Olfactory detection of human bladder cancer by dogs: proof of principle study.

OBJECTIVE: To determine whether dogs can be trained to identify people with bladder cancer on the basis of urine odour more successfully than would be expected by chance alone. DESIGN: Experimental, "proof of principle" study in which six dogs were trained to discriminate between urine from patients with bladder cancer and urine from diseased and healthy controls and then evaluated in tests requiring the selection of one bladder cancer urine sample from six controls. PARTICIPANTS: 36 male and female patients (age range 48-90 years) presenting with new or recurrent transitional cell carcinoma of the bladder (27 samples used for training; 9 used for formal testing); 108 male and female controls (diseased and healthy, age range 18-85 years--54 samples used in training; 54 used for testing). MAIN OUTCOME MEASURE: Mean proportion of successes per dog achieved during evaluation, compared with an expected value of 1 in 7 (14%). RESULTS: Taken as a group, the dogs correctly selected urine from patients with bladder cancer on 22 out of 54 occasions. This gave a mean success rate of 41% (95% confidence intervals 23% to 58% under assumptions of normality, 26% to 52% using bootstrap methods), compared with 14% expected by chance alone. Multivariate analysis suggested that the dogs' capacity to recognise a characteristic bladder cancer odour was independent of other chemical aspects of the urine detectable by urinalysis. CONCLUSIONS: Dogs can be trained to distinguish patients with bladder cancer on the basis of urine odour more successfully than would be expected by chance alone. This suggests that tumour related volatile compounds are present in urine, imparting a characteristic odour signature distinct from those associated with secondary effects of the tumour, such as bleeding, inflammation, and infection.

Effects of hyperbaric oxygen therapy on hydroxyapatite orbital implant vascularization in rabbits.

PURPOSE: To deterrmine if hyperbaric oxygen therapy affects the rate of hydroxyapatite orbital implant vascularization in normal rabbit orbits. METHODS: We performed a randomized comparative experimental pilot study involving 6 rabbits. All rabbits were enucleated and implanted with hydroxyapatite orbital spheres. The animals were randomized for enucleation of the right or left eye and for treatment or nontreatment (control) with hyperbaric oxygen. The implants were removed after 3 weeks of treatment and histologically examined for fibrovascular ingrowth, inflammation, and multinucleated giant cells. Each parameter was graded on a numeric scale and analyzed. RESULTS: Hyperbaric oxygen therapy did not increase implant vascularization compared with nontreatment implants. Although treated implants had less central fibrovascular maturity compared with control implants, the difference was not statistically significant (p < 0.055). There was no significant difference in inflammation or the number of multinucleated giant cells between treated and control implants. CONCLUSIONS: In this pilot study, hyperbaric oxygen therapy did not increase hydroxyapatite vascular ingrowth and possibly delayed fibrovascular maturation in normal sockets. Further studies with more subject numbers are needed to confirm these conclusions. The effect of hyperbaric oxygen therapy in vascularly compromised sockets also needs to be determined.

The risk of diplopia following orbital floor and medial wall decompression in subtypes of ophthalmic Graves' disease.

We preoperatively divided 58 ophthalmic Graves' disease patients into types I and II categories before two-wall orbital decompression. Type I classification was given to patients who had no diplopia and essentially normal versions. Type II classification was assigned to patients with restrictive motility loss and diplopia within 20 degrees of the primary position. Ocular motility was assessed before and after two-wall orbital decompression. Only one of 25 type I patients (4%) experienced diplopia after orbital decompression, while seven of 14 (50%) (p = 0.001) type II patients without preoperative primary-position diplopia had primary diplopia postoperatively. Of 12 type II patients who had preoperative primary-position diplopia, esotropia increased by an average of 12.4 diopters postoperatively. Vertical deviation increased an average of 13.4 diopters for 10 patients who underwent unilateral two-wall decompression. The likelihood of new or worsening diplopia in all type II patients following decompression was 22 of 36 (61%). We conclude that adverse motility change following two-wall orbital decompression is rare in type I disease patients, but it occurs 61% of the time in type II disease patients. Predicting preoperatively which patients are likely to develop adverse motility change and diplopia may help clarify indications and risks of orbital decompression surgery in patients with ophthalmic Graves' disease.

5-Methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole: a novel 5-HT2C/5-HT2B receptor antagonist with improved affinity, selectivity, and oral activity.

The preparation of a series of conformationally restricted analogues of indolylurea 1, namely tetrahydropyrroloindoles and tetrahydropyrroloquinolines, is described. The binding affinities of these compounds at 5-HT2A, 5-HT2B, and 5-HT2C receptors were determined. Of these compounds, the 1,2,3,5-tetrahydropyrrolo[2,3-f]indole derivative, compound 11, was found to have high affinity for the 5-HT2C (pKI 8.0) and 5-HT2B receptors (pA2 8.5), with excellent selectivity over the 5-HT2A and various other receptors (pKI < 6). 11 is also considerably more active than 1 in both an in vitro functional model, 5-HT-stimulated phosphoinositol hydrolysis (pKB 8.8), and an in vivo functional model, mCPP-induced hypolocomotion (ID50 5.5 mg/kg po). 11 should therefore be of significant utility as a pharmacological tool to delineate the functional significance of blockade of 5-HT2B and 5-HT2C receptors.

Eccrine adenocarcinoma of the eyelid in a young patient.

Malignant eccrine adenocarcinoma of the lower eyelids is described in a 16-year-old girl. This rare tumor has previously been reported only in males, whose average age was 64 years. Our patient remains tumor free 7 years after wide resection of the eyelid and reconstruction.

The association of cigarette smoking with clinical subtypes of ophthalmic Graves' disease.

We retrospectively reviewed the smoking habits of 124 patients with Graves' ophthalmopathy. We divided these patients into those without restrictive myopathy (type I) and those with restrictive myopathy (type II). Sixty-three percent of type I and 83% of type II patients were smokers at the time of diagnosis. The incidence of smoking in an age- and gender-matched randomly selected control population in the same geographic area was 30% for controls matched to our type I group and 26.6% for controls matched to our type II group. We believe smoking is an important factor in the development of both clinical subtypes of Graves' ophthalmopathy.

Extrusion rate of silicone spherical anophthalmic socket implants.

The most popular technique of placement of an anophthalmic spherical implant was first described by Frost and Lange in 1886, and has remained essentially unchanged since that time. That technique incorporates imbrication of recti muscles over an 18 mm spherical implant, and purse stringing of conjunctiva and Tenon's fascia in a single layered closure. The Frost-Lange technique has led to previously reported extrusion rates as high as 11.3%. The technique is also associated with superotemporal implant migration and poor prosthetic motility. Our technique modification includes suturing recti muscles independently to a 20 mm spherical implant reinforced with autogenous fascia or preserved sclera. We then close Tenon's fascia and conjunctiva independently as separate layers. The extrusion rate for our patients during a 10 year study period was 0.84% (1 of 119). We found no implant migration, no painful socket, and prosthetic motility was good. We recommend our technique modification to replace the traditional Frost-Lange technique.

Effects of radiation on the use of hydroxyapatite for orbital reconstruction in the rabbit.

The gross and histopathologic effects of external beam radiation on host response to subperiosteal implantation of dense hydroxyapatite (HA) blocks along the superior orbital rim was investigated, using the rabbit as an experimental model. Three study groups were employed: those with no radiation, those receiving 500 cGy, and those receiving 1,500 cGy. The hydroxyapatite blocks were surgically implanted 2 weeks after administration of the radiation. The pathologic specimens, including the HA block and the neighboring bone segment, were harvested and examined at either the fourth or 12th postsurgical week. There was essentially no inflammatory reaction stimulated by the implanted HA blocks, nor was there any evidence of abnormal bone remodeling in the underlying orbital rim segments. The most secure bonding between the HA block and bone was found in the specimens having received either 500 cGy or 1,500 cGy and harvested at 12 weeks. We conclude that HA serves as an acceptable bone graft substitute in areas previously treated with radiation. The various properties of HA are also reviewed.

Exposure rate of hydroxyapatite spheres in the anophthalmic socket: histopathologic correlation and comparison with silicone sphere implants.

We retrospectively reviewed enucleations and secondary anophthalmic socket sphere implantations for a 3 year period. We compared the incidence of exposure of hydroxyapatite implants to the incidence of exposure of silicone implants. We found that the incidence of hydroxyapatite exposure following enucleation was 3 of 27 (11.1%), and following secondary anophthalmic socket implantation was 3 of 32 (9.4%). The incidence of silicone sphere exposure following enucleation was 0 of 48 (0%), and following secondary implantation was 1 of 30 (3.3%). The difference in exposure rate between hydroxyapatite and silicone reached statistical significance in the enucleation group (p = 0.043) and in the combined enucleation and secondary implantation group (p = 0.033), but not in the secondary implantation group when considered separately. Osteoinduction and fibrovascular infiltration were found in all hydroxyapatite specimens examined histopathologically. In the exposed implants, liquefaction necrosis of the implant occurred. In the nonexposed implant, complete fibrovascular ingrowth was noted at 7 months. We believe that the hydroxyapatite anophthalmic sphere is associated with a higher incidence of exposure and postoperative inflammation when compared to silicone anophthalmic spheres. Patient selection and technique modification may reduce the incidence of hydroxyapatite implant exposure.

Substituted benzamides with conformationally restricted side chains. 5. Azabicyclo[x.y.z] derivatives as 5-HT4 receptor agonists and gastric motility stimulants.

The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.

Stimulation of orbital growth by the use of expandable implants in the anophthalmic cat orbit.

We evaluated the efficacy of expandable orbital implants to stimulate bone growth in the anophthalmic cat orbit. Eighteen cats unilaterally enucleated at 2 weeks of age received either expandable orbital implants (groups A1 and A2), solid silicone sphere implants of 12 mm or 8 mm (groups B1 and B2), or no implant (group C). Those cats with expandable implants (group A) had the implant size increased by 0.5 ml injections of saline at 2-week intervals starting at 8 weeks of age until a final volume of 4 cc was reached. Four of the expandable implants were found to be only partially inflated at 20 weeks and were subgrouped A2. At 20 weeks of age, the anophthalmic orbits with fully inflated expanders showed no significant difference in either orbital volume or orbital entrance area when compared with control orbits: volume (91.2%), area (95.7%) (p = 0.01). These same orbits also showed a significant increase in both orbital volume and orbital entrance area when compared with the growth obtained by any other group. These other groups showed growth, expressed as a percentage of normal growth, as follows: partially inflated implant: volume (63.0%), area (69.0%); 12-mm sphere implant: volume (57.0%), area (54.5%); 8-mm sphere implant: volume (46.5%), area (44.6%); no implant: volume (47.6%), area (43.6%) (p = 0.01). This study suggests that the use of expandable orbital implants stimulates bony growth in the immature cat orbit. Bony stimulation was proportional to volume implanted, and expandable orbital implants achieved maximum bony stimulation in the groups studied.