBO) has been proposed as the ideal burn wound dressing both for burns of the face and other sites. Proponents of MEBO claim that it accelerates wound healing and results in scarless wound healing and at the same time reduce bacterial colonisation and the need for analgesics. We present here our experience with MEBO in the management of partial thickness burns of the face., Materials and Methods: One hundred and fifteen patients with partial thickness burns were randomly assigned to conventional treatment or MEBO. Out of this, 112 were analysed. Thirty-nine patients sustained facial burns; 17 received MEBO and 22 received silver sulphadiazine. Patients were followed up daily until the burn wounds were reduced by 75% of original body surface area (BSA)., Results: In patients with facial burns, MEBO was similar to silver sulphadiazine therapy with respect to rate of wound healing. Minimal slough was present over the wounds in MEBO-treated wounds resulting in clearer assessment of healing progression., Conclusions: Advantages of MEBO as compared to silver sulphadiazine in the management of partial thickness burns of the face include convenient change of dressing and easier assessment of healing progression. This suggests that MEBO is a useful alternative therapy for partial thickness burns of the face.

Gastrointestinal hemorrhage is a known but rare complication of major burns. This case report describes the management of this potentially life threatening problem in a young adult with 45% body surface area burns who developed massive gastrointestinal-tract bleeding. The patient required a total gastrectomy that was complicated by a burst abdomen. Despite undergoing a series of major insults. the patient survived and was eventually discharged from hospital with an acceptable level of morbidity. The problems faced by the burn centre team and the issues involved in the decision making process are discussed in the management of this unusually devastating complication.

We report a 58-year-old Chinese female who presented with a pigmented skin lesion on the right thigh, associated with a single ipsilateral inguinal lymph node without distant metastases detected. A wide excision of the tumour, split skin graft coverage and an en-bloc ipsilateral superficial groin dissection was performed. Histopathology revealed malignant skin adnexal tumour or porocarcinoma, with nodal metastases. She is presently at six months follow-up without any recurrence.

Radionuclide imaging using the 99mTc sestamibi either singly or as a subtraction technique with pertechnetate is a recent and reliable method in localising parathyroid adenomas prior to surgery. This is of use in pre-operative planning, as well as in failed first neck exploration. Four local patients with primary hyperparathyroidism whose parathyroid adenomas were localised by this scintigraphy are presented. The value and limitations of this imaging modality are discussed.

Oral thyrotrophin-releasing hormone (TRH) and lithium were given to patients on follow-up for well-differentiated thyroid carcinoma to see their effect on serum thyrotrophin level (TSH) and radioiodine (I-131) uptake (RAIU). The study was randomised and doubled-blinded and consisted of a total of 19 patients in 3 groups. Group 1 received placebo and TRH, group 2 received lithium and placebo, and group 3 received lithium and TRH. Serum TSH and RAIU at 24 hours were measured before, and after treatment, with TRH, lithium, and/or placebo. In group 1, mean (+/-SEM) TSH increased from 48.9 (+/-15.2) mU/l to 148.2 (+/-48.0) mU/l (p < 0.05); in group 2, the change of 24.9 (+/- 15.9) mU/l to 31.7 (+/-14.1) mU/l in TSH was not statistically significant; and in group 3, TSH increased from 108.1 (+/-13.8) mU/l to 187.0 (+/-39.1) mU/l (p < 0.05). However, despite the significant change in TSH, there was no significant increase in I-131 uptake in any group: 7.70% to 10.43%, 7.15% to 7.43% and 2.49% to 2.61%, in groups 1, 2 and 3 respectively (p > 0.05). We conclude that while oral TRH will increase endogenous serum TSH significantly, there is no significant increase in I-131 uptake. Lithium was not an useful adjunct in increasing serum TSH or I-131 uptake in these patients.

It has long been recognised that significant bone tracer localisation in the myocardium is a good indicator for amyloid involvement of the heart in the clinical context of systemic amyloidosis. In this case report, although myocardial tissue diagnosis of amyloidosis was not made, the massive myocardial uptake of bone tracer strongly suggested the presence of amyloid infiltration in the heart, and this finding eventually led to the histological diagnosis of familial amyloid polyneuropathy by skin and sural nerve biopsy. Interesting findings were noted in the single photon emission computerised tomography (SPECT) studies of the myocardium with Technetium-99m diphosphono-propanedicarboxylic acid bone agent and Technetium-99m sestamibi myocardial perfusion agent. Such findings suggest that there is a lack of correlation between the intensity of myocardial uptake of bone tracer and viability of the myocardium, and that amyloid will not deposit in infarcted myocardial tissue.

