Unique analogues of anandamide: arachidonyl ethers and carbamates and norarachidonyl carbamates and ureas.

To examine the effect of changing the amide bond of anandamide (5, AN) to a less hydrolyzable moiety, analogues 1a-1l, 2a-2c, 3a-3c, and 4a-4h were synthesized from commercially available arachidonyl alcohol or arachidonic acid and tested for their pharmacological activity. Arachidonyl ethers 1a-1k were obtained through the coupling of the arachidonyl mesylate (6) (generated from the mesylation of arachidonyl alcohol) with the appropriate alcohol in potassium hydroxide. Arachidonyl ether 1l was obtained through the phase-transfer coupling of arachidonyl alcohol with 2-(2-iodoethoxy)tetrahydropyran (which was generated from its bromide) followed by cleavage of the tetrahydropyran group with Dowex resin. Arachidonyl carbamates 2a-2c were obtained through the coupling of arachidonyl alcohol with the appropriate isocyanates. Norarachidonyl carbamates 3a-3c and ureas 4a-4h were obtained through the coupling of the norarachidonyl isocyanate (generated from arachidonic acid using diphenyl phosphorazidate and triethylamine upon heating) with the appropriate alcohols and amines, respectively. AN analogues 1-3 have shown poor binding affinities to the CB1 receptor and fail to produce significant pharmacological effect at doses up to 30 mg/kg. Several ether analogues 1 were also evaluated in the CB2 binding assay and were found to be of low affinity. However, norarachidonyl urea analogues 4 have shown generally good binding affinities to the CB1 receptor (Ki = 55-746 nM) and pharmacological activity with AN-like profiles. The most potent analogue of this series is the 2-fluoroethyl analogue 4f which binds 2 times better than AN and was more active in several mouse behavioral assays. It was also observed that urea analogues 4a and 4g, which have weak binding affinities to the CB1 receptor (Ki = 436 and 347 nM, respectively), produced surprisingly potent pharmacological activity. These urea analogues have also shown hydrolytic stability toward the amidase enzymes, responsible for the primary degradation pathway of anandamide, in binding affinity assays in the absence of the enzyme inhibitor PMSF.

Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management.

Acute hyperleukocytic leukemias (AHL) are associated with a very high early mortality rate mostly due to respiratory failure or intracranial bleeding. The pathophysiological process leading to these complications is called leukostasis but the biological mechanisms underlying its development and progression remain unclear. Although traditionally related to "over-crowding" of leukemic blasts in the capillaries of the microcirculation, leukostasis is likely to result from direct endothelial cell damage. This damage is probably mediated by soluble cytokines released during the interaction between leukemic cells and vascular endothelium and by the subsequent migration of leukemic blasts in the perivascular space. Leukemic cell's ability to respond to chemotactic cytokines and their expression of specific adhesion molecules are probably more important in determining whether leukostasis will develop than the number of circulating blasts. This could explain why leukostasis does not develop in all patients with AHL. The identification of the adhesion molecules, cytokines and receptors mediating endothelial cell damage in AHL should become a priority if therapeutic improvements are desired. Leukapheresis is widely used but it is unclear whether it provides additional benefit to a simpler and less invasive intervention with allopurinol, hydroxyurea and intravenous fluids. Cranial irradiation is not generally recommended. Induction chemotherapy should be started without delay. It is hoped that specific pharmacological inhibitors of the interaction between leukemic cells and vascular endothelium will result in an improved outcome for this very high-risk population.

Transient formed visual hallucinations following macular translocation for subfoveal choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE: To report the occurrence of transient formed visual hallucinations following macular translocation. METHODS: Two case reports. RESULTS: Two white women aged 84 and 83 years with bilateral age-related macular degeneration and unilateral subfoveal choroidal neovascularization underwent macular translocation with punctate retinotomy (limited macular translocation) and chorioscleral infolding in the eye with neovascularization. They complained of formed visual hallucinations which began within 24 hours following macular translocation and ceased 7 and 3 days postoperatively, respectively. Their symptoms occurred in the presence of normal cognition, orientation and insight, were not associated with other psychiatric symptoms, and were characteristic of Charles Bonnet syndrome (CBS). CONCLUSION: The temporary deliberate retinal detachment and/or poor vision following macular translocation may be associated with postoperative CBS, and this report extends the spectrum of conditions associated with CBS.

Treatment of experimental Staphylococcus epidermidis endophthalmitis with oral trovafloxacin.

PURPOSE: To investigate the ocular pharmacokinetics and efficacy of oral trovafloxacin, a novel fluoroquinolone antibiotic, in Staphylococcus epidermidis endophthalmitis. METHODS: Albino rabbits (n = 20) were infected with an intravitreal inoculum of S epidermidis (1.0 x 10(8) colony-forming units [CFU/0.1 ml) and 24 hours later received a single oral dose of trovafloxacin (250 mg/kg). Serum and intraocular samples from infected and control (noninfected) eyes were obtained up to 24 hours after antibiotic administration for measurement of trovafloxacin levels. A second group of rabbits (n = 72) was infected intraocularly and randomized 24 hours later to oral trovafloxacin (250 mg/kg twice a day) for 6 days or no treatment (control). Treatment efficacy was assessed by vitreous culture, clinical examination, and histopathology. RESULTS: Following a single dose of trovafloxacin, maximal vitreous levels were achieved at 8 hours in infected eyes, with a penetration ratio of 36%. Vitreous levels were greater than 15 times the minimum inhibitory concentration of the strain employed. In animals with established endophthalmitis, treated eyes were sterilized after 5 days (P = .0495) compared with control eyes, which autosterilized at 14 days. Clinical and histologic examination revealed significant amelioration of anterior segment inflammation in treated eyes, although severe destruction of posterior segment structures occurred in both groups after 6 days of therapy. CONCLUSIONS: These data support trovafloxacin as a potential oral agent for treatment or prophylaxis of S epidermidis endophthalmitis, although retinal alterations that occur over the period required for vitreous sterilization suggest that it will not replace intravitreal therapy in established endophthalmitis.

Macular translocation: unifying concepts, terminology, and classification.

PURPOSE: To describe some unifying concepts, terminology, and classification of macular translocation so as to facilitate communication within the scientific community. METHODS: A panel of ophthalmologists with expertise in macular translocation reviewed available data and developed some unifying concepts, terminology, and classification of macular translocation. RESULTS: Macular translocation may be defined as any surgery that has a primary goal of relocating the central neurosensory retina or fovea intraoperatively or postoperatively specifically for the management of macular disease. It may be classified according to the size of the retinotomy and, where applicable, the technique of chorioscleral shortening used. The direction of macular translocation is denoted by the movement of the neurosensory macula relative to the underlying tissues. Effective macular translocation may be defined as successful intraoperative or postoperative relocation of the fovea overlying a subfoveal lesion to an area outside the border of the lesion. The concepts of minimum desired translocation and median postoperative foveal displacement can give some useful idea of the likelihood of effective macular translocation before surgery. CONCLUSIONS: Use of a common standardized terminology for macular translocation will facilitate communication within the scientific community and enhance further research in this area. However, the definitions, terms, classification, and concepts concerning macular translocation are likely to continue to evolve as macular translocation undergoes further modifications and refinements.

In vitro bacterial adherence to hydrogel and poly(methyl methacrylate) intraocular lenses.

PURPOSE: To compare the in vitro adherence of Staphylococcus epidermidis to poly-(hydroxyethyl methacrylate) (polyHEMA) or hydrogel intraocular lenses (IOLs) and poly(methyl methacrylate) (PMMA) IOLs. SETTING: Lions Eye Institute, Perth, Western Australia. METHODS: One-piece hydrogel lenses and one-piece PMMA lenses were suspended for 60 minutes in standardized suspensions of a well-characterized strain of S. epidermidis and then sonicated in a known quantity of balanced salt solution to remove the adherent bacteria. Quantitative cultures of the sonicates were performed and the results analyzed statistically. RESULTS: The mean bacterial adherence of S. epidermidis to the PMMA IOLs (58,400 CFU) was more than 20 times greater than that to the hydrogel IOLs (1953 CFU). The difference was statistically significant (P < .001). CONCLUSIONS: Adherence of S. epidermidis to hydrogel IOLs is significantly lower than to PMMA IOLs. This suggests that the risk of postoperative endophthalmitis after cataract extraction and IOL implantation may be lower with the use of hydrogel IOLs.

A phase II study of carboplatin plus gemcitabine in advanced non-small-cell lung cancer (NSCLC): a hoosier oncology group study.

The purpose of this study was to evaluate the toxicity and determine the response rate, duration of remission, and survival using gemcitabine plus carboplatin in non-small cell lung cancer (NSCLC). This was a phase II study of gemcitabine and carboplatin in chemotherapy-naive patients with advanced NSCLC and Karnofsky Performance Status of at least 80. Gemcitabine was administered intravenously at 1,000 mg/m2 weekly for 3 weeks followed by 1 week rest. Carboplatin was administered immediately after gemcitabine at an area under the curve (AUC) of 5 given intravenously on day 1 of an every-4-week cycle. Seven patients were entered in the study and five were evaluable for toxicity. The median age of patients was 68 years (range, 52-72). The protocol was prematurely terminated because of severe and unexpected hematologic toxicity. Grade 3-4 thrombocytopenia was observed in four of the first five patients. These toxicities were all observed with the first course of chemotherapy. There were no objective responses seen. Median survival time was 130 days. Carboplatin plus gemcitabine was a logical combination. However, because of the severe thrombocytopenia associated with this regimen, we do not recommend this two-drug combination in the dose and schedule used in this study.

The management of common ocular infections.

Bacterial and viral infections involving the anterior segment of the eye and ocular adnexa present commonly in general practice, affecting patients of all ages. Careful assessment of the patient is necessary to distinguish between benign conditions and those with more serious complications. An understanding of the microbiology and pathogenesis of these conditions is helpful in rationalising current therapeutic approaches. This article focuses on the clinical presentation of common infections of the lids, conjunctiva and cornea, with a discussion of relevant therapeutic regimens for each condition.

Navigation Endoscopic Assisted Tumor (NEAT) surgery for benign bone tumors of the extremities.

A novel technique of using both a navigation system and an endoscope in intra-lesional curettage of benign bone tumors enables safe and adequate tumor removal via a minimal access approach. We performed curettage of benign bone tumors in five consecutive patients (4 female, 1 male, mean age 31.4 years) using a commercial CT-based navigation system supplemented by visual guidance through a shoulder arthroscope. The bone defect was filled with bone cement in four patients and with artificial bone substitute in one patient. Mean follow-up time was 8.8 months (range: 7-12 months). Mean duration of surgery was 144 min (range: 120-165 min). Mean wound length of each portal site was 19.5 mm (range: 15-25 mm). All patients could achieve a full range of joint movement and walk unaided at 4 weeks post-surgery. No local recurrence was noted.

Integration of CAD/CAM planning into computer assisted orthopaedic surgery.

Modern Computer Aided Design/Modeling (CAD/CAM) software allows complex surgical simulations, but it is often difficult to transfer and execute precisely the planned scenarios during actual operations. We describe a new method of integrating CAD/CAM surgical plans directly into a computer surgical navigation system, and demonstrate its use to guide three complex orthopaedic surgical procedures: a periacetabular osteotomy of a dysplastic hip, a corrective osteotomy of a post-traumatic tibial deformity, and a multi-planar resection of a distal femoral tumor followed by reconstruction with a CAD custom prosthesis.

Localized sequential use of resilient lining to generate orthodontic force in thermoformed active removable appliances.

A new modality of orthodontic treatment based on the thermoformed appliance was developed and trialled clinically. A light-cured resilient lining material commonly used for denture relining was placed locally and sequentially in thermoformed appliances to generate orthodontic forces. The new method appeared to be effective. All the presented cases showed substantial improvement in dental alignment. A number of orthodontic movements were demonstrated. Localized use of resilient lining in thermoformed orthodontic appliances appeared to be a promising alternative to other thermoformed active removable appliance (TARA) treatments. Further studies are required to optimize the procedures and explore its full potential.

Sacrococcygeal teratoma in adults: case reports and a review of the literature.

BACKGROUND: The sacrococcygeal area is the most frequent site of teratoma in infants, but it is a rare location for teratoma in adults. METHODS: The authors report two patients in their sixth decade of life with the pathologic diagnosis of sacrococcygeal teratoma. The clinical presentations, the histologic findings, and the patients' clinical outcomes are described. A review of the literature on sacrococcygeal teratoma in adults is also presented. RESULTS: In the first patient, who had no evidence of recurrence after adequate resection, examination of the specimens showed mature teratoma. The second patient had mature teratoma with adenocarcinomatous component and possible leptomeningeal involvement. She died 2 months after the operation. CONCLUSIONS: Although rare in adults, sacrococcygeal teratoma should be considered in the differential diagnosis of patients with a pelvic mass presenting with obstructive symptoms. These two cases suggest that sacrococcygeal mature teratoma is surgically curable if teratoma is completely resected. The presence of leptomeningeal involvement and malignant transformation are associated with a less favorable outcome.

Implication of pneumolysin as a virulence factor in Streptococcus pneumoniae endophthalmitis.

PURPOSE: To determine if pneumolysin, a multifunctional cytotoxin produced by Streptococcus pneumoniae, may be a virulence determinant in the pathogenesis of pneumococcal endophthalmitis. METHODS: Lewis rats (n = 20) were injected intravitreally with purified recombinant pneumolysin at the following doses; 3.9 hemolytic units (HU), 39 HU, 390 HU, 3.9 x 10(3) HU, and 3.9 x 10(4) HU. After 24 hours, eyes were examined clinically and enucleated for histopathologic examination to elucidate the dose-response relationship. To determine the temporal progression of the disease model, a second group of rats (n = 8) were injected intravitreally with 390 HU of pneumolysin. At 6 and 48 hours, eyes were examined clinically and enucleated for histopathology. RESULTS: Eyes injected with pneumolysin demonstrated increasing anterior and posterior segment inflammation in response to increasing doses of administered toxin. The onset of inflammation and tissue damage occurred rapidly, and was maximal at 24 to 48 hours. The clinical and histopathologic changes observed mimicked those of S. pneumoniae endophthalmitis. Histopathologic analysis demonstrated rapid onset of iridocyclitis and vitritis with polymorphonuclear leukocyte influx, inner retinal necrosis, and retinal detachment. Retinal pigment epithelial necrosis and choroiditis were noted at the highest doses administered. Inflamed eyes were shown to be sterile. CONCLUSIONS: Pneumolysin injected intravitreally induces many of the clinical and histopathologic features of pneumococcal endophthalmitis, and may play an important role in the inflammation and tissue damage that occurs in pneumococcal endophthalmitis.