While continuous ambulatory peritoneal dialysis (CAPD) offers several advantages over haemodialysis in patients with end-stage renal disease, several complications have been recognised. The intraperitoneal instillation of dialysate increases intra-abdominal pressure and consequently predisposes to leaks and herniations through defects in the abdominal wall. This can lead to disruption of CAPD therapy. Peritoneal scintigraphy with Tc99m colloid has been used to identify such leaks of dialysate. This report analyses the clinical role of peritoneal scintigraphy in patients on the CAPD programme in the Singapore General Hospital. The results of 25 scans performed over a two-and-a-half year period were correlated with clinical and surgical findings. The clinical presentations of suspected dialysate leakage were varied, but can be broadly classified into three subsets for this analysis: (A) swellings confined to the inguinal and genital region, (B) peri-catheter, umbilical and incisional swellings, and (C) diffuse pattern of swellings in the abdominal wall, pelvic and genital region. In group A, the scan proved to be clearly helpful, correctly identifying 10/10 inguinal hernias, all of which resolved after herniorrhaphy. In group B, the scan correctly identified 7/9 leaks and hernias in the ventral abdominal wall. There was one false negative scan in a patient with a peri-catheter leak, and an equivocal result in another with fluid leakage in the lower anterior abdominal wall. In group C, which presented the greatest difficulty in clinical diagnosis, 2/3 cases were correctly diagnosed by scintigraphy. An equivocal result was seen in a patient who had had multiple operations for recurrent incisional hernias.(ABSTRACT TRUNCATED AT 250 WORDS)

An ideal diagnostic imaging method in cancer management should be one which surveys the entire body for occult or small tumour foci in a single procedure. Imaging with radiolabelled antibodies appears to have such potential if the limiting factors which we have encountered in the last 40 years can be completely eliminated. These factors include antibody-dependent factors, radionuclide-dependent factors, host-dependent factors and imaging modality-dependent factors. Advances in immunology and bio-genetic engineering have enabled production of various antibody fragments and genetically engineered antibody molecules (i.e. chimeric/humanized antibodies and the single-chain antigen binding protein), giving a promise of overcoming the problem of cross-reactivity and host immuno-response. The rapid development in radiopharmacy and labelling chemistry has led to the establishment of various pre-targetted methods which are aimed to improve the tumour to non-tumour ratio. The recent success of producing Tc99m labelled monoclonal antibodies preparation in a kit form has certainly encouraged its clinical applications and made antibody imaging a less tedious task. The progression in computer technology has made "image fusion" possible and hence improve the accuracy of anatomical localization of tumour foci in antibody imaging. It would appear possible to overcome most, if not all, of the limiting factors mentioned above in the near future. The prospect of radiolabelled antibodies in tumour imaging is promising and the dream of a "magic bullet" will soon be fulfilled.

Technetium-99m sestamibi (MIBI) is a routinely used myocardial perfusion imaging agent. We have studied groups of patients with differentiated thyroid carcinoma, in order to evaluate the usefulness of this agent in localising regional neck and nodal disease and metastases. There are three groups of patients. Group 1 consisted of patients with known nodal disease or metastases (22 patients) and with raised serum thyroglobulin levels (Tg). Group 2 comprised patients with normal I-131 scans and normal Tg levels (nine patients). Non-thyroid malignancies (six patients) comprised an additional group 3. In group 1, the MIBI scan showed 47 sites of metastases, while the I-131 scan revealed 49 sites. The MIBI scan was positive in two patients where the I-131 scan was negative, while in two other patients, the MIBI study was negative whereas the I-131 scan was positive. In group 2, 6/9 patients had no disease, 2/9 had thyroid remnants, and 1/9 had a fresh primary lung tumour, unrelated to the earlier thyroid cancer. All of them had normal MIBI scans. In group 3, two patients with lung cancer and two with breast cancer and metastases had normal MIBI scans. A further two patients with nasopharyngeal cancer (NPC) had mildly increased MIBI localisation in neck nodes and bone metastases. In summary, Tc-99m sestamibi appears to be as good as I-131 in search for thyroid carcinoma metastatic spread, especially nodal disease and this tracer does not localise well in the primary or metastases of other cancers.(ABSTRACT TRUNCATED AT 250 WORDS)

The bone scan is sensitive in detection of active bone/joint lesions. A normal bone scan virtually excludes the presence of an inflammatory process with high precision, but the poor specificity of bone scans is well known. In recent years, various new agents including 99Tcm-hexamethylpropylene amine oxime (HMPAO)-labelled white blood cells, nanocolloid, polyclonal IgG, anti-granulocyte antibody, 111In-labelled IgG, leucocytes, chemotactic peptides etc. have been widely evaluated in inflammatory imaging, especially in the orthopaedic context. This study was undertaken to compare the usefulness of 99Tcm-nanocolloid and 99Tcm-polyclonal IgG in the detection of focal bone/joint inflammation. Twenty-seven patients with a common presentation of bone/joint pain resulting from various pathologies were included in the study. A total of 47 lesions were imaged. The overall sensitivity and specificity of both nanocolloid scan and IgG scan were identical with 95% sensitivity and 100% specificity, in detecting inflammatory foci. However, specificity dropped to 18% with nanocolloid scans and 16% with IgG scans when an attempt was made to distinguish noninfective from infective inflammatory processes; thus neither type of scan permits differentiation between septic and nonseptic inflammatory processes with sufficient accuracy. As both nanocolloid and IgG scans are equally sensitive and specific in detecting inflammation, the choice of type of scan will depend on cost, imaging time and availability of the radiopharmaceutical.

There have been changes in the national policy regarding population growth in Malaysia from 1982. This report studies the changes in contraceptive practice among the three racial groups in this country, i.e. Malays, Chinese and Indians, over a 5-year period with an interval of 10 years. This is a retrospective study based on the attendance at the same family planning clinic in an urban setting. The striking change noted is the change in the racial composition of contraceptive usage in the two study periods with a shift from the Chinese being predominant in 1975-1979 to Malays in 1985-1989. There was no change among the numbers of Indians using contraception. The results also reveal a significant trend of change for users of the pill and those undergoing sterilization. There were no significant changes in IUD, condom and injectable usage. The study demonstrates how national policies, level of education and rural urban migration can significantly alter contraceptive practice.

The usefulness of radionuclide imaging studies with 99m-technetium diethylenetriaminepentaacetic acid (Tc-DTPA) for quantitating the glomerular filtration rate (GFR) in children was studied. This was compared to the conventional methods for measuring GFR using 51-chromium-EDTA clearance (Cr-EDTA), creatinine clearance and a height/plasma creatinine formula. In the 22 children studied, the correlation coefficient between renal uptake of DTPA and Cr-EDTA was 0.90 (p less than 0.001). In contrast, there was a poorer correlation between Cr-EDTA and creatinine clearance (r = 0.69) or the derived GFR using height/creatinine formula (r = 0.83). The regression line between Tc-DTPA uptake and Cr-EDTA clearance was used to derive a formula for calculating the predicted GFR. This was tested in 10 additional children, and the correlation between the predicted GFR and measured GFR (using Cr-EDTA clearance studies) was 0.92 (p less than 0.001). Quantitative estimation of the GFR during renal imaging studies is a feasible and convenient method of assessing renal function.

Technetium-99m-(tin) colloid uptake in renal transplants was quantified to evaluate rejection. A dynamic acquisition following i.v. injection of 110 MBq of this radiopharmaceutical enabled quantification of 15 to 20 min transplant uptake (PU), in terms of percentage of an injected dose after allowing for attenuation in the patient. An uptake ratio (UR) i.e. the ratio of 15 to 20 min uptake over the 0 to 5 min uptake was also derived. Normal values were obtained in 20 stable functioning transplants (normal PU less than or equal to 1%, normal UR less than or equal to 0.7). In 66 patients, PU and UR were compared with clinical, biochemical, histological and radiological, evidence of rejection. A sensitivity of 70% and specificity of 85% was obtained for this 99Tcm-(tin) colloid study in the diagnosis of renal transplant rejection